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Antitumor activity of 4-Arylcoumarins from endophytic Streptomyces aureofaciens CMUAc130
Abstract
In a search for antitumor agents, we carried out a screening of 4-arylcoumarins isolated from endophytic Streptomyces aureofaciens CMUAc130, by examining their possible inhibitory effect on the growth of s.c. transplanted Lewis lung carcinoma (LLC) in BDF-1 mice by intraperitoneal (i.p.) administration. The 4-arylcoumarins showed antitumor activity with T/C values of 80.8 and 50.0% at doses of 1 and 10 mg/kg of 5,7-dimethoxy-4-p-methoxylphenylcoumarin treatment, respectively and 81.5 and 44.9% at doses of 1 and 10 mg/kg of 5,7-dimethoxy-4-phenylcoumarin treatment, respectively, compared to adriamycin, which was used a positive control, with T/C value of 55.9% at 2 mg/kg. Furthermore, we investigated the possible effects of these compounds on expression of the bcl-2 and Bax oncoproteins in A427, a human lung cancer cell lines. The cells were cultured in vitro for 24 h in RPMI 1640 with 1.5% (v/v) ethanol, 100 microg/ml 5,7-dimethoxy-4-p-methoxylphenylcoumarin or 5,7-dimethoxy-4-phenylcoumarin. Viability was determined by an MTT assay. Total protein was extracted from cell lysates and the bcl-2 and Bax oncoproteins were identified. Western blotting showed a decrease in bcl-2 and an increase in Bax in A427 cell cultured with 5,7-dimethoxy-4-p-methoxylphenylcoumarin or 5,7-dimethoxy-4-phenylcoumarin. We conclude that 5,7-dimethoxy-4-phenylcoumarin is a more potent inhibitor of cell proliferation than 5,7-dimethoxy-4-p-methoxylphenylcoumarin and has more marked effects on oncoprotein expression.
... The interaction of several active compounds was given better impact than a single compound [25]. Metabolites produced by endophytic bacteria similar their host plant include alkaloids, steroids, terpenoids, peptides, polyketones, flavonoids, quinols, phenols, and coumarins [26][27][28]. These compounds are important for disease management because it used for treatment of various disease. ...
... Secondary metabolites produced by endophytic have activities similar with their host plant. Most endophytic generally have various activities such as antimicrobial, antioxidant, anticancer, anti-inflammatory properties, antimalarial and antidiabetic [11][12][13][27][28]. ...
Endophytic bacteria can be a potential source of new bioactive molecules which has medicinal properties like their host plant. One of the Indonesian herbs is Sanrego plant (Lunasia amara Blanco), which is empirically used as antidiabetic by people in South Sulawesi. This study aimed to isolate the endophytic bacteria producing α-glucosidase inhibitor from the Sanrego plant. The endophytic bacteria isolated from leaf and stem of Sanrego plant, and screening of the target bacteria using thin layer chromatography (TLC) with scopoletin as the control due to scopoletin is the secondary metabolite of the Sanrego plant which has antidiabetic activity by in-silico. Alpha-glucosidase inhibitory test carried out by colorimetric method using pNPG substrate, at 405 nm wavelength compared to acarbose. This study found 14 isolates from Sanrego leaf and 25 isolates from Sanrego stem. The ten isolates of them showed α- glucosidase inhibitory effect, which were three isolates from leaves (D1-D3) and seven isolates from stems (B1-B7). The appearance of the endophytic bacteria was circular, convex, and yellow in color; while the cell morphology mostly were Gram- positive bacteria. Statistical analysis indicated the D1 isolate had the highest inhibition value than the other isolates (ANOVA, p=0.002). Interestingly, the inhibition value of the D1 isolate (8.67%±2.56) was higher compared to acarbose (3.73%±1.23). It can be concluded that the endophytic bacteria from the Sanrego plant produce α-glucosidase inhibitor compound, and the D1 isolate can be further investigated its potency as a source of α-glucosidase inhibitor.
... Антибиотики ингибируют рост грибов, а также обладают активностью в отношении возбудителя малярии P.falciparum [46]. Штамм Streptomyces laceyi MS53 синтезирует 6алкилсалициловые кислотысалацеины А и В, которые показывают цитотоксичность в отношении линии клеток рака молочной железы человека SKBR3 с IC50 значениями 3,0 и 5,5 ^М соответственно [47,48]. Из эндофитного актиномицета Streptomyces hygroscopicus TP-A045 был выделен птероцидин. ...
... Antibiotics inhibit the growth of fungi, and also have activity against the pathogen of malaria P.falciparum [46]. Streptomyces laceyi MS53 strain synthesizes 6-alkylsalicylic acids -salaceins A and B, which show cytotoxicity against the human breast cancer cell line SKBR3 with IC50 values of 3.0 and 5.5^M, respectively [47,48]. Pterocidin was isolated from the endophytic actinomycete Streptomyces hygroscopicus TP-A045. ...
Устойчивость к антибиотикам возрастает во всем мире и является одной из самых больших проблем в современной медицине и глобальной угрозой для здравоохранения. Новые механизмы резистентности появляются и распространяются повсюду, угрожая способности лечить распространенные инфекционные заболевания. Ввиду этого, большое значение имеет вопрос поиска новых эффективных антибиотиков, синтезируемых различными микроорганизмами – актинобактериями, немицелиальными бактериями, грибами. В настоящее время исследователи сосредоточены на выделении актинобактерий из необычных мест обитания: мангровых зарослей, пустыней, морских и пресноводных резервуаров, а также внутренних тканей растений. Микроорганизмы-эндофиты — богатый и ещё не полностью изученный источник новых природных биологически активных соединений, привлекающий внимание многих учёных во всем мире. Большой интерес представляют эндофитные актиномицеты, синтезирующие разнообразные биологические активные вещества и дающие практически неограниченные возможности для разработки новых лекарственных препаратов. В обзоре представлены данные о биологически активных метаболитах, продуцируемых эндофитными актиномицетами, обладающих противоопухолевыми, противовоспалительными, антиоксидантными, антибактериальными свойствами.
Antibiotic resistance is on the rise worldwide, one of the biggest problems in modern medicine and a global public health threat. New resistance mechanisms are emerging and spreading everywhere, threatening the ability to treat common infectious diseases. In view of this, the question of finding new effective antibiotics, the main source of which are natural compounds synthesized by various microorganisms - actinobacteria, nonmycelial bacteria, fungi, is of great importance. Currently, researchers are focusing on isolating actinobacteria from unusual habitats: mangroves, deserts, marine and freshwater reservoirs, and internal plant tissues. Microorganisms-endophytes are a rich and not yet fully studied source of new natural biologically active compounds, attracting the attention of many scientists around the world. Of great interest are endophytic actinomycetes, which synthesize a variety of biologically active substances and provide practically unlimited opportunities for the development of new medicines. The review presents data that various biologically active metabolites of endophytic actinomycetes have antitumor, anti-inflammatory, antioxidant, and antibacterial properties.
... Furthermore, Taechowisan et al. [32] reported the anticancer activity of arylcoumarins isolated from an endophytic bacterial strain, ...
... CMUAc130. Interestingly, the bioactive compound inhibited the growth of 'Lewis lung carcinoma (LLC)' in experimental mice through apoptotic mechanism related to reduction in BCL-2 and overexpression of BAX [32]. The cytotoxic effects of extracts from the following endophytes: Fomitopsis sp. ...
Morbidity and mortality rates are on the upward trajectory globally, probably due to lack of effective treatments and poor healthcare. Most effective drugs are, however, characterized by serious side effects upon long usage. It is, therefore, imperative to explore natural sources for efficient therapeutics with little or no side effects. This paper outlines the therapeutic potentials of endophytes using published articles on endophytes in both Web of Science (WoS) and Scopus (1990–2020). Scientific evidences discussed in this review suggest endophytic microbes as reservoirs of novel bioactive compounds belonging to the following classes alkaloid, xanthones, methoxyphenols, depsipeptide, bicyclic lactones, depsidoenes, butenolides, maleimide-bearing compounds, ergosterol, spirobisnaphthalenes, benzopyran derivatives, isofuranonaphthalenone, butyrolactones, diketopiperazine, sesquiterpenoids, cytochalasin-related compounds, pestalols and cyclic pentapeptides. The identified compounds are characterized by promising therapeutic potentials such as antioxidant, anti-inflammatory, antimicrobial, anticancer, antidiabetic, antiviral, neuroprotective, and hepatoprotective properties, which are significant to healthy living and sustainable healthcare. This review further discusses the emerging potentials of endophytes in the production of antibiofilm, antimultiresistant Staphylococcus aureus (anti-MRSA) and lipase inhibitors (LIs). The prospective applications of endophytes in the development of anti-COVID-19 medications and therapeutics for the management of neglected tropical diseases (NTDs) are also advocated in this review. The therapeutic potentials of endophytes, if properly harnessed, would in no small measure contribute to good health, which is an integral part of the sustainable development goals (SDGs) of the United Nations (UN).
... CMUAc130, the 5,7-dimethoxy-4phenylcoumarin(Figure1-14a)showsamorepotentantitumoractivity against NSCLC thandoxorubicineven atahalfequivalentdose. (200) PDF created with pdfFactory Pro trial version www.pdffactory.com ...
... (288) 2.Each of 5,7-dimethoxy-4-phenylcoumarin and 6-hydroxy-4methylcoumarinhasadirectantitumor activity. (200,202) 3.DCAisasmallmoleculeinhibitor (289) thatactsasapotentiatorof5-FUantitumoractivity (99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111) ,inadditiontohaveseveralselfantitumorproperties. (112) 4.LVisapotentiatorof5-FUantitumoractivity (120)(121)(122)(123)(124)(125) andis transportedthroughcellmembraneviaareducedfolatecarrier (119) , therebyitcanbeemployedasaprecursorforthepreparationofa Trojan horse prodrug (290) . ...
Since its first rational development in 1957, 5-fluorouracil (5-FU) has
been widely used as a chemotherapeutic agent for the treatment of various types of cancer. However, its clinical use has questioned because of serious side effects, poor selectivity and tumor resistance.
Although different methods have been applied to improve the clinical
efficiency of 5-FU as the synthesis of new fluoropyrimidine derivatives,
combination or conjugation with other compounds, entrapment in polymer devices and attachment to polymer chains, prodrug strategy is still representing a promising approach to fulfill this intention.
In this thesis, coumarin-based prodrug system has been used to
synthesize nine prodrugs categorized into three series of compounds namely A, B and C; in an attempt to modify the physicochemical properties of 5-FU and to aid its delivery to the desired site of action.
The synthetic plan of each prodrug was designed to be a modification to that described in 1996 by Wang et al, and was comprised of a series of 7 linear steps starting from coumarin or one of its derivatives.
The synthesis of series (A) prodrugs involved the reduction of coumarin into diol by LiAlH4 with a relatively low yield; the allylic hydroxyl group was selectively protected as silyl ether while the phenolic hydroxyl group was then esterified with acyl chloride. When a protective group was cleaved, the resulted allylic hydroxyl group was selectively oxidized via MnO2 to allylic aldehyde. The allylic carboxylic acid group resulted from aldehyde oxidation by sodium chlorite and hydrogen peroxide was then coupled with 5-FU using a coupling system affording the target prodrugs.
... As a consequence, the natural endophyte-derived metabolites have attracted peculiar attention with the purpose of being human cancer-chemopreventive compounds and anticancer chemotherapeutic drugs (Cardoso-Filho, 2018; Figures 3B,C). Endophytic Gram-positive bacterial natural products have emerged as one of the most reliable alternative treatment sources (Gutierrez et al., 2012;Chen et al., 2013), including antitumor agents such as anthracyclines, anthraquinones, aureolic acids, β-glucans, carzinophilin, coumarins, enediynes, flavonoids, glycopeptides, macrotetrolides, mitomycins, naphthoquinones, polysaccharides, and quinoxalines (Waring and Wakelin, 1974;Igarashi et al., 2007;Taechowisan et al., 2007;Chen et al., 2013;Cardoso-Filho, 2018; Figures 3B,C and Supplementary Table S4). ...
... Alnus glutinosa-endophytic Streptomyces alnumycin was reported to inhibit the growth of K562 human leukemia cells (Bieber et al., 1998; Figure 3C), whereas Ricinus communis-endophytic salaceyins-producing Streptomyces laceyi strain MS53 was observed to be cytotoxic against the human breast cancer cell line SKBR3 (Kim et al., 2006; Figure 3B). In addition, herbaceous and arbor plants-pterocidin-producing endophytic Streptomyces hygroscopicus strain TP-A0451 was reported to inhibit human cancer cell lines NCI-H522, OVCAR-3, SF539, and LOX-IMVI growth (Igarashi et al., 2006;Qin et al., 2011), and Z. officinale 4-arylcoumarins-producingendophytic Streptomyces aureofaciens strain CMUAc130 was shown to be cytotoxic against murine Lewis lung carcinoma (Taechowisan et al., 2007;Qin et al., 2011; Figure 3C and Supplementary Table S4). ...
Endophytes constitute plant-colonizing microorganisms in a mutualistic symbiosis relationship. They are found in most ecosystems reducing plant crops’ biotic and abiotic stressors by stimulating immune responses, excluding plant pathogens by niche competition, and participating in antioxidant activities and phenylpropanoid metabolism, whose activation produces plant defense, structural support, and survival molecules. In fact, metabolomic studies have demonstrated that endophyte genes associated to specific metabolites are involved in plant growth promotion (PGP) by stimulating plant hormones production such as auxins and gibberellins or as plant protective agents against microbial pathogens, cancer, and insect pests, but eco-friendly and eco-safe. A number of metabolites of Gram-positive endophytes isolated from agriculture, forest, mangrove, and medicinal plants, mainly related to the Firmicutes phyla, possess distinctive biocontrol and plant growth-promoting activities. In general, Actinobacteria and Bacillus endophytes produce aromatic compounds, lipopeptides, plant hormones, polysaccharides, and several enzymes linked to phenylpropanoid metabolism, thus representing high potential for PGP and crop management strategies. Furthermore, Actinobacteria have been shown to produce metabolites with antimicrobial and antitumor activities, useful in agriculture, medicine, and veterinary areas. The great endophytes diversity, their metabolites production, and their adaptation to stress conditions make them a suitable and unlimited source of novel metabolites, whose application could reduce agrochemicals usage in food and drugs production.
... O ver the past decade, streptomycetes from medicinal plants have emerged as promising sources of bioactive compounds, particularly antimicrobial and antitumor agents (1)(2)(3)(4)(5)(6)(7)(8). This is partly because they are relatively unexploited sources (1). ...
We report the genome sequence of Streptomyces sp. OS603R, isolated from holy basil roots. The strain possesses genes potentially responsible for antimicrobial and antitumor agents. The genome assembly comprises 7,521,075 bps with 72.29% GC content. The genome provides the basis for studies involving genes related to relevant bioactive compounds.
... Structural assignments were based on 13 C-APT, Mass spectral data and elemental analysis). The compounds antimicrobial screening against representative panel of bacteria (Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Aspergillus niger and Coumarins, dicoumarins,krohnke synthesis, antimicrobial screening, broth dilution ones) are well known lactones isolated from variety of plant .Coumarins have a wide range of applications in the field of pharmaceuticals due to their diverse pharmacological and biological propertiessuch as , antitumor 4 , anti-, anticonvulsant 7 , 10 etc.A wide number ofcoumarin derivatives have been found in literature which contain nucleus like pyridine, indole, imidazole, diazole, thiazole, and triazole etc. as a substituent group possess important biological activities [11][12][13][14][15] . ...
... Endophytic actinomycetes are associated with a diverse range of secondary metabolites exhibiting anticancer activities [37]. Endophytic Streptomyces aureofaciens produces 4-aryleoumarins which exhibit inhibitory effect against oncoproteins Bax and bcl-2 genes in human lung cancer cells [97]. Actinobacteria produce chemical scaffolds with antimicrobial and antitumor activities with range of applications in many industries [58]. ...
Endophytes (mostly fungi and bacteria) are the microorganisms living in close symbiotic association with plants. Endophytes growing within medicinal plants in hostile environments are considered to produce novel as well as chemically and structurally diverse secondary metabolites. These metabolites are being used as clinical grade drug targets due to their less toxicity over other conventional drugs for diseases like cancer, microbial infections. Endophytes extracts are also exploited in food, agrichemical and biotechnology industries. Asparaginase of bacterial origin is widely used antitumor drug. The quint essential role of endophytes is their activity against microorganisms which can open gates in the field of biomedical research. This review mainly focuses on endophytes from medicinal plants as a source of antitumor and antimicrobial agents. Also highlights the need to focus on finding alternatives methods of endophytes isolation and production as well as characterization, purification and genetic transformations in order get maximum benefits.
... Over the past decade, endophytic streptomycetes from medicinal plants in various ecotopes, as relatively unexploited fascinating sources of novel natural products, have been explored extensively and gained some remarkable results. For example, reports covering new endophytic Streptomyces species and their novel secondary metabolites along with antimicrobial and antioxidant activities have sprung up [11][12][13][14]. Moreover, endophytic streptomycetes have been reported to possess anticancer activities as well. ...
Background
Endophytic actinomycetes, as emerging sources of bioactive metabolites, have been paid great attention over the years. Recent reports demonstrated that endophytic streptomycetes could yield compounds with potent anticancer properties that may be developed as chemotherapeutic drugs.
Results
Here, a total of 15 actinomycete-like isolates were obtained from the root tissues of Lilium davidii var. unicolor (Hoog) Cotton based on their morphological appearance, mycelia coloration and diffusible pigments. The preliminary screening of antagonistic capabilities of the 15 isolates showed that isolate LRE541 displayed antimicrobial activities against all of the seven tested pathogenic microorganisms. Further in vitro cytotoxicity test of the LRE541 extract revealed that this isolate possesses potent anticancer activities with IC 50 values of 0.021, 0.2904, 1.484, 4.861, 6.986, 8.106, 10.87, 12.98, and 16.94 μg/mL against cancer cell lines RKO, 7901, HepG2, CAL-27, MCF-7, K562, Hela, SW1990, and A549, respectively. LRE541 was characterized and identified as belonging to the genus Streptomyces based on the 16S rRNA gene sequence analysis. It produced extensively branched red substrate and vivid pink aerial hyphae that changed into amaranth, with elliptic spores sessile to the aerial mycelia. To further explore the mechanism underlying the decrease of cancer cell viability following the LRE541 extract treatment, cell apoptosis and cell cycle arrest assays were conducted in two cancer cell lines, RKO and 7901. The result demonstrated that LRE541 extract inhibited cell proliferation of RKO and 7901 by causing cell cycle arrest both at the S phase and inducing apoptosis in a dose-dependent manner. The chemical profile of LRE541 extract performed by the UHPLC-MS/MS analysis revealed the presence of thirty-nine antitumor compounds in the extract. Further chemical investigation of the LRE541 extract led to the discovery of one prenylated indole diketopiperazine (DKP) alkaloid, elucidated as neoechinulin A, a known antitumor agent firstly detected in Streptomyces ; two anthraquinones 4-deoxy- ε -pyrromycinone (1) and epsilon-pyrromycinone (2) both displaying anticancer activities against RKO, SW1990, A549, and HepG2 with IC 50 values of 14.96 ± 2.6 − 20.42 ± 4.24 μg/mL for (1); 12.9 ± 2.13, 19.3 ± 4.32, 16.8 ± 0.75, and 18.6 ± 3.03 μg/mL for (2), respectively.
Conclusion
Our work evaluated the anticarcinogenic potential of the endophyte, Streptomyces sp. LRE541 and obtained one prenylated indole diketopiperazine alkaloid and two anthraquinones. Neoechinulin A, as a known antitumor agent, was identified for the first time in Streptomyces . Though previously found in Streptomyces , epsilon-pyrromycinone and 4-deoxy- ε -pyrromycinone were firstly shown to possess anticancer activities.
Graphical Abstract
... Pterocidin from S. hygroscopicus TP-A0451 inhibits cancerous growth tested against cell lines NCI-H522, OVCAR-3, and SF539 (Qin et al. 2011;Igarashi et al. 2006) and S. cavourensis YBQ59 effectively inhibited the growth of human lung adenocarcinoma in vitro (Vu et al. 2018). Furthermore, 4-arylcoumarins from endophytic S. aureofaciens CMUAc130 is reported to be cytotoxic on Lewis lung carcinoma in the murine model in vivo (Taechowisan et al. 2007). ...
Endophytic bacteria reside within plant tissues having mutually symbiotic relationship. They are ubiquitous in nature and known to acclimatize in extreme environmental conditions. Plant-endophyte interaction also helps in signaling and bacterial communication. Apart from the mutual benefits, it imparts to plants it also produces plethora of bioactive compounds of medicinal potential. Secondary metabolites like alkaloids, polyketides, terpenoids, peptides, flavonoids, quinines, and steroids are instances of the array of compounds, the endophytic bacteria produce. These bioactive compounds are known to be effective as antimicrobial, anticancerous, antibiotic, antioxidant, antiviral, etc. With the global burden of increasing drug resistance against diseases and their side effects, natural resources such as endophytes need to be explored further to discover novel bioactive compounds. Furthermore, exploration and characterization of bacterial endophytes from diverse environment conditions producing novel bioactive compounds, have promising applications in medicine, agriculture, and veterinary sciences, enabling us to counter health challenges in ecofriendly manner.
... Another antitumor compound brartemicin was extracted from the actinomycete Nonomuraea sp. that was isolated from Artemisia vulgaris. Brartemicin is a trehalose-derived metabolite that was able to inhibit the invasion of murine colon carcinoma 26-L5 cells with an IC 50 value of 0.39 μM [46]. ...
Endophytes are microorganisms that are associated with the plant tissues without having any harmful effect on the host plant. Various medicinal plants are valuable sources of endophytic actinobacteria that exhibit high economic impact. The endophytic microbes can synthesis a wide range of novel compounds that found great applications in agricultural, pharmaceutical, as well as other industries. It is noteworthy to focus the current research on valuable applications of these microbial populations that could help in solving many problems related to the environment, agriculture, and health. Moreover, the characterization of different endophytic actinobacteria that are associated with valuable medicinal plants may help understanding plant-endophyte interactions. The current review discusses the diversity of endophytic actinobacteria rich in therapeutic agents that have been known for their medicinal applications.
... Endophytic Gram-positive bacterial natural compounds have arisen as among the most effective potential treatment sources, including antitumor agents such as anthracyclines, anthraquinones, aureolic acids, β-glucans, carzinophilin, coumarins, enediynes, flavonoids, glycopeptides, macrotetrolides, mitomycins, naphthoquinones, polysaccharides and quinoxalines [100]. Endophytic bacteria Streptomyces aureofaciens isolated from Zingiber officinale (Ginger) produced 4-arylcoumarins have shown antitumor activity against lung carcinoma [101]. Moreover, the endophytic bacteria Streptomyces cavourensis which was isolated from the Cinnamomum cassia have the potential to inhibit the growth of human lung adenocarcinoma cells [102]. ...
Cancer is a collective name for a variety of diseases that can begin in virtually every organ or body tissue as abnormal cells develop uncontrollably and ten million new cancer cases are diagnosed all over the world at present. Whereas HIV is a virus that makes people susceptible to infection and contributes to the condition of acquired immune deficiency syndrome (AIDS). Almost 37 million people are currently diagnosed with HIV and 1 million people die every year, which is the worst-case scenario. Potential medicinal compounds have played a crucial role in the production of certain clinically beneficial novel anti-cancer and anti-HIV agents that are produced from natural sources especially from plants. These include Taxol, Vinblastine, Podophyllotoxin, Betulinic acid, Camptothecin, and Vincristine, etc. In the past decades, bioactive compounds were extracted directly from the plant sources which was more time consuming, led to low yield productivity, high cost, and bad impact on biodiversity. Endophytes, the microorganisms that reside inside the host plant by not causing any kind of harm to them and have potential applications in agriculture, medicine, pollution, and food industries. Therefore, by isolating and characterizing novel endophytes from medicinal plants and extracting their secondary metabolites to produce useful bioactive compounds can be beneficial for well-being and society as a future therapeutics. This approach is not harmful to biodiversity economical, timesaving, low cost, and can lead to the discovery of various industrial and commercially important novel anti-tumor and anti-HIV agents in the future. The Himalayas are home to several medicinal plants and the endophytic microbial biodiversity of the Himalayan region is also not much explored yet. However, the effect of compounds from these endophytes on anticancer and antiviral activity, especially anti-HIV has been largely unexplored. Hence, the present review is designed to the exploration of endophytic microbial diversity that can give rise to the discovery of various novel potential industrially valuable bioactive compounds that can lessen the rate of such type of pandemic diseases in the future by providing low-cost future therapeutics in future.
Graphic Abstract
... from medicinal plants in various ecotopes, as relatively unexploited fascinating sources of novel natural products, have been explored extensively and gained some remarkable results. For example, reports covering new endophytic Streptomyces species and their novel secondary metabolites along with antimicrobial and antioxidant activities have sprung up (14)(15)(16)(17). Moreover, anticancer and cytotoxic compounds have also been discovered in endophytic Streptomyces spp., although such reports are sporadic compared to marine actinomycetes; however, their anticancer effects or cytotoxic activities are comparable to those of their marine counterparts, even stronger (18,19). ...
Background: Endophytic actinomycetes, as emerging sources of bioactive metabolites, play a vital role in pharmaceutical development. Recent reports demonstrated that endophytic Streptomyces isolates could yield compounds with potent anticancer and antimicrobial properties that may be developed into chemotherapeutic drugs. Our study displayed that Streptomyces sp. LRE541 obtained from the root tissues of Lilium davidii var. unicolor Cotton, could be a potential source of anticarcinogens and antimicrobials.
Results: Isolate LRE541 was characterized and identified as belonging to the genus Streptomyces based on the 16S rDNA sequence analysis, with highest sequence similarity to Streptomyces tauricus JCM4837T (98.81%). It produced extensively branched red substrate and vivid pink aerial hyphae that changed into amaranth, with elliptic spores sessile to the aerial mycelia. The secondary metabolites (EtOAc extract) produced by isolate LRE541 exhibited significant anticancer activities with IC50 values of 0.021, 0.2904, 1.484, 4.861, 6.986, 8.106, 10.87, 12.98, and 16.94 μg/mL against cancer cells RKO, 7901, HepG2, CAL-27, MCF-7, K562, Hela, SW1190 and A549, respectively, evaluated by the MTT assay. In contrast, the EtOAc extract showed less cytotoxicity activity against the normal human pulmonary artery endothelial cell (HPAEC) with an IC50 value of > 20 μg/mL than that of the cancer cells. To further explore the mechanism underlying the decrease in viability of cancer cells following the EtOAc extract treatment, cell apoptosis and cell cycle arrest assays were performed using two cancer cell lines, RKO and 7901. The result demonstrated that the EtOAc extract inhibited cell proliferation of RKO and 7901 cells by causing cell cycle arrest both at the S phase and inducing apoptosis in a dose‑dependent manner. Moreover, the EtOAc extract of isolate LRE541 with the concentrations within 100 μg/mL also possessed the antagonistic activities against E. coli ATCC 25922, MRSA ATCC 25923, P. aeruginosa and C. albicans ATCC 66415, and the antagonistic potent against the tested pathogens all displayed a dose-dependent manner. The UHPLC-MS/MS analysis of the EtOAc extract revealed that the presence of antitumor, potential antitumor and antimicrobial compounds could account for the potent antineoplasmic and antagonistic properties of the extract.
Conclusion: This study provides the potential therapeutic applications of the bioactive metabolites from Streptomyces sp. LRE541 as novel antimicrobial and anticancer agents.
... The coumarin nucleus is also significantly prevalent in numerous natural products, clinical pharmaceuticals and biologically active drug molecules ( Fig. 16) [328,329]. Given the well recognized and diverse medicinal and drug discovery applications of this heterocyclic framework in the form of anticoagulant [330,331] antitumor [332], antimalarial [333], anti-HIV [334], antimicrobial [335], antiinflammatory, antiviral, antiprotozoal, antidiabetic [336][337][338][339], anticancer [340] antipsoriasis, antidepressant [328,341] antitumor [338] and antioxidant [342] activities and its inhibitory activity against alkaline phosphatase, aldose reductase, cholinesterase, glucosidase, urease, p450 [343][344][345][346][347][348][349][350][351] and monoamine oxidase [352,353] enzymes, provide ample opportunity for organic chemists to develop attractive and feasible methods under mild conditions utilizing simple and readily accessible starting materials. Traditional methods for the synthesis of coumarins include the Wittig reaction, Pechmann reaction, Knoevenagel condensation reaction [354][355][356], Mizorogi-Heck/lactonization [357,358], Kostanecki reaction [359,360] and Perkin reaction [361][362][363]; however, Scheme 49 Palladium-catalyzed intermolecular cyclization of alkynes and isocyanides to form polysubstituted maleimide derivatives newly developed metal-free and transition-metal-catalyzed strategies offer powerful and atom-economic methods. ...
Heterocycles, heteroaromatics and spirocyclic entities are ubiquitous components of a wide plethora of synthetic drugs, biologically active natural products, marketed pharmaceuticals and agrochemical targets. Recognizing their high proportion in drugs and rich pharmacological potential, these invaluable structural motifs have garnered significant interest, thus enabling the development of efficient catalytic methodologies providing access to architecturally complex and diverse molecules with high atom-economy and low cost. These chemical processes not only allow the formation of diverse heterocycles but also utilize a range of flexible and easily accessible building units in a single operation to discover diversity-oriented synthetic approaches. Alkynoates are significantly important, diverse and powerful building blocks in organic chemistry due to their unique and inherent properties such as the electronic bias on carbon–carbon triple bonds posed by electron-withdrawing groups or the metallic coordination site provided by carbonyl groups. The present review highlights the comprehensive picture of the utility of alkynoates (2007–2019) for the synthesis of various heterocycles (> 50 types) using transition-metal catalysts (Ru, Rh, Pd, Ir, Ag, Au, Pt, Cu, Mn, Fe) in various forms. The valuable function of versatile alkynoates (bearing multifunctional groups) as simple and useful starting materials is explored, thus cyclizing with an array of coupling partners to deliver a broad range of oxygen-, nitrogen-, sulfur-containing heterocycles alongside fused-, and spiro-heterocyclic compounds. In addition, these examples will also focus the scope and reaction limitations, as well as mechanistic investigations into the synthesis of these heterocycles. The biological significance will also be discussed, citing relevant examples of drug molecules highlighting each class of heterocycles.
Graphic Abstract
This review summarizes the recent developments in the synthetic methods for the synthesis of various heterocycles using alkynoates as readily available starting materials under transition-metal catalysis.
... GT2002611 isolated from mangrove plant Aegiceras corniculatum used in the pharma industry (Lin et al. 2008). Two antimicrobial compounds namely isocutellarin and cichoriin of Streptomyces sp.TC052 from Alpinia galanga reported to be active against Gram-positive and Gram-negative bacteria as well as against yeast cells (Taechowisan et al. 2007(Taechowisan et al. , 2008. ...
The strains of actinobacteria are unique as they lie between true fungi and bacteria and several of them were reported as endophytic actinobacteria as they were isolated from the inner regions of various plant parts and will enhance uptake of nutrients and improve defense against pathogens. Literature and scientific communications reported the relationship between the endo-phytes and plants, most of them concluded the association as commensalism. Remarkably, bioactive compounds from endophytic Streptomyces sp. were confirmed with various applications. A retrospective consolidation on the endophytic Streptomyces sp. and their metabolite application in day to day life is presented here. It was deduced that this group of the organism are a source for a wide range of bioactive compounds including anticancer agents, immune suppressor , plant growth promoters, anti-inflammatory agents, anti-tumor agents, enzymes and anti-microbial substances. These antimicrobial metabolites show broad-spectrum activity and are effective against bacteria and fungi. The mechanism of action of secondary metabolites from endophytes and its positive influence on the host plants are noted as involvement in deterrence, antifeedant activity, toxicity against common pests, and as enhancers for physical mechanisms such as water uptake and sunlight absorption, thus supporting the growth of host plants.
... Our results showed that endophytes and plant parts of Carica papaya can significantly produce antitumor compounds which after further scale up production (fermentation), purification and identification could be developed as potential drug candidates (Figure 4). Antitumor compounds from endophytic actinobacteria and Bacillus has been reported by Taechowisan et al. (2007) who screened an antitumor compound; 4arylcoumarins from the endophytic Streptomyces aerufaciens. Similarly, Chen et al. (2013) isolated endophytic Bacillus amyloliquifaciens whose extracted exoploysaccharides exhibited remarkable antitumor activity against gastric cancer. ...
Microbes have always been the noteworthy source of antibiotics, enzymes and various other compounds. The emerging issue of multidrug resistance has increased the demand for mining out novel sources of antimicrobial agents. Thus, researchers are now trying to explore the underexplored microbial resources for getting new therapeutics. In this study, 42 endophytic bacteria were isolated, which includes 22 actinobacteria and 20 general bacterial strains from different parts (roots, shoots and leaves) of Carica papaya Linn. The crude extracts of endophytes and plant tissues showed remarkable antimicrobial activity against different pathogenic bacteria such as methicillin resistant Staphylococcus aureus (MRSA), E. coli and Pseudomonas aeruginosa. The extracts also exhibited notable in vitro cytotoxicity against colorectal carcinoma cell lines (HTC 116, ATTC CCL-247) by MTT assay, at the lowest concentration of 0.1mg/ml showing growth inhibition up to 80%. The plant extracts were more potent against MRSA and Bacillus, in comparison to the extracts of endophytic bacteria. Our findings suggested that endophytic bacteria and plant tissue extracts of medicinal plant Carica papaya are promising source of antimicrobial and antitumor compounds. The purification and identification of active compounds from these sources may yield some useful drug candidates.
... Genus Streptomyces is a promising source of biological active materials with broad biological action as Streptomyces Tc052 and Streptomyces displayed antioxidant activity (Taechowisan et al., 2009). Likewise, S. aureofaciens CMUAc130 exhibited anti-inflammatory and antitumor potency (Taechowisan et al., 2007), also Taechowisan et al. (2005) declared that Streptomyces aureofaciens CMUAc130 presented antifungal activity. In 2014, Tanvir et al. reported that Streptomyces albovinaceus and S. badius are insecticidal. ...
... A new anti-inflammatory compound, 5, 7-dimethoxy-4-p-methoxylphenylcoumarin (118), and 5, 7dimethoxy-4-phenylcoumarin (119) were isolated from endophytic Streptomyces aureofaciens CMUAc130 [103,104]. ...
This review describes examples of naturally occurring bioactive compounds obtained from fungal endophytes from various host plants. The main topics addressed are sources, identification, biological activity, biosynthesis, and ecological and chemosystematic significance of those bioactive compounds whose sources were well defined.
... Hedaya48 with significant antimycotic activity specifically against dermatophytes (El-Gendy and El-Bondkly, 2010). 5, 7-Dimethoxy-4-phenylcoumarin extracted from endophytic S. aureofaciens was effective in preventing or delaying formation of metastases (Taechowisan et al., 2007). ...
Actinobacteria are wide spread in nature and represent the
largest taxonomic group within the domain Bacteria. They are
abundant in soil and have been extensively explored for their
therapeutic applications. This versatile group of bacteria has
adapted to diverse ecological habitats, which has drawn
considerable attention of the scientific community in recent
times as it has opened up new possibilities for novel
metabolites that may help in solving some of the most
challenging problems of the day, for example, novel drugs for
drug-resistant human pathogens, affordable means to
maintain ecological balance in various habitats and alternative
practices for sustainable agriculture. Traditionally, free
dwelling soil actinobacteria have been the subject of intensive
research. Of late, symbiotic actinobacteria residing as
endophytes within the plant tissues have generated immense
interest as potential source of novel compounds, which may
find applications in medicine, agriculture and environment. In
the light of these possibilities, this review focuses on the
diversity of endophytic actinobacteria isolated from the plants
of extreme habitats and specific ecological niches.
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7/17/2018 Frontiers | Diversity and Applications of Endophytic Actinobacteria of Plants in Special and other Ecological Niches | Microbiology
https://www.frontiersin.org/articles/10.3389/fmicb.2018.01767/abstract 2/2
Furthermore, an attempt has been made to assign chemical
class to the compounds obtained from endophytic
actinobacteria. Potential therapeutic applications of these
compounds and the utility of endophytic actinobacteria in
agriculture and environment are discussed.
... Recientemente han sido demostrado que las bacterias endófitas se encuentran asociadas a diferentes tejidos de plantas leñosas, incluidas gimnospermas y angiospermas (CHANWAY, 1998), en las cuales según los informen producen un número de metabolitos como antibióticos (CASTILLO et al., 2002), metabolitos secundarios incluyendo algunos compuestos antitumorales (IGARASHI et al., 2007), agentes anti-inflamatorios (TAECHOWISAN et al., 2007), sustancias que promueven el crecimiento vegetal y el control biológico. ...
Las bacterias endófitas habitan dentro de los tejidos de las plantas al menos durante una parte de su ciclo de vida sin causar daño alguno al hospedero, establecen asociación simbiótica y producen grandes beneficios para las plantas. Las bacterias endófitas cumplen una gran diversidad de funciones como promotoras de crecimiento vegetal, control biológico sobre una diversidad de fitopatógenos, mejoran la eficiencia de los procesos de fitoremediación de compuesto tóxicos en la rizósfera. Estos microorganismo son fuentes inagotable de más de 20.000 compuestos biológicamente activos, los cuales influyen de manera directa en el rendimiento y supervivencia de las plantas hospederas. Las bacterias endófitas son reportadas por producir un número de metabolitos como antibióticos, metabolitos secundarios incluyendo algunos compuestos antitumorales, agentes antiinflamatorios.
... In addition, 4-Arylcoumarin analogues compounds were extracted from Streptomyces aureofaciens CMUAc130, which showed antitumor activity and inhibitory effects on transplanted LLC in mice. The biochemical mechanisms for inhibition of tumor proliferation was experimented with adenocarcinoma cell line (A427) for the over-expression of oncoproteins, which suggested that 5, 7-dimethoxy-4-phenylcoumarin delayed the intracellular signal leading to tumor proliferation (Taechowisan et al., 2007a(Taechowisan et al., ,2007b. Antidiabetic potential of endophytic actinobacteria have been reported based on enzyme inhibitors like α-glucosidase and α-amylase. ...
Actinobacteria are potential source of antibiotics which contributes approximately two-thirds of known antibiotics. Endophytic actinobacteria colonize or reside inside the plant tissue without causing harmful effects to the host plant and present almost every plant on earth. Invasion of endophytic actinobacteria takes place through roots and spread to other parts of the host plant. Endophytes promote plant growth by producing phytohormones, polymer degrading enzymes and diverse secondary metabolites as result of competition or antibiosis. Endophytic actinobacteria enhance plant growth indirectly by incresing the availability of nutrients and induction of systemic resistance. They produce broad range of structurally diverse secondary metabolites in association with medicinal plants through beneficial interactions or to withstand threshold level inside the host under different climatic conditions. Bioactive metabolities produced from endophytic actinomycete may serve as promising source to combat various phytopathogens, drug resistant clinical pathogens related to humans and bioremediation in the environment. This chapter focus on the metabolic potential of endophytic actinobacteria such as (a) Biocontrol agents against phytopathogens (b) Antibacterial agents against human pathogens (c) Bioremediation in the environment. Exploration of secondary metabolites from endophytic actinobacteria association with medicinal plants will provide further insights into plant endophyte interactions, enhanced level of fitness between the microorganisms and plants.
Key words: Endophytic actinobacteria, Biocontrol agents, Antimicrobials, Medicinal plants, Sustainable agriculture, Bioremediation
... Bacterial endophytes have been reported from tissues of woody plants, including gymnosperms and angiosperms (Chanway, 1998). They are reported to produce a number of metabolites such as antibiotics (Castillo et al., 2002), secondary metabolites including some antitumor compounds (Igarashi et al., 2007), anti inflammatory agents (Taechowisan et al., 2007), plant growth promoting agents and biological control agents (Sheng et al., 2011). Here, we report the isolation of four endophytic bacterial isolates from M. dentata Bedd. ...
Background
Camptothecin (CPT), a quinoline alkaloid, is a potent inhibitor of eukaryotic topoisomerase I. Because of this property, several derivatives of CPT are used as chemotherapeutic agents. CPT is produced by several plant species belonging to the Asterid clade as well as by a number of endophytic fungal associates of these plants. In this study, we report the production of CPT by four bacterial endophytes and show the possible role of a plasmid in the biosynthesis of CPT.
Methods
Endophytic bacteria were isolated from leaves, stems and fruits of Pyrenacantha volubilis Hook. (Icacinanceae). The bacterial isolates were purified and analyzed for production of CPT by ESI-MS/MS and NMR analysis. Bacterial identity was established based on the morphology and 16s rRNA sequence analysis. Crude extracts of the bacterial endophytes were evaluated for their cytotoxicity using colon cancer cell lines. The role of plasmid in the production of CPT was studied by purging the plasmid, using acriflavine, as well as reconstituting the bacteria with the plasmid.
Results
Four bacterial isolates, Bacillus sp. (KP125955 and KP125956), Bacillus subtilis (KY741853) and Bacillus amyloliquefaciens (KY741854) were found to produce CPT in culture. Both based on ESI-MS/MS and NMR analysis, the identity of CPT was found to be similar to that produced by the host plant. The CPT was biologically active as evident by its cytotoxicity against colon cancer cell line. The production of CPT by the endophyte (Bacillus subtilis, KY741853) attenuated with sub-culture. A likely role of a plasmid in the production of CPT was established. A 5 kbp plasmid was recovered from the bacteria. Bacterial isolate cured of plasmid failed to produce CPT.
Conclusion
Our study implies a possible role of a plasmid in the production of CPT by the endophytic bacteria and opens up further work to unravel the exact mechanisms that might be involved.
... 5,7-dimethoxy-4-pmethoxylphenylcoumarin and 5,7-dimethoxy-4-phenylcoumarin isolated from endophytic actinomycetes Streptomyces aureofaciens CMUac130 shows strong antitumor and antifungal activity. 4-arylcoumarins isolated from endophytic Streptomyces aureofaciens CMUAc130, also shows inhibitory activity against lung carcinoma (Taechowisan et al., 2005;Thongchai et al., 2007). In conclusion, endophytic microorganisms are to be found in virtually every plant on earth. ...
Endophytic actinomycetes from medicinal plants of Rajkot district were isolated and screened for their antibacterial activity against several pathogenic bacteria. A total of 36 separate endophytic isolates were obtained from 7 medicinal plants and 22.22% of these showed antagonistic activity against pathogens. Most of the endophytic actinomycetes were recovered from roots (55.56% of all isolates) followed by leaves (44.44%). No epiphytes were grown during isolation which shows the effectiveness of surface sterilization technique. Six (16.67%) endophytic actinomycetes showed broad spectrum antibacterial activity inhibited both Gram-positive and Gram-negative bacteria including multi drug resistant S. aureus, where as two (5.56%) actinomycetes was effective against only gram negative bacteria. One of the potential endophytic actinomycetes EA7 was chosen for further study on the basis of zone of inhibition and broad spectrum activity. Antibacterial compound from EA7 was efficiently separated by analytical TLC using Chloroform-Methanol, 24:1 solvent system and further UV absorption spectrum maxima recorded at 223 nm. These results indicate that endophytic actinomycetes from medicinal plants have potential antibacterial activity that could be further exploited for industrial applications.
This volume is a compilation of reviews on the industrial usage of soil microorganisms. The contents include 16 brief reviews on different soil microbe assisted industrial processes. Readers will be updated about recent applications of soil bacteria, fungi and algae in sectors such as agriculture, biotechnology, environmental management.
The reviews also cover special topics like sustainable agriculture, biodiversity, ecology, and intellectual property rights of patented strains, giving a broad perspective on industrial applications of soil microbes.
Volume 3 emphasizes various soil microorganisms including cyanobacteria and mycorrhiza. The 16 chapters cover the ecological significance of mycorrhiza to and their role in sustainable agriculture, microbial interactions with nematodes, microbes as biocontrol agents, and the use of endophytes in agriculture, Chapters also shed light on industrial aspects and microbial biotransformation, providing a comprehensive view of sustainable agricultural practices. Special topics such as the microbial carotenoids are also included.
Medicinal plants remain a valuable source for natural drug bioprospecting owing to their multi-target spectrum. However, their use as raw materials for novel drug synthesis has been greatly limited by unsustainable harvesting leading to decimation of their wild populations coupled with inherent low concentrations of constituent secondary metabolites per unit mass. Thus, adding value to the medicinal plants research dynamics calls for adequate attention. In light of this, medicinal plants harbour endophytes which are believed to be contributing towards the host plant survival and bioactive metabolites through series of physiological interference. Stimulating secondary metabolite production in medicinal plants by using endophytes as plant growth regulators has been demonstrated to be one of the most effective methods for increasing metabolite syntheses. Use of endophytes as plant growth promotors could help to ensure continuous supply of medicinal plants, and mitigate issues with fear of extinction. Endophytes minimize heavy metal toxicity in medicinal plants. It has been hypothesized that when medicinal plants are exposed to harsh conditions, associated endophytes are the primary signalling channels that induce defensive reactions. Endophytes go through different biochemical processes which lead to activation of defence mechanisms in the host plants. Thus, through signal transduction pathways, endophytic microorganisms influence genes involved in the generation of secondary metabolites by plant cells. Additionally, elucidating the role of gene clusters in production of secondary metabolites could expose factors associated with low secondary metabolites by medicinal plants. Promising endophyte strains can be manipulated for enhanced production of metabolites, hence, better probability of novel bioactive metabolites through strain improvement, mutagenesis, co-cultivation, and media adjustment.
Mycology is the specialist branch of fungal study. Fungi are the most diverse group of heterotrophic organisms and second largest biotic community after insects on earth. They are grouped into separate Kingdom Fungi. Fungi have thalloid body without cells being organized into tissues and organs. Fungi are the parasitic, saprophytic or symbiotic in nature. They also play key role in terrestrial ecosystems. Fungi are the primary decomposers of lignocellulosic material and the main keepers of great carbon storage in soil as well as dead organic materials. Their edibility, medicinal properties, mycorrhizal and parasitic association with the forest trees make them economically and ecologically important for investigation. The term macro fungi are generally applied to the fruiting bodies of fungi belonging to Ascomycetes and Basidiomycetes. Ascomycetes and Basidiomycetes are either Epigeous or Hypogeous, large enough to be seen by naked eyes hence they can be picked by hand. Micro fungi may cause pathological disease to the plants, animals, and human. Furthermore, most of fungi are microscopic in nature, invisible and they cause their action.
Microbes exist as mutualists, parasites, and symbionts or as pathogens in nature. In plant microbiota, plant immunity determines whether the interaction with microbes is friendly or hostile. Friendly interaction may have an eccentric way of mutual interrelations for a resource contribution. This interaction is called plant-endophyte mutualistic or symbiotic relation in which microorganisms (fungi, bacteria, and actinomycetes) live within robust plant tissues. It has been discovered that almost all plant species investigated by various researchers harbor one or more endophytes. They benefit their host by producing various secondary metabolites that can be employed in agriculture and medicine. Endophytes are a treasure house of many novel bioactive compounds such as steroids, tannins, terpenoids, quinones, alkaloids, saponins, and phenolic acids which makes them a potential candidate for anticancer, antibiotic, antioxidant, anti-inflammatory, antiviral, antidiabetic properties, etc. Endophytes continue to be the peculiar source of various potential drugs. This review intends to shed light on the function and potential applications of endophytes as a forthcoming source of medications for a range of illnesses/diseases as well as other potential medical uses.
Endophytic actinomycetes, Gram-positive filamentous bacteria, live inside the plant tissues of different organs including roots, stems, leaves, flowers, fruits, and seeds. They not only harm the living plants, but also have proper effects on their host plants such as promoting plant growth and defending phytopathogens. Numerous classes of bioactive natural compounds, polyketides, macrolides, alkaloids, peptides, and terpenes, with various bioactivities: antibacterial, antifungal, anti-phytopathogens, immunosuppressant, anticancer, antioxidant, and anti-inflammatory, were produced by Streptomyces kebangsaanensis, Streptomyces albidoflavus, Actinoallomurus fulvus, Micromonospora lupini, M. endophytica, Polymorphospora rubra, and Streptosporangium oxazolinicum strains. Moreover, their novel compounds are also continued to discover and develop for preclinical stages. Thus, endophytic actinomycetes are the most key sources of potential bioactive metabolites, as well as a reservoir to mine for novel chemical structures. Moreover, with the progress in high-throughput genome sequencing techniques, many genome mining methods has been developed and helped to link the discovered compounds to their biosynthetic gene clusters (BGCs). This chapter highlights bioactive compounds derived from endophytic actinomycetes on their biological activity and biotechnological potential together with the modern disciplines, and genome mining tools for discovery of the novel compounds.
Exploration of untapped environments in discovering novel bioactive metabolites is one of the priority areas of research. Different environments and ecosystems like alkaline, mangrove ecosystems, marine sponges, hypersaline lakes, alkaline soils, medicinal plants, and insect intestine have explored for the recovery of many bioactive metabolites. Many culture-based studies have revealed that actinobacteria recovered from the hot spring environments comprise substantial synthesis potentials for various biological active compounds. The potential actinobacterial variety and distribution endemic to the hot spring environments can be explored in recovering novel metabolites and compounds. In the present scenario, the discovery of novel antagonist drugs in controlling the multidrug-resistant bacteria and biofilm forming bacteria is in high demand. However, due to the use of similar and repeated screening methods, results in previously reported compounds and are the major limitations to endure. Nowadays, integrated molecular networking approaches such as mass spectrometry profiles using the unknown complex samples have gained considerable interest in discovering novel metabolites. Despite the use of these advanced techniques, researchers should also look to explore untapped ecosystems for the discovery of potential therapeutic applications.KeywordsActinobacteriaSecondary metabolitesBioactive compoundsEcosystemsScreening of novel secondary metabolites
Plant-based secondary metabolite production system is well established. However, host–endophyte interaction in the production of secondary metabolite is a new less exploited area that is overcoming barriers and evolving as one of the prospective fields. Endophytes such as bacteria or fungi have the ability to produce some of the secondary metabolites that mimic the plant metabolites therefore escaping the host defence system. Coumarin is one such metabolite with immense biological functions. Most of the studies have demonstrated coumarin production from fungal endophytes but not bacterial endophytes. Herein, we present an overview of all the coumarin derivatives produced from endophytic sources and their biosynthetic pathways. Furthermore, the review also throws light on the isolation of these coumarins and different derivatives with respect to their biological activity. The biotransformation of coumarin derivatives by the action of endophytic fungi is also elaborated. The present review provides an insight on the challenges faced in the coumarin production through fungal endophytes.
A diverse array of organic volatiles and secondary metabolites are extracted from microorganisms including bacteria, fungi, and actinomycetes residing within plant parts termed as endophytes. These metabolites and volatiles play an important role in the establishment of symbiotic relationship with their hosts under a highly competitive environment and also for intra- and interkingdom signaling. Secondary metabolites including acids, alcohols, aromatic compounds, aldehydes, esters, ketones, terpenes, etc. have the potential to be used in agriculture for crop production or have industrial applications. Several organic volatiles has been reported with the properties to inhibit plant and human pathogens, thereby providing an alternative to chemical methods for controlling these pathogens. Many endophytes are known to produce volatiles including alkanes, alkenes, esters, benzene derivatives, etc. with fuel properties. The present chapter highlights the chemical diversity of important secondary metabolites and organic volatiles produced by endophytes and their use in agriculture and pharmaceutical industries.
Plants benefit extensively from endophytic bacteria, which live in host plant tissues exerting no harmful effects. Bacterial endophytes promote the growth of host plants and enhance their resistance toward various pathogens and environmental stresses. They can also regulate the synthesis of secondary metabolites with significant medicinal properties and produce various biological effects. This review summarizes recent studies on the relationships between bacterial endophytes and medicinal plants. Endophytic bacteria have numerous applications in agriculture, medicine, and other industries: improving plant growth, promoting resistance toward both biotic and abiotic stresses, and producing metabolites with medicinal potential. Their distribution and population structure are affected by their host plant’s genetic characteristics and health and by the ecology of the surrounding environment. Understanding bacterial endophytes can help us use them more effectively and apply them to medicinal plants to improve yield and quality.
Natural products are one of the resources for discovering novel fungicidal leads. As a natural fungicide, osthole was used as a coumarin-based lead compound for the development of novel fungicides. Here, a series of 3,4-dichloroisothiazole-containing 7-hydroxycoumarins were rationally designed, synthesized, and characterized by introducing a bioactive substructure, 3,4-dichloroisothiazole, into the coumarin skeleton. In vitro bioassay indicated that compound 7g displayed good activity against Rhizoctonia solani, Physalospora piricola, Sclerotinia sclerotiorum, and Botrytis cinerea. Its median effective concentration (EC50) value against each of these fungi fell between 0.88 and 2.50 μg/mL, which was much lower than that of osthole against the corresponding pathogen (between 7.38 and 74.59 μg/mL). In vivo screening validated that 7k exhibited 100%, 60%, and 20% efficacy against R. solani Kühn at 200, 100, and 50 μg/mL, respectively. RNA sequence analysis implied that growth inhibition of R. solani by 7k might result from potential disruptions of fungal membrane formation and intracellular metabolism. Furthermore, a field experiment with cucumber plants indicated that 7b showed 62.73% and 74.03% efficacy against Pseudoperonospora cubensis (Berk. & Curt.) Rostov. at rates of 12.5 g a.i./ha and 25 g a.i./ha, respectively, which showed no significant difference between 7b and osthole at 30 g a.i./ha. Our studies suggested that 7b, 7g, and 7k might be used as fungicidal leads for further optimization.
Twenty-one novel 3,4-dichloroisothiazolocoumarin-containing strobilurins were rationally designed and synthesized. Preliminary bioassay showed that compounds 7c, 7h and 7l exhibited over 80% inhibitory rate against Sclerotinia sclerotiorum at 50 μg/mL, 7c exhibited good activity against S. sclerotiorum with median effective concentration (EC50) of 4.08 μg/mL, while the positive control coumoxystrobin showed EC50 of 1.00 μg/mL. In addition, 7d showed better fungicidal activity with a lower EC50 value of 7.65 μg/mL against Botrytis cinerea than that of positive control trifloxystrobin with its EC50 value of 21.96 μg/mL. This study indicated that 3,4-dichloroisothiazolocoumarin-containing strobilurin was a promising fungicide lead deserved for further study.
Graphic abstract
Endophytes are abundant in plants and studies are continuously emanating on their ability to protect plants from pathogens that cause diseases especially in the field of agriculture. The advantage that endophytes have over other biocontrol agents is the ability to colonize plant's internal tissues. Despite this attributes, a deep understanding of the mechanism employed by endophytes in protecting the plant from diseases is still required for both effectiveness and commercialization. Also, there are increasing cases of antibiotics resistance among most causative agents of diseases in human beings, which calls for an alternative drug discovery using natural sources. Endophytes present themselves as a storehouse of many bioactive metabolites such as phenolic acids, alkaloids, quinones, steroids, saponins, tannins, and terpenoids which makes them a promising candidate for anticancer, antimalarial, antituberculosis, antiviral, antidiabetic, anti-inflammatory, antiarthritis, and immunosuppressive properties among many others, even though the primary function of bioactive compounds from endophytes is to make the host plants resistant to both abiotic and biotic stresses. Endophytes still present themselves as a peculiar source of possible drugs. This study elucidates the mechanisms employed by endophytes in protecting the plant from diseases and different bioactivities of importance to humans with a focus on endophytic bacteria and fungi.
Seeking solutions from nature for solving one and all problems is the age-old practice for mankind, and natural products are proved to be the most effective one for keeping up the balance of development as well as the “healthy, wealthy, and well” condition of mother nature. Fungal pathogens are proved to be a common and popular contaminant of agroecosystem that approximately causes 70–80% of total microbial crop loss. To meet the proper global increasing need of food products as a result of population explosion, managing agricultural system in an eco-friendly and profitable manner is the prime target; thus the word “sustainable agriculture” plays it part, and this package is highly effective when coupled with nature-derived fungicidal products that can minimize the event of fungal infections in agrarian ecosystem. Present study enlists the most common and effective natural products that might be of plant or microbial origin, their mode of action, day-by-day development of phytopathogenic resistance against the prevailing fungicides, and also their role in maintenance of sustainability of agricultural practices with special emphasis on their acceptance over the synthetic or chemical one. A large number of bioactive compounds ranging from direct plant (both cryptogams algae and moss and phanerogams)-derived natural extracts, essential oil of aromatic plants, and low-molecular-weight antimicrobial compounds known as phytoalexins to secondary metabolites that are both volatile and nonvolatile organic compounds of microbes (fungal and actinobacterial members) residing inside the host tissue, called endophyte, are widely used as agricultural bioweapons. The rhizospheric partners of plant, mycorrhizae, are also a prime agent of this chemical warfare and protect their green partners from fungal invaders and emphasize the concept of “sustainable agriculture.”
Pyrethroids are the synthetic compounds derived from the Chrysanthemum cinerariaefolium plant. The first synthetic pyrethroids developed in the United States are allethrin and bioallethrin. According to the World Health Organization, the classification pyrethroids has a place in the fourth group of insecticides and includes 42 substances. More than 30% of pyrethroid insecticides are used worldwide. In the year 2015, the global market of pyrethroid insecticides has been estimated at USD 4.67 billion and is expected to touch USD 6.45 billion by the year 2021. Pyrethroid insecticides are potent against an extensive variety of pests belonging to the orders Coleoptera, Diptera, Hemiptera, Hymenoptera, Lepidoptera, Orthoptera, and Thysanoptera. Pyrethroid insecticides interrupt the functioning of the peripheral nervous system by reacting with the voltage-gated sodium channels and cause a series of bursts and paralyses. The low tendency to accumulate in organisms, short biodegradation period, and economic value have led to the overuse of pyrethroids with unavoidable consequences. The increase in the production of mites in cotton, in tea, and in vegetables was reported by the constant use of synthetic pyrethroids. Even at a very low concentration in water, pyrethroids are strongly absorbed by the gills of fish due to their lipophilic nature and lead to their toxicity and even altered homing ability in honeybees. Pyrethroid metabolites were detected in the breast milk of women in various parts of the world. Long-term exposure of pyrethroids leads to aggressive behavior in humans due to the leftover traces of pyrethroid metabolites in urine. Further research should be done to prove the toxicity of pesticides in the ecosystem, the effects of pesticide residues, and their interaction with nutrients.
Symbiosis research has been undertaken by researchers working independently of one another and often focused on a broad range of symbiotic interactions ranging from bipartite microbial consortia to multicellular hosts and their complex microbial communities. Recent investigations in symbiosis can impact areas such as agriculture sustainability, where a basic understanding of plant-microbe symbiosis will provide foundational information on the increasingly important issue of climate change. In this respect, in this chapter, we provided comments and references to finally establish symbiosis as an overdue central discipline of biological science. The interactions between medicinal plants and beneficial microorganisms, such as some Actinobacteria, Firmicutes, etc., proved the importance of these interactions to both symbionts in terms of enhanced adaptability, survival, and fitness of plants under different environmental stresses.
A direct electrochemical oxidative cyclization of alkynoates and alkynamides with diselenide or disulfide for the synthesis of the coumarins and quinolinones bearing a chalcogen functional group has been developed. This green and efficiency approach was realized through the constant current electrolysis in an undivided cell under metal-free and oxidant-free conditions. Moreover, a series of selenium/sulfur-substituted coumarins and quinolinones products were obtained in moderate to good yields with broad scope and functional group tolerance.
Background
Non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, aspirin, indomethacin, flufenamic acid and phenylbutazone used to treat most of the inflammatory disorders. These NSAIDs are also associated with serious side effects including gastric ulceration, nephrotoxicity, and bleeding, mainly due to acidic nature. Hence, there is a need to identify highly potent and safer treatment for inflammatory disorders.
Methods
Herein, Synthetic hydrazinyl thiazole substituted coumarins and chromones 1-48 were evaluated for ROS inhibitory activity. ROS were generated from zymosan activated whole blood phagocytes.
Results
Among all tested compounds, compounds 1 (IC50 = 38.3 ± 7.1 µM), 2 (IC50 = 5.7 ± 0.2 µM), 5 (IC50 = 28.3 ± 3.5 µM), 23 (IC50 = 12.5 ± 3.1 µM), 27 (IC50 = 32.8 ± 1.1 µM), 39 (IC50 = 20.2 ± 1.6 µM), and 42 (IC50 = 43.2 ± 3.8 µM) showed potent ROS inhibition as compared to standard ibuprofen (IC50 = 54.3 ± 1.9 µM). Whereas, compounds 3 (IC50 = 134.7 ± 1.0 µM), 16 (IC50 = 75.4 ± 7.2 µM), 24 (IC50 = 102.4 ± 1.0 µM), and 31 (IC50 = 86.6 ± 1.5 µM) were found to be moderately active. Cytotoxicity was also checked for all active compounds on NIH-3T3 cell line. Cyclohexamide (IC50 = 0.13 ± 0.02 µM) was used as standard.
Conclusion
Identified active compounds from these libraries may serve as lead candidates for future research in order to obtain more potent, and safer antiinflammatory agent.
From the discovery to the golden age of antibiotics (miracle), millions of lives have been saved. Era of negligence towards chemotherapeutic agents gave birth to drug resistance. Among all the regulators of drug resistance the drug transporters are considered to be the key regulator for multidrug resistance. These transporters are prevalent from prokaryotes to eukaryotes. Endophytes are one of the unexplored wealth of nature. Endophytes are model mutualistic partner of plants. They are reservoir of novel therapeutics. The present review deals with the endophytes as novel drug resistance reversal agents by inhibiting the drug transporters across the genera. This review is also focusing on the drug transporters, mutualistic chemical diversity, exploring novel wealth and drug transporter modulating potential of endophytes.
Alpha-glucosidase inhibitors are compounds that can prevent the digestion of complex carbohydrates into glucose, so potentially used as a diabetes drug. This study aims to examine the production and extraction of alpha-glucosidase inhibitor compound from Isolate Aktinomiset JP-3 from the sea. The supernatant obtained from the culture of the JP-3 isolate was extracted using various solvents to obtain the active compound. The solvents used were chloroform, methanol, and ethyl acetate. An assay of inhibitor activity of the α-glucosidase using p-nitrophenyl α-D-glucopyranoside substrate. The activity of the enzyme is measured based on the absorbance of p-nitrophenol produced from the breaking reaction of the substrate. The results showed that extraction of alpha-glucosidase inhibitor compound with ethyl acetate yielded extract with highest inhibitor activity. Keywords: alpha-glucosidase inhibitors, actinomycetes, diabetes, extraction, fractionation
Il est plus que nécessaire aujourd'hui d'apporter de nouvelles avancées dans le domaine des traitements anti-cancéreux. Il est également bien établi que dans la famille des produits bioactifs d'origine naturelle, les composés azotés sont largement représentés et ce dans la plupart des classes thérapeutiques. Aussi, ces travaux se sont concentrés sur l'obtention de composés azotés bioactifs d'origine naturelle en ciblant des produits cytotoxiques. Ce travail est divisé en trois parties. Tout d'abord, nous avons choisi d'étudier les souches bactériennes associées aux lichens. En effet, le réseau symbiotique complexe que représente le lichen est d'un grand intérêt pour l'identification de nouvelles souches bactériennes avec des potentiels de production de composés d'intérêt et notamment d'un point de vue biotechnologique. Dans un premier temps, un travail d'optimisation des conditions de culture d'une souche d'Actinobactérie, Nocardia sp, isolée à partir d'un lichen, Collema auriforme, a été réalisé dans le but de favoriser la production de composés cytotoxiques. Dans un second temps, l'étude bactériochimique de cette souche a permis l'isolement de 13 composés azotés, dont deux dicétopipérazines bromées qui sont nouvellement décrites ainsi que des dérivés puriques et pyrimidiques. Enfin, un travail de ciblage des composés actifs, par réseaux moléculaires et analyses multivariées de données de spectrométrie de masse, a mis en évidence des molécules potentiellement responsables de l'activité. La seconde partie de ce travail apporte des éléments de réponse sur la nature de la relation bactérie-lichen en observant les effets de certains composés lichéniques sur la croissance et le métabolisme bactériens ainsi qu'en étudiant le potentiel de biotransformation de trois bactéries associées aux lichens (une Firmicutes, une beta-protéobactérie et une Actinobactérie). Les souches sélectionnées ont toutes montré des capacités de biotransformation des composés lichéniques testés (notamment acide usnique et méthyl-beta-orcinolcarboxylate). Enfin, la troisième partie de ce travail décrit une nouvelle méthode d'obtention de composés azotés bioactifs d'origine naturelle par la voie synthétique. Ainsi, une nouvelle méthode de synthèse de la bgugaine, la coniine et la tylophorine a été étudiée et a permis d'obtenir la N-Boc-2-heptylpyrrolidine, démontrant la possibilité de synthétiser des alcaloïdes de type pyrrolidine et d'envisager la synthèse des cibles sélectionnées.
A tert-butyl peroxybenzoate (TBPB) mediated cycloalkylation and formamidation took place effectively in chlorobenzene or in respective formamides at 120 oC, while the former process requires the presence of acetic acid, the later goes in its absence. This radical mediated process gives moderate to good yields of the product having broad substrate scope.
Malaysia hosts a diverse range of medicinal plants having therapeutic values including anticancer properties. Over the years, a group of microorganisms called endophytes producing bioactive compounds similar to their host plants has been discovered. These endophytes, producing important compounds such as Taxol, L-asparaginase, and sclerotiorin, can be isolated and cultured in large scale to produce valuable compounds. This alternative approach of producing bioactive compounds is more sustainable than plants, as endophytes are renewable sources. In this chapter, endophytes from Malaysian medicinal plants have been discussed, highlighting the diversity of endophytes, the valuable compounds produced, the current methods used in biosourcing of endophytes, and the future prospects of anticancer agents derived from endophytes of Malaysian medicinal plants.
A visible-light-mediated radical addition of alkynoates to generate 3-bromocoumarins by using of N-bromosuccinimide as the bromo source has been accomplished. This procedure provides a bromo radical addition/spirocyclization/ester migration cascade reaction under very mild reaction conditions without using of any catalyst or strong oxidant and does not need high reaction temperature. Furthermore, the reaction can also be enlarged to gram scale, and the product 3-bromocoumarins can be further applied in the synthesis of complex compounds.
A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
Of 59 endophytic actinomycetes, were isolated from the roots of Zingiber offici- nale and Alpinia galanga, and tested against Candida albicans and phytopathogenic fungi, Colletotrichum musae and Fusarium oxysporum, ten produced substances that inhibited both phytopathogens and nine had activity against Candida albicans. The strain identified as Streptomyces aureofaciens CMUAc130 was the most effective in antifungal activity amongst those investigated. Moreover, the extracts of its ferment broth had activity against tested fungi at a concentration of 10 mg ml-1.
A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
The proto-oncogene bcl-2 encodes a protein that inhibits programmed cell death (apoptosis). The protein is expressed in basal cells in normal human epithelium, but no data are available on the frequency or clinical importance of its expression in carcinoma. We studied bcl-2 expression in patients with non-small-cell lung carcinoma and correlated this phenomenon with survival.
Immunochemical analysis with a monoclonal antibody specific for bcl-2 was used to detect the protein in tumor samples from 122 patients undergoing surgery for squamous-cell carcinoma (80 patients) or adenocarcinoma (42 patients). The possibility that bcl-2 expression correlated with survival was investigated with use of the log-rank test, hazard ratios, and their confidence intervals.
We detected bcl-2 protein in 25 percent of squamous-cell carcinomas (20 of 80) and 12 percent of adenocarcinomas (5 of 42). In adjacent normal respiratory epithelium, bcl-2 was expressed only in basal cells. Survival at five years was higher among patients with bcl-2-positive tumors, both in the group as a whole (P < 0.1) and in the group with squamous-cell carcinoma (P < 0.02). Patients 60 years of age or older who had bcl-2-positive tumors had the best prognoses, both in the group as a whole (P < 0.02) and in the group with squamous-cell carcinoma (P < 0.01).
The proto-oncogene bcl-2 is abnormally expressed in some lung carcinomas, and its expression may have prognostic importance.
Streptomyces aureofaciens CMUAc130 was isolated from the root tissue of Zingiber officinale Rosc. (Zingiberaceae). It was an antagonist of Colletotrichum musae and Fusarium oxysporum, the causative agents of anthracnose of banana and wilt of wheat, respectively. Evidence for the in vitro antibiosis of S. aureofaciens CMUAc130 was demonstrated by the zone of fungal-growth inhibition. Microscopic observations showed thickness and bulbous structures at the edges of the inhibited fungal hyphae. The culture filtrate and crude extract from this strain were all inhibitory to tested phytopathogenic fungi. The major active ingredients from the culture filtrate of S. aureofaciens CMUAc130 were purified by silica gel-column chromatography and identified to be (i) 5,7-dimethoxy-4-p-methoxylphenylcoumarin and (ii) 5,7-dimethoxy-4-phenylcoumarin by NMR and mass-spectral data, respectively. Bioassay studies showed that compounds (i) and (ii) had antifungal activities against tested fungi, and their MICs were found to be 120 and 150 microg ml(-1), respectively. This is the first report of compounds (i) and (ii) from micro-organisms as active ingredients for the control of phytopathogenic fungi.
The BCL-2 gene was first discovered because of its involvement in the t(14;18) chromosomal translocations commonly found in lymphomas, which result in deregulation of BCL-2 gene expression and cause inappropriately high levels of Bcl-2 protein production. Expression of the BCL-2 gene can also become altered in human cancers through other mechanisms, including loss of the p53 tumor suppressor which normally functions as a repressor of BCL-2 gene expression in some tissues. Bcl-2 is a blocker of programmed cell death and apoptosis that contributes to neoplastic cell expansion by preventing cell turnover caused by physiological cell death mechanisms, as opposed to accelerating rates of cell division. Overproduction of the Bcl-2 protein also prevents cell death induced by nearly all cytotoxic anticancer drugs and radiation, thus contributing to treatment failures in patients with some types of cancer. Several homologs of Bcl-2 have recently been discovered, some of which function as inhibitors of cell death and others as promoters of apoptosis that oppose the actions of the Bcl-2 protein. Many of these Bcl-2 family proteins can interact through formation of homo- and heterotypic dimers. In addition, several nonhomologous proteins have been identified that bind to Bcl-2 and that can modulate apoptosis. These protein-protein interactions may eventual serve as targets for pharmacologically manipulating the physiological cell death pathway for treatment of cancer and several other diseases. © 1996 Wiley-Liss, Inc.
Most members of the Bcl-2 protein family of apoptosis regulating proteins contain two evolutionarily conserved domains, termed BH1 and BH2. Both BH1 and BH2 in the Bcl-2 protein are required for its function as an inhibitor of cell death and for heterodimerization with the proapoptotic protein Bax. In this report, we mapped the region in Bax required for heterodimerization with Bcl-2 and homodimerization with Bax, using yeast two-hybrid and in vitro protein-protein interaction assays. Neither the BH1 nor the BH2 domain of Bax was required for binding to the wild-type Bcl-2 and Bax proteins. Moreover, Bax (Delta BH1) and Bax (Delta BH2) mutant proteins bound efficiently to themselves and each other, further confirming the lack of requirement for BH1 and BH2 for Bax/Bax homodimerization. Bax/Bax homodimerization was not dependent on the inclusion of the NH2-terminal 58 amino acids of the Bax protein in each dimerization partner, unlike Bcl-2/Bcl-2 homodimers which involve head-to-tail interactions between the region of Bcl-2 where BH1 and BH2 resides, and an NH2-terminal domain in Bcl-2 that contains another domain BH4 which is conserved among antiapoptotic members of the Bcl-2 family. Similarly, heterodimerization with Bcl-2 occurred without the NH2-terminal domain of either Bax or Bcl-2, suggesting a tail-to-tail interaction. The essential region in Bax required for both homodimerization with Bax and heterodimerization with Bcl-2 was mapped to residues 59-101. This region in Bax contains a stretch of 15 amino acids that is highly homologous in several members of the Bcl-2 protein family, suggesting the existence of a novel functional domain which we have termed BH3. Deletion of this 15-amino acid region abolished the ability of Bax to dimerize with itself and to heterodimerize with Bcl-2. The findings suggest that the structural features of Bax and Bcl-2 that allow them to participate in homo- and heterodimerization phenomena are markedly different, despite their amino-acid sequence similarity.
Two antileukemic daphnane esters, Pimelea factor P2 (I) and the new compound dircin (II), were isolated from the twigs and flowers of Dirca occidentalis A. Gray (Thymelaeaceae). Three lignans, (−)-medioresinol (III), (+)-syringaresinol (IV), and (−)-lariciresinol (V), as well as the coumarin daphnoretin (VI), were found to be additional cytotoxic constitents of this taxon.
The isolation of endophytic actinomycetes from surface-sterilized tissues of 36 plant species was made using humic acid–vitamin (HV) agar as a selection medium. Of the 330 isolates recovered, 212 were from roots, 97 from leaves and 21 isolates from stems with a prevalence of 3.9, 1.7 and 0.3%, respectively. Identification of endophytic actinomycetes was based on their morphology and the amino acid composition of the whole-cell extract. Most isolates were classified as Streptomyces sp. (n = 277); with the remainder belonging to Microbispora sp. (n = 14), Nocardia sp. (n = 8) and Micromonospora sp. (n = 4). Four isolates were unclassified and 23 were lost during subculture. The most prevalent group of isolates were the Streptomyces sp. occurring in 6.4% of the tissue samples of Zingiber officinale. Scanning electron microscopy investigation of this plant revealed that 7.5% of the root and 5% of the leaf samples contained endophytes. Three of the Streptomyces sp. isolates strongly inhibited Colletotrichum musae, five were very active against Fusarium oxysporum and two strongly inhibited growth of both test fungi.
A number of 2-cyanoindan-1,3-diones and 3-cyano-4-hydroxycoumarins have been prepared and assessed for potential antiallergy activity as measured by their ability to inhibit passive cutaneous anaphylaxis in the rat, mediated by rat serum containing antigen specific IgE. The structural requirements for activity were similar not only for both series of compounds but also for the analogous 2-nitroindan-1,3-diones and 4-hydroxy-3-nitrocoumarins previously reported. The most active compounds were 2-cyano-5,6-diethylindan-1,3-dione (4e) and 3-cyano-6,7-diethyl-4-hydroxycoumarin (11h).
Polymethoxylated flavones and C-glycosyl derivatives isolated from medicinal plants besides other flavonoid compounds were studied for their influence on lipid peroxidation induced by FeSO4+ cysteine in rat liver microsomes. A number of hydroxyflavones (e.g. luteolin); C-glycosyl-flavones (e.g. orientin); methoxyflavones (e.g. gardenin D) and flavonols (e.g. datiscetin), as well as the flavanol leucocyanidol and the biflavone amentoflavone behaved as inhibitors of non-enzymic lipid peroxidation. Structure-activity relationships were established and it was observed that the structural features for active polyhydroxylated compounds were different from those of polymethoxylated flavones, antiperoxidative flavonoids possessing a high lipophilicity.
The antitumor effect of the novel angiogenesis inhibitor O-(Chloroacetyl-carbamoyl) fumagillol, TNP-470 (TNP, s.c.), a synthetic analogue of fumagillin, was studied in combination with cytotoxic agents--mitomycin C (MMC, i.p.), Adriamycin (i.p.), cisplatin (i.p.), and 5-fluorouracil (i.p.), using B16BL6 melanoma (B16 M) and Lewis lung carcinoma in C57BL/6 mice. When the mice were treated on days 3 and 5, addition of MMC (total dose, 5 mg/kg) or 5-fluorouracil (140 mg/kg) to TNP (150 mg/kg) maximally reduced s.c. B16 M volume from 60 to 15% or from 68 to 40% of control, respectively, and addition of MMC (5 mg/kg) to TNP (150 mg/kg) reduced s.c. Lewis lung carcinoma volume from 75 to 62% of control (P < 0.02, compared to the corresponding single drug treatments). During treatment on days 3, 5, 7, 9, and 11, addition of MMC (5 mg/kg) to TNP (150 mg/kg) reduced s.c. B16 M volume from 43 to 6% of control and reduced the number of pulmonary metastasis of i.v. B16 M from 26 to 5% of control (P < 0.001). For established tumors (> 5 mm in maximal diameter), addition of MMC (12-14 mg/kg), Adriamycin (15-17.5 mg/kg), or cisplatin (4 mg/kg, by one shot) to TNP (120-140 mg/kg) with a 6-7 fractionated dosing schedule reduced s.c. B16 M volume from 50 to 20, 24, or 31% of control and reduced s.c. Lewis lung carcinoma volume from 52 to 34, 27, or 34% of control, respectively (P < 0.02). The effect of combination therapy was additive and dose-dependent, and the earlier fractionated dosing schedule exerted more enhanced antitumor effects. TNP reduced the body weight by approximately 10% of control at maximum, but this toxicity was reversible and was not affected by addition of the cytotoxic agents. The results suggest that the combination of angiogenesis inhibitor TNP and standard cytotoxic agents can be a beneficial addition to the treatment of solid tumors.
A family of Bcl-2-related proteins regulates cell death and shares highly conserved BH1 and BH2 domains. BH1 and BH2 domains of Bcl-2 were required for it to heterodimerize with Bax and to repress apoptosis. A yeast two-hybrid assay accurately reproduced this interaction and defined a selectivity and hierarchy of further dimerizations. Bax also heterodimerizes with Bcl-xL, Mcl-1, and A1. A Gly-159-->Ala substitution in BH1 of Bcl-xL disrupted its heterodimerization with Bax and abrogated its inhibition of apoptosis in mammalian cells. This suggests that the susceptibility to apoptosis is determined by multiple competing dimerizations in which Bax may be a common partner.
A novel series of 8-substituted-9,1-[(N-methylimino)methano]- 7-fluoro-5-oxo-5H-thiazolo[3,2-alpha]-quinoline-4-carboxylic acids 5a-q having a unique thiazolopyrazine-incorporated tetracyclic structure were synthesized, and the in vitro and in vivo activities were determined against Gram-positive and Gram-negative bacteria. All compounds 5a-q had more potent activity than ofloxacin (6), which is one of the most popular quinolones, against Gram-positive and Gram-negative bacteria. The 8-pyrrolidinyl, 5a-e, and 8-morpholino, 5p, derivatives showed the most potent activity against Gram-positive bacteria. It is also significant that these compounds, 5a-q, showed more potent antibacterial activity against methicillin-resistant Staphylococcus aureus isolates (MRSA) than ofloxacin (6). The combination of the morpholino group and this unique tetracyclic thiazolopyrazine skeleton contributes to the enhancement of the antibacterial activity against MRSA isolates. The in vivo antibacterial activities of these compounds, 5a-q, were limited and depended on the structure of the 8-substituent. The 8-(4-alkyl-1-piperazinyl) derivatives 5g, 5h, 5j, and 5n provided good oral efficacy and exhibited more potent activity than ofloxacin (6) against the systematic infection with S. aureus IID 803 in mice.
The effects of coumarin (1,2-benzopyrone) on ras oncogene expression during the cell cycle of an MTV-EJras cell line was determined by flow cytometry. ras oncogene expression in cells was induced by dexamethasone and increased fivefold during G1/G0 phase and threefold in S phase. Dexamethasone also increased the percentage of cells in S phase from 21% to 31%, compared to phosphate-buffered-saline-treated control cells (P < 0.01). Coumarin decreased the percentage of dexamethasone-treated cells in S phase from 31% to 19%, with a concomitant increase in the percentage of cells in G1/G0 compared to control levels. Coumarin also reduced ras expression (mean fluorescence) by 40% in G1/G0 phase and 30% in S phase. We conclude that coumarin significantly reduces the cell-cycle progression of MTV-EJras cells and decreases ras expression in both G1 and S phases. These findings suggest a novel approach to the selective control of proliferation of malignant cells.
Whereas apoptosis is a critical mode of cell deletion in normal organism development, apoptotic cells are also observed in tumors, especially following cytotoxic treatments, leading to questions about their role in tumor response to therapy. We have conducted a series of studies using murine tumor models and found that the ability of the tumor cells to undergo apoptosis correlates with tumor response to radiation. The best correlation was with the pretreatment apoptotic index, suggesting that apoptosis in some tumors may govern radiocurability by regulating the number of tumor clonogens. However, other roles for apoptosis in tumor response to radiation have not been ruled out. One of the important observations that has come from this work has been the heterogeneity in apoptosis propensity both within the cell population of a given tumor and among different types of tumors. Such findings underscore the fact that apoptosis is under complex genetic control and that some of the same oncogenes and tumor suppressor genes that are responsible for tumor initiation and progression to malignancy also dictate the apoptotic response to treatment. Understanding the biochemical and molecular pathways that govern this process may ultimately allow the development of strategies for modulating apoptosis for therapeutic benefit.
1. More than 300 coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. More complex related compounds based on the coumarin nucleus include the dicoumarol/warfarin anticoagulants, aflatoxins and the psoralens (photosensitizing agents). 2. Coumarin itself (1,2-benzopyrone) has long-established efficacy in slow-onset long-term reduction of lymphoedema in man, as confirmed in recent double-blind trials against elephantiasis and postmastectomy swelling of the arm. The mechanism of action is uncertain, but may involve macrophage-induced proteolysis of oedema protein. However, coumarin has low absolute bioavailability in man (< 5%), due to extensive first-pass hepatic conversion to 7-hydroxycoumarin followed by glucuronidation. It may, therefore, be a prodrug. 3. Scoparone (6,7-dimethoxycoumarin) has been purified from the hypolipidaemic Chinese herb Artemisia scoparia and shown to reduce the proliferative responses of human peripheral mononuclear cells, to relax smooth muscle, to reduce total cholesterol and triglycerides and to retard the characteristic pathomorphological changes in hypercholesterolaemic diabetic rabbits. Various properties of scoparone were suggested to account for these findings, including ability to scavenge reactive oxygen species, inhibition of tyrosine kinases and potentiation of prostaglandin generation. 4. Osthole (7-methoxy-8-[3-methylpent-2-enyl]coumarin) from Angelica pubescens, used also in Chinese medicine, causes hypotension in vivo, and inhibits platelet aggregation and smooth muscle contraction in vitro. It may interfere with calcium influx and with cyclic nucleotide phosphodiesterases. 5. Cloricromene, a synthetic coumarin derivative, also possesses antithrombotic antiplatelet actions, inhibits PMN neutrophil function and causes vasodilatation. Some of these properties of cloricromene have been ascribed to inhibition of arachidonate release from membrane phospholipids. 6. Simple coumarins possessing ortho-dihydroxy functions, such as fraxetin and 4-methyldaphnetin, are potent inhibitors (low micromolar) of lipid peroxidation and scavengers of superoxide anion radicals and of aqueous alkylperoxyl radicals, but may be pro-oxidant (enhancing generation of hydroxyl radicals) in the presence of free iron ions. These coumarins also inhibit the proinflammatory 5-lipoxygenase enzyme at micromolar concentrations. Another related coumarin, 5,7-dihydroxy-4-methylcoumarin, is of special interest as it inhibits lipid peroxidation, and scavenges alkylperoxyl and superoxide radicals. Unlike most other simple coumarins studied, 5,7-dihydroxy-4-methylcoumarin also scavenges hypochlorous acid, and is a potent inhibitor of cyclo-oxygenase, but is not pro-oxidant. 7. 5,7- and 6,7-dihydroxy-4-methylcoumarin both reduced the duration of ventricular fibrillation in postischaemic reperfused isolated perfused rat hearts (in which oxygen-derived free radicals are implicated), showing that these antioxidant coumarins possess beneficial properties in this pathophysiological model. 8. In view of the established low toxicity, relative cheapness, presence in the diet and occurrence in various herbal remedies of coumarins, it appears prudent to evaluate their properties and applications further.
Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents
cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation
of the apoptotic program, suggesting a possible connection between Bcl-2 and cytochrome c, which is normally located in the
mitochondrial intermembrane space. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol
and a corresponding decrease in the mitochondria. Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria
and the initiation of apoptosis. Thus, one possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release
from mitochondria.
Apoptosis is essential for the precise regulation of cellular homeostasis and development. The role in vivo of Apaf1, a mammalian homolog of C. elegans CED-4, was investigated in gene-targeted Apaf1-/- mice. Apaf1-deficient mice exhibited reduced apoptosis in the brain and striking craniofacial abnormalities with hyperproliferation of neuronal cells. Apaf1-deficient cells were resistant to a variety of apoptotic stimuli, and the processing of Caspases 2, 3, and 8 was impaired. However, both Apaf1-/- thymocytes and activated T lymphocytes were sensitive to Fas-induced killing, showing that Fas-mediated apoptosis in these cells is independent of Apaf1. These data indicate that Apaf1 plays a central role in the common events of mitochondria-dependent apoptosis in most death pathways and that this role is critical for normal development.
Overexpression of the Bax protein in human head and neck squamous cell carcinoma A253 cells was reported to result in an increased sensitivity to various chemotherapeutic agents in vitro (Guo et al., Oncol. Res., 11: 91-99, 1999). In the present study, the relationship between Bax expression and response to chemotherapy was further investigated in vitro and in vivo model systems. For in vitro study, A253, A253/Vec (pcDNA3 vector transfectant), and A253/Bax (pcDNA3/Bax transfectant, expressing 50-fold higher Bax protein than A253 and A253/Vec) cells were exposed to various concentrations of raltitrexed (a specific thymidylate synthase inhibitor) and SN-38 (a topoisomerase I inhibitor) for 2 h, and cell growth inhibition was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide clonogenic assay. Compared to A253/Vec, A253/Bax cells exhibited 9.5- and 13.5-fold increases in sensitivity to raltitrexed and SN-38, respectively. For in vivo study, A253/Vec and A253/Bax tumor xenografts were established by s.c. injection of tumor cells into nude mice. The antitumor activity and toxicity of raltitrexed (i.v. push daily for 5 days) and irinotecan (a prodrug of SN-38; i.v. push daily for 3 days) were evaluated. The maximum tolerated doses of raltitrexed and irinotecan were 30 and 100 mg/kg/day, respectively. At the maximum tolerated doses, minimal antitumor activity was observed with raltitrexed, although irinotecan was more active than raltitrexed against A253 or A253/Vec tumors. In contrast, both raltitrexed and irinotecan were significantly more active against A253/Bax xenografts than against A253/Vec xenografts; the yield for complete tumor regression (cure) was 40% and 100% with raltitrexed and irinotecan, respectively, with no significant toxicity. Furthermore, the observed increase of antitumor activity in A253/Bax tumors was associated with an enhanced induction of apoptosis in vivo. The in vivo results demonstrated a proof of the principal concept that selecting up-regulation of the proapoptosis gene Bax can provide the basis for a greater therapeutic efficacy to a variety of chemotherapeutic agents with different structures and mechanisms of action.
Twenty-one coumarins were examined for their antiproliferative activity towards several cancer cell lines, namely lung carcinoma (A549), melanin pigment producing mouse melanoma (B16 melanoma 4A5), human T-cell leukemia (CCRF-HSB-2), and human gastric cancer, lymph node metastasized (TGBC11TKB). The structure-activity relationship established from the results revealed that the 6,7-dihydroxy moiety had an important role for their antiproliferative activity. Analysis of cell cycle distribution indicated that esculetin-treated cells accumulated in the G1 (at 400 microM) or in S phase (at 100 microM).
The serine-threonine kinase Akt exerts its anti-apoptotic effects through several downstream targets, including the pro-apoptotic Bc1-2 family member Bad, Forkhead transcription factors, and the cyclic AMP response element-binding protein (CREB). In this report we demonstrate that Akt inhibits a conformational change in the pro-apoptotic Bax protein and its translocation to mitochondria, thus preventing the disruption of the mitochondrial inner membrane potential (DeltaPsi(m)), caspase-3 activation, and apoptosis in pre-B hematopoietic cells FL5.12 following interleukin-3 (IL-3) withdrawal. Inhibition of PI-3 kinase, but not MAPK kinase, promotes this conformational change in Bax. Moreover, overexpression of Akt suppresses the relocalization of GFP-Bax to mitochondria and apoptosis in Hela cells induced by the DNA-damaging agent methyl methanesulphonate. However, Akt does not abolish the ability of a conformationally changed Bax mutant, GFP-Bax (DeltaS184), to translocate to mitochondria and to induce apoptosis. These findings indicate that Akt exerts its anti-apoptotic effects in cells at a premitochondrial stage, at least in part, by inhibiting Bax conformational change and its redistribution to the mitochondrial membranes.
The synthesis of several novel coumarin derivatives with a 7-azomethine linkage was carried out starting from 7-formyl-coumarin. The compounds were tested in vivo for their anti-inflammatory activity and in vitro for their antioxidant ability. Compounds 3a and 3e possess significant protection against carrageenin induced rat paw edema.
Treatment of 3-hydroxy-beta-lapachone 4 with ylide 5 gave the coumarin derivative 7a, which was transformed to compounds 10-14. Compound 14 was then transformed to benzo[f]seselin 15 as well as to benzo[l]khellactones 16, 18 from which the title compounds 17, 19(I), 19(II), 20, 21(I) and 21(II) were prepared. All the tested compounds were found to interact with DPPH in a concentration and time dependent manner. All the tested compounds highly inhibited the soybean lipoxygenase, whereas compounds 12, 17 and 19(II) highly compete with DMSO for (*)OH. Compounds 7a, 7b, 12 and 17 induced at 48.7-58.9% protection against carrageenin induced rat paw edema.
A series of 4-hydroxycoumarin derivatives was prepared and evaluated for antitumor activity against five human tumor cell lines. A series of 4-hydroxycoumarin derivatives was prepared and evaluated for antitumor activity. The key fragments were 2a-c, 5c, 12b, 13b, 17, and 18 which were prepared via dianion ring cyclization, Friedel-Crafts acylation, and Reformatsky reaction. Compound 20b showed the most potent antitumor activity among the total 12 derivatives and compounds 19a and 19b exhibited efficacy comparable to etoposide in vitro antitumor activity.
Several natural products with a coumarinic moiety have been reported to have multiple biological activities. It is to be expected that, in a similar way to isomeric flavonoids, coumarins might affect the formation and scavenging of reactive oxygen species (ROS) and influence processes involving free radical-mediated injury. Coumarin can reduce tissue edema and inflammation. Moreover coumarin and its 7-hydroxy-derivative inhibit prostaglandin biosynthesis, which involves fatty acid hydroperoxy intermediates. Natural products like esculetin, fraxetin, daphnetin and other related coumarin derivatives are recognised as inhibitors not only of the lipoxygenase and cycloxygenase enzymic systems, but also of the neutrophil-dependent superoxide anion generation. Due to the unquestionable importance of coumarin derivatives considerable efforts have been made by several investigators, to prepare new compounds bearing single substituents, or more complicated systems, including heterocyclic rings mainly at 3-, 4- and/or 7-positions. In this review we shall deal with naturally occurring or synthetically derived coumarin derivatives, which possess anti-inflammatory as well as antioxidant activities.
Vitamin K is an essential cofactor for the synthesis of several blood coagulation factors. It has been suggested that the apolipoprotein E (ApoE) genotype has profound effects on vitamin K status. Therefore, we investigated whether this common genetic polymorphism influenced dose requirements and effects of coumarin anticoagulants.
We did a cohort study in 1637 patients from an outpatient anticoagulation clinic treated with acenocoumarol or phenprocoumon.
To attain the same level of anticoagulation, patients with genotype epsilon4/epsilon4 and genotype epsilon3/epsilon4 required respectively 3.4 mg (95%CI: -6.0 to -0.9) and 0.8 mg (95%CI: -1.6 to 0.1) acenocoumarol per week less than patients with genotype epsilon3/epsilon3. Patients homozygous for the epsilon2 allele required 3.5 mg (95%CI: 0.1 to 6.9) acenocoumarol per week more than patients with genotype epsilon3/epsilon3. The acenocoumarol maintenance dose showed a gene dose effect of the epsilon4 allele, but not of the epsilon2 allele. No significant dose difference was observed for phenprocoumon, possibly because of low numbers.
The ApoE genotype affects the dose requirements of acenocoumarol.
Thailand Research Fund MRG4980137 and Faculty of Science
- Source
- Support
Source of Support: Thailand Research Fund MRG4980137
and Faculty of Science, Silpakorn University, Nakorn Pathom,
Thailand, Confl ict of Interest: None declared.
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