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Abstract
Nature has been a source of medicinal agents for thousands of years and continues to be an abundant source of novel chemotypes and pharmacophores. With only 5 to 15% of the approximately 250 000 species of higher plants systematically investigated, and the potential of the marine environment barely tapped, these areas will remain a rich source of novel bioactive compounds. Less than 1% of bacterial and 5% of fungal species are currently known, and the potential of novel microbial sources, particularly those found in extreme environments, seems unbounded. To these natural sources can be added the potential to investigate the rational design of novel structure types within certain classes of microbial metabolites through genetic engineering. It is apparent that Nature can provide the novel chemical scaffolds for elaboration by combinatorial approaches (chemical and biochemical), thus leading to agents that have been optimized on the basis of their pharmacological activities. The proven natural product drug discovery track record, coupled with the continuing threat to biodiversity through the destruction of terrestrial and marine ecosystems and the current low number of new chemical entities in pharmaceutical industry pipelines, provides a compelling argument in favor of expanded multidisciplinary and international collaboration in the exploration of Nature as a source of novel leads for the development of drugs and other valuable bioactive agents.
... The Egyptian Ebers Papyrus (2900 BC) documents up to 700 plant-based drugs to create prescriptions, ointments, potions, inhalers, and pills to cure certain conditions. Opium, cannabis, and linseed oil were used (Cragg and Newman, 2005). The Chinese materia medica (1100 BC) (Wu Shi Er Bing Fang, comprises 52 prescriptions), Shennong Herbal (~100 BC, 365 drugs), and the Tang Herbal (659 AD, 850 drugs) are documented archives of the utilization of NPs (Cragg and Newman, 2005). ...
... Opium, cannabis, and linseed oil were used (Cragg and Newman, 2005). The Chinese materia medica (1100 BC) (Wu Shi Er Bing Fang, comprises 52 prescriptions), Shennong Herbal (~100 BC, 365 drugs), and the Tang Herbal (659 AD, 850 drugs) are documented archives of the utilization of NPs (Cragg and Newman, 2005). The Greek physician Hippocrates, , the father of modern ...
... Although these bioactive molecules have perfect chemical diversity, less than 10% of the globe's biodiversity has been evaluated for potential biological activity. Numerous beneficial natural lead compounds await discovery, with the challenge being accessing this natural chemical diversity [1]. and membrane lipids, and leading to cell death. ...
... Then the MTT reduction product (formazan) was dissolved in 100 µL of DMSO with continuous shaking, and absorbance was read at 570 nm and 630 nm using an ELISA reader [35]. The cell viability was calculated using the below formula: % Cell viability = OD of treated cells OD of Untreated cells R 1 × 100 (2) ...
... Although these bioactive molecules have perfect chemical diversity, less than 10% of the globe's biodiversity has been evaluated for potential biological activity. Numerous beneficial natural lead compounds await discovery, with the challenge being accessing this natural chemical diversity [1]. and membrane lipids, and leading to cell death. ...
... Then the MTT reduction product (formazan) was dissolved in 100 µL of DMSO with continuous shaking, and absorbance was read at 570 nm and 630 nm using an ELISA reader [35]. The cell viability was calculated using the below formula: % Cell viability = OD of treated cells OD of Untreated cells R 1 × 100 (2) ...
Rhizospheric soil is the richest niche of different microbes that produce biologically active metabolites. The current study investigated the antimicrobial, antifungal and anticancer activities of ethyl acetate extract of the potent rhizospheric fungus Aspergillus niger AK6 (AK-6). A total of six fungal isolates were isolated, and isolate AK-6 was selected based on primary screening. Further, it exhibited moderate antimicrobial activity against pathogens such as Klebsiella pneumonia, Candida albicans, Escherichia coli, Shigella flexneri, Bacillus subtilis and Staphylococcus aureus. The morphological and molecular characterization (18S rRNA) confirmed that the isolate AK-6 belonged to Aspergillus niger. Further, AK-6 showed potent antifungal activity with 47.2%, 59.4% and 64.1% of inhibition against Sclerotium rolfsii, Cercospora canescens and Fusarium sambucinum phytopathogens. FT-IR analysis displayed different biological functional groups. Consequently, the GC-MS analysis displayed bioactive compounds, namely, n-didehydrohexacarboxyl-2,4,5-trimethylpiperazine (23.82%), dibutyl phthalate (14.65%), e-5-heptadecanol (8.98%), and 2,4-ditert-butylphenol (8.60%), among the total of 15 compounds isolated. Further, the anticancer activity of AK-6 was exhibited against the MCF-7 cell line of human breast adenocarcinoma with an IC50 value of 102.01 μg/mL. Furthermore, flow cytometry depicted 17.3%, 26.43%, and 3.16% of early and late apoptosis and necrosis in the AK-6 extarct treated MCF-7 cell line, respectively. The results of the present analysis suggest that the isolated Aspergillus niger strain AK-6 extract has the potential to be explored as a promising antimicrobial, antifungal and anticancer drug for medical and agricultural applications.
... Antioxidants also turn free radicals into waste by-products, which are eliminated from the body. 1 India is among the biggest producer of herbal medicines. Be that as it may, because of complex nature of herbal extract, expansive dosages, poor bioavailability and dose frequency, there use in present day therapeutic framework is restricted. ...
The objective of the present study was to prepare phytosomal formulation loaded with aqueous extract of Pithecellobium bijeninum leaves. The extraction of leaf powder was done by maceration technique using 90:10 ethanol-water mixture with an extraction yield of 6.12%. The extract was found to contain alkaloids, and flavonoids and the total phenolic content was found to be 23.2 ± 0.827 %w/w. Phytosomes of the extract were prepared by solvent evaporation method using lecithin as the lipid molecule. The particle size of the phytosomes was from 468 nm to 1827 nm in size with a polydispersity index varying between 0.178 - 0.464. The phytosomes were visible as rigid, almost spherical vesicles in SEM image. The surface of the phytosome vesicles was found to be regular and smooth. The point prediction suggested level 3 (0.3 g) of lipid concentration and level 2 (0.2 g) of extract concentration to present the lowest particle size. Sharp and distinct endothermic peaks in DSC revealed the formulation of stable phytosomes due to molecular interactions between the extract and lecithin. The phytosomes were found to possess good antioxidant action against DPPH radical in the in vitro scavenging assay. The IC50 value of the extract against DPPH was found to be 48.24 µg and that of the phytosomal formulation loaded with the extract (F4) was obtained to be 48.90 µg. KEYWORDS: Phytosome, extraction, lecithin, Pithecellobium, antioxidant
... Historically, plants have been an invaluable source of bioactive compounds, with many traditional medicines derived from plant extracts [9][10][11][12]. In recent years, advances in plant biotechnology and natural product discovery have shed light on the untapped potential of plants as a rich reservoir of antimicrobial agents [13][14][15][16][17][18]. ...
Antimicrobial resistance (AMR) poses a critical global health challenge, jeopardizing the efficacy of infectious disease treatments and necessitating innovative solutions. The exploration of plants, renowned for their wealth of bioactive compounds, as sustainable sources of antimicrobials is gaining momentum. Sansevieria, a succulent plant genus, boasts ornamental, medicinal, and pollution-remediating attributes owing to its phytochemical richness. Notably, specific species exhibit inherent antimicrobial properties, positioning them as promising reservoirs of alternative antimicrobial agents. Efficient cultivation methods are imperative for the economically viable production of Sansevierias with potential medicinal benefits. In addressing this need, in vitro micropropagation emerges as a strategic solution, enabling mass multiplication and germplasm conservation. Leveraging our previous success in achieving efficient in vitro regeneration of Sansevieria trifasciata through elevated temperatures and auxin supplementation, we present a novel PTC-assisted antimicrobial elicitation platform. This innovative approach resulted in significantly augmented biomass production, heightened concentrations of potent phytochemicals, and increased antibacterial activity in tissue extracts compared to their field-grown counterparts. Gas chromatography-mass spectrometry (GCMS) profiling confirmed the upregulation of phytochemicals known for their antibacterial efficacy. Notably, Citronellol, 7,8-Epoxylanostan-11-ol, 3-acetoxy, and several new compounds were markedly elevated in PTC-raised Sansevieria trifasciata. Our study furnishes compelling evidence for the efficacy of in vitro techniques in enhancing the growth and phytochemical profiles of Sansevieria plants. This opens new avenues for their commercial production, particularly in addressing the challenges posed by antimicrobial resistance. Importantly, this study represents the first exploration of phytochemical bioprospecting in the Sansevieria genus through in vitro tissue culture endeavors.
... Over the past two decades, herbal medicine practice and the use of natural therapies have increased significantly in industrialized countries (Van Andel and Carvalheiro, 2013;Ekor, 2014;Oyebode et al., 2016;James et al., 2018;Welz et al., 2018;Tangkiatkumjai et al., 2020). Pharmaceutical establishments use medicinal plants as starting material for the production of other semi-synthetic pharmacologically active substances as seen in many drugs (Cragg and Newman, 2005;Arceusz et al., 2010;Hao and Xiao, 2020;Newman and Cragg, 2020;Salmerón-Manzano et al., 2020). About thirty percent of drugs sold worldwide contain compounds derived from plant material (Wachtel-Galor and Benzie, 2011;WHO, 2013;Calixto, 2019). ...
... Secondary metabolites serve as competitive weapons used against other bacteria, fungi, amoebae, plants, insects, and large animals (Bell and Charlwood, 1981) metal transporting agents, as agents of symbiosis between microbes and plants, nematodes, insects, and higher animals, as sexual hormones, as differentiation effectors (Demain and Fang, 2000). Humans use secondary metabolites as medicines, flavourings and recreational drugs (Cragg andNewman, 2005, Eswaraiah, 2020) Secondary metabolism plays a pinnacle role in keeping all of the plants systems working properly. Secondary plant metabolites are also used in signaling and regulation of primary metabolic pathways. ...
... Similarly, quinine is a Food and Drug Administration (FDA) approved drug against malaria, procured from Cinchona succirubra Pav. ex Klotsch bark, Pilocarpine, a drug against acute angleclosure and chronic open-angle glaucoma derived from Pilocarpus jaborandi (Rutaceae) revels that plant-based drug investigation is an incredible consideration in order to find new molecules having high medicinal reputes 3,4 . Therapeutic herbs contain a rich well spring of naturally powerful molecules having significant medicinal importance like alkaloids, glycosides, tannins, saponins, sterols, direct phenolic blends, quinones, terpenoids, carotenoids, flavonoids, polyphenols, terpenoids, sugars, proteins, synthetic concoctions, fats and oils, minerals, supplements and so on. ...
From the primitive era to the current generation, natural extracts or products played the most conservative therapeutic and nutritional resources. Starting from the era of folklore or ancient, mother nature has protected us from various diseases by producing various natural products having strong medicinal implications like quinine, taxol, vinblastine, etc. Among the many available sources of natural products, pharma-herb being a new member has drawn considerable attention of the researcher in order to have a new pool of products having pronounced pharmaceutical activity. Now Basella alba is one of the brightest candidates belonging to pharma-herb because of its considerably enriched pharmacologically important product stocks like vitamin C, flavonoid compounds, carotenoids, saponins as well as a large number of different minerals and numerous amino acids. This plant is a perennial vine that is often cultivated as a food crop during the cooler months. It is also able to grow very fast and can resist temperatures that are quite high. Basella alba has been referred to by a number of different names throughout history, including Indian-, Malabar-, climber-, Ceylon-, and vine-spinach. Poi is the term that the majority of people in India use when referring to it. The various natural products isolated from B. alba have significant medicinal utilization because of its antimicrobial, anti-ulcer, wound healing, antiviral, anti- inflammatory depressant, androgenic potential, hepatoprotective, antidiabetic, antioxidant, anti-anxiety, diuretic and antiurolithiatic activities. This review will cover a detailed journey about Basella alba L. ranging from phytochemical to toxicological, morphological, pharmacological as well as medicinal importance.
... Since 1981, chemical factors derived from herbal and plants, as well as their derivatives and mimetic compounds have represented almost two-thirds of the new small-molecule drugs. 1,2 The Cannabis sativa plant has more than 445 thousand chemical compounds, including cannabinoids, terpenes, and flavonoids. At least 120 of these phytochemicals have been identified as cannabinoids, of which the most abundant are cannabidiol (CBD) and D-9-tetrahydrocannabinol (D 9 -THC). ...
Introduction: Cannabidiol (CBD), the main non-psychoactive cannabinoid of the Cannabis sativa plant, is a powerful antioxidant compound that in recent years has increased interest due to causes effects in a wide range of biological functions. Zika virus (ZIKV) is a virus transmitted mainly by the Aedes aegypti mosquitoes, which causes neurological diseases, such as microcephaly and Guillain-Barre syndrome. Although the frequency of viral outbreaks has increased recently, no vaccinations or particular chemotherapeutic treatments are available for ZIKV infection. Objectives: The major aim of this study was to explore the in vitro antiviral activity of CBD against ZIKV, expanding also to other dissimilar viruses. Materials and Methods: Cell cultures were infected with enveloped and nonenveloped viruses and treated with non-cytotoxic concentrations of CBD and then, viral titers were determined. Additionally, the mechanism of action of the compound during ZIKV in vitro infections was studied. To study the possible immunomodulatory role of CBD, infected and uninfected Huh-7 cells were exposed to 10 μM CBD during 48 h and levels of interleukins 6 and 8 and interferon-beta (IFN-β) expression levels were measured. On the other hand, the effect of CBD on cellular membranes was studied. For this, an immunofluorescence assay was performed, in which cell membranes were labeled with wheat germ agglutinin. Finally, intracellular cholesterol levels were measured. Results: CBD exhibited a potent antiviral activity against all the tested viruses in different cell lines with half maximal effective concentration values (CE50) ranging from 0.87 to 8.55 μM. Regarding the immunomodulatory effect of CBD during ZIKV in vitro infections, CBD-treated cells exhibited significantly IFN-β increased levels, meanwhile, interleukins 6 and 8 were not induced. Furthermore, it was determined that CBD affects cellular membranes due to the higher fluorescence intensity that was observed in CBD-treated cells and lowers intracellular cholesterol levels, thus affecting the multiplication of ZIKV and other viruses. Conclusions: It was demonstrated that CBD inhibits structurally dissimilar viruses, suggesting that this phytochemical has broad-spectrum antiviral effect, representing a valuable alternative in emergency situations during viral outbreaks, like the one caused by severe acute respiratory syndrome coronavirus 2 in 2020.
... [3] A long-term program conducted by the National Cancer Institute (NCI) from 1955 to 1982, which screened plant extracts, led to the discovery of numerous natural or semi-synthetic anticancer agents such as paclitaxel, topotecan, and irinotecan. [4] Since then, various groups have screened plants from different geographical regions for anticancer properties. [5][6][7] These studies varied in terms of the number of plants, cell lines, treatment duration, and the methods used to detect cytotoxicity. ...
Anatolia is rich in floristic diversity with a high rate of endemism. Eight plant species from northwestern Anatolia were evaluated for their anti-growth properties in two malignant (MCF-7 and MDA-MB-231) and a non-malignant (MCF-10A) breast cell line. The two most active extracts, Achillea multifida (AME) and Astragalus sibthorpianus (ASE), induced apoptotic cell death in all cell lines. The major phenolic compounds in AME were identified as chlorogenic acid, and catechins in ASE. ASE displayed selective cytotoxicity against breast cancer cells, with DNA damage repair in non-malignant cells contributing to its selectivity. Conversely, AME induced DNA damage in a time-dependent manner and displayed a dual dose-dependent biological activity, resulting in mitotic catastrophe and apoptosis at different doses. Most plant species exhibited moderate to strong cytotoxicity, highlighting their medicinal and economic potential and the need for their protection.
... It has been estimated that about 5000 plant species have been studied in detail as possible sources of new drugs (Tantry, 2009) [54] . Since less than 10% of the world's biodiversity has been evaluated for potential biological activity, many more useful natural lead compounds await discovery with the challenge being how to ac-cess this natural chemical diversity (Cragg and New-man, 2005) [9] . ...
... In recent times, plants are being extensively explored for harboring medicinal properties. Studies by various researchers have proved that plants are one of the major sources for drug discovery and development (Rates, 2001), Gordon and David (2005). Plants are reported to have antimicrobial, anticancer, anti inflammatory, antidiabetic, hemolytic, antioxidant, larvicidal properties etc. ...
During the present investigation, in vitro studies were carried out to evaluate the antibacterial and antifungal activity of two selected plant species viz, Calotropis procera and Citrullus colocynthis. Ethanolic, methanolic and aqueous extracts of leaf were examined for their antibacterial, antifungal activities. Methanolic leaf extracts were found to be more active against gram positive bacteria (Bacillus subtilis: ATCC 6059 and Staphylococcus aureus: ATCC 6538) as well as gram negative bacteria (Pseudomonas aeruginosa: ATCC 7221 and Klebsiella pneumoniae) than water and ethanol extracts of leaves. The leaf extracts from C. colocynthis showed greater inhibitory activity against gram positive and gram negative bacteria as compared to that of C. procera leaf extract. Antifungal activity of the two plant species was performed with both methanolic and aqueous extract against Aspergillus fumigatus. The results revealed that methanolic as well as aqueous extract of C. procera were found to be most effective in inhibiting the growth of selected fungal strain. It is inferred from the present investigation that the ability of extracts of C. colocynthis and C. procera to inhibit the growth of bacteria and fungi is an indication of their broad spectrum antimicrobial potential which may be implicated in the management of microbial infections.
... Molecular function emerges from structure, but it is not always obvious how this emerges from first principles due to the dependence of function on the target molecule [1]. Traditionally, exploration of natural products has led to the identification of vital pharmaceuticals and specialty chemicals [2][3][4][5]. These first generation molecules act as starting points, upon which new molecules are engineered for furthering desired functionality [6]. ...
Chemical similarity searches are widely used in-silico methods for identifying new drug-like molecules. These methods have historically relied on structure-based comparisons to compute molecular similarity. Here, we use a chemical language model to create a vector-based chemical search. We extend implementations by creating a prompt engineering strategy that utilizes two different chemical string representation algorithms: one for the query and the other for the database. We explore this method by reviewing the search results from five drug-like query molecules (penicillin G, nirmatrelvir, zidovudine, lysergic acid diethylamide, and fentanyl) and three dye-like query molecules (acid blue 25, avobenzone, and 2-diphenylaminocarbazole). We find that this novel method identifies molecules that are functionally similar to the query, indicated by the associated patent literature, and that many of these molecules are structurally distinct from the query, making them unlikely to be found with traditional chemical similarity search methods. This method may aid in the discovery of novel structural classes of molecules that achieve target functionality.
... Serendipity and man's expedition for the drug in nature inaugurated the discovery of medicines. Nature has been an incredible cradle of medicinal agents since ages where a striking number of modern drugs have been isolated from natural sources, many of these derivations were grounded on the utilization of the agents in traditional medicine [1]. Since a long, plants have been exploited as medicines. ...
... Archaeological evidence shows that Iraq and China have used herbal medicine for 6,000 and 8,000 years ago, respectively (Leroi-Gourhan, 1975;Pan et al., 2014). The earliest records of natural products are from Mesopotamia (2600 B.C.), where clay tablets documented the use of oils derived from Commiphora species (myrrh) and Cupressus sempervirens L. (Cypress) to treat coughs, colds, and inflammation (Cragg and Newman, 2005). In the past 40 years, both developing and developed countries have used more herbs and herbal products for health. ...
... Archaeological evidence shows that Iraq and China have used herbal medicine for 6,000 and 8,000 years ago, respectively (Leroi-Gourhan, 1975;Pan et al., 2014). The earliest records of natural products are from Mesopotamia (2600 B.C.), where clay tablets documented the use of oils derived from Commiphora species (myrrh) and Cupressus sempervirens L. (Cypress) to treat coughs, colds, and inflammation (Cragg and Newman, 2005). In the past 40 years, both developing and developed countries have used more herbs and herbal products for health. ...
Advances in biomedical research have demonstrated that inflammation and its related diseases are the greatest threat to public health. Inflammatory action is the pathological response of the body towards the external stimuli such as infections, environmental factors, and autoimmune conditions to reduce tissue damage and improve patient comfort. However, when detrimental signal-transduction pathways are activated and inflammatory mediators are released over an extended period of time, the inflammatory process continues and a mild but persistent pro-inflammatory state may develop. Numerous degenerative disorders and chronic health issues including arthritis, diabetes, obesity, cancer, and cardiovascular diseases, among others, are associated with the emergence of a low-grade inflammatory state. Though, anti-inflammatory steroidal, as well as non-steroidal drugs, are extensively used against different inflammatory conditions, they show undesirable side effects upon long-term exposure, at times, leading to life-threatening consequences. Thus, drugs targeting chronic inflammation need to be developed to achieve better therapeutic management without or with a fewer side effects. Plants have been well known for their medicinal use for thousands of years due to their pharmacologically active phytochemicals belonging to diverse chemical classes with a number of these demonstrating potent anti-inflammatory activity. Some typical examples include colchicine (alkaloid), escin (triterpenoid saponin), capsaicin (methoxy phenol), bicyclol (lignan), borneol (monoterpene), and quercetin (flavonoid). These phytochemicals often act via regulating molecular mechanisms that synergize the anti-inflammatory pathways such as increased production of anti-inflammatory cytokines or interfere with the inflammatory pathways such as to reduce the production of pro-inflammatory cytokines and other modulators to improve the underlying pathological condition. This review describes the anti-inflammatory properties of a number of biologically active compounds derived from medicinal plants, and their mechanisms of pharmacological intervention to alleviate inflammation-associated diseases. The emphasis is given to information on anti-inflammatory phytochemicals that have been evaluated at the preclinical and clinical levels. Recent trends and gaps in the development of phytochemical-based anti-inflammatory drugs have also been included.
... Higher plants, a source of bioactive compounds and play a main role in the maintenance of human health since ancient times (Agnel RA and Mohan VR.) [1] (Amutha IDJ and Kottai MA.) [2]. Large numbers of modern clinical drugs are of natural plant origin and natural products play important role in drug discovery (Cragg GM and Newman DJ.) [3]. The medicinal value of plants lies in some bioactive constituents that possess a definite physiological action on the human body. ...
Cis-Z-alpha-bisabolene epoxide (bisabolene) compound is extracted from Cassia fistula plant bark, which is a medicinal tree that contains many useful drug substances, the compound can act as a drug predictably similar to vitamin E, with the same function as an antioxidant which can act on pregnane X receptor on the body cells. The gas chromatography-mass spectrometry (GC-MS) analysis was used to identify the constituents of the n-hexane extract. Drug Bank was used to find similar compounds. The ID of the pregnane x receptor (PXR) was retrieved from the PDB database. Then the bisabolene ligand was used for docking with the receptor using Swiss Dock. Finally, the Swiss ADME was used to study and predict the pharmacological parameters. It was found that bisabolene can act as an antioxidant and alternative to vitamin E in the pregnane x receptor and with good pharmacological predicted results. When bisabolene is used as an effective ligand with pregnane X receptor alternative to vitamin E, care must be taken because the compound can penetrate the blood-brain barrier (BBB) with a specific amount.
... Hadavand Mirzaei H et al. report the effects of three potent anticancer terpenoids previously isolated from Salvia lachnocalyx, including geranyl farnesol (1), sahandinone (2), and 4-dehydrosalvilimbinol (3) on cancer cell cycle alterations and reactive oxygen species (ROS) production. Interactions of compounds 1-3 with topoisomerase I were also investigated by using molecular docking and dynamics simulation. ...
... The phytochemical research based on ethanopharmacological information is considered an effective 3 . The chemical substances used by plants for approach in the discovery of new agents from higher plants defense system and serve as the bioactive principle for various drugs in modern chemotherapy 4 .The GCMS is composed of two major building blocks; the gas chromatograph and the Mass spectrometer. The gas chromatograph utilizes a capillary column which depends on the columns dimension as well as the phase properties. ...
... The bioactive secondary metabolites such as alkaloids, phenolics, essential oils and terpenes, sterols, flavonoids, lignins, tannins, etc. are present in different parts of medicinal plants (Fig. 13.3) (Ramawat et al. 2009). It is estimated that 60% of anti-infectious drugs already on the market or undergoing clinical trials are of natural origin (Cragg and Newman 2005;Newman and Cragg 2020). ...
Drug resistance is currently acknowledged as the most concerning healthcare issue worldwide. Antibiotic resistance in all clinically significant pathogens, a halt in the discovery and development of new antibiotics, and recurrent infections brought on by multidrug-resistant pathogens are some of the problematic aspects of the current antibiotic crisis that affect both developing and developed countries. All these issues are impeding the effectiveness of conventional antibiotics as a therapeutic option, which is why non-traditional approaches are becoming more popular. Despite several non-traditional approaches to fight drug resistance have gained interest, their use is restricted since they call for advanced diagnostics that go beyond pathogen identification, and only a few therapies have reached late-stage clinical trials. Exotoxin-targeted therapies are one of the most advanced non-traditional therapies used to treat infections caused by Staphylococcus aureus and Clostridium difficile. Another important non-traditional approach to treat or prevent C. difficile infection is the microbiome therapy. It is more likely that after approval of any non-traditional therapy, it would be used concomitantly with antibiotics to fudge multidrug resistance. This chapter discusses the characteristics of such unconventional therapies and how they can be applied to treat multidrug-resistant diseases.
... The term "modern medicine" refers to the numerous compositions that are established in a scientific way by trying to make use of sophisticated technology and knowledge of how they are now implemented in sophisticated pharmacopoeias for the purpose of treating diseases and improving health. These compounds are used in modern medicine to treat and prevent infection (Cragg and Newman, 2005). Scientists worked hard to discover and isolate bioactive components with therapeutic applications, which are now used in the manufacturing of modern medicine. ...
The aim of this study was to determine the anthelmintic activity of ethanolic extract of F. racemosa against bovine parasite. After that, the isolated compounds were put through molecular docking and an ADME/T evaluation. The current investigation includes the use of ethanol extraction on dried leaves. The anthelmintic activity of the compound was determined with the help of an experimental model utilizing the worm Paramphistomum cervi, Schrödinger-Maestro v10.1 docking fitness was then used to conduct a molecular docking analysis to discover compounds with the highest activity against the Tubulin-Colchicine enzyme. Moreover, the Swiss ADME online-based application was used to review the ADME/T profiles. Preliminary phytochemical screening of ELFR revealed that it contains alkaloids, glycoside, flavonoids, tannins, gums, carbohydrate and quinone. ELFR showed a dose-dependent and statistically significant anthelmintic activity on experimental worm (Paramphistomum cervi). ELFR having a concentration of 200 mg/ml showed lowest paralysis and death time of 8.33 and 12.84 min, respectively, which is comparable with that of standard drug albendazole. Moreover, the molecular docking study reveals that among the seven compounds isolated from the plant, β-sitosterol has the best docking score of-15.4 kcal/mol against Tubulin-Colchicine and ADME/T analysis using web-based tool ensures that the compound has not violated Lipinski's rule of five indicating its safety consumption. The findings from both in vitro and in silico studies corroborate the anthelmintic activity of Ficus racemosa leaves. The data support beta-sitosterol to be a potential anthelmintic agent worthy of further comprehensive clinical studies and exploring its drug-like properties.
... Due to these evolutionary processes, natural compounds consist of various biological activities in different races. Because of these characteristics, the wide range of products from natural resources are identified as privileged structural molecules [2,3]. They are highly diverse with respect to structure, pharmacological, and physiological properties. ...
Natural products and their derivatives are the most promising and prolific resources in identifying the therapeutic small compounds with potential therapeutic activity. Nowadays, working with herbal or natural products can be boosted by collecting the data available for their chemical, pharmacological, and biological characteristics properties. Using in silico tools and methods, we can enhance the chances of getting a better result in a precise way. It can support experiments to emphasis their sources in fruitful directions. Though due to their limitations with respect to current knowledge, quality, quantity, relevance of the present data as well as the scope and limitations of cheminformatics methods, herbal product-based drug discovery is limited. The pharmaceutical re-profiling is done with the main objective to establish strategies by using approved drugs and rejected drug candidates in the diagnosis of new diseases. Drug repurposing offers safety lower average processing cost for already approved, withdrawn drug candidates. In silico methods could be oppressed for discovering the actions of un-investigated phytochemicals by identification of their molecular targets using an incorporation of chemical informatics and bioinformatics along with systems biological approaches, hence advantageous for small-molecule drug identification. The methods like rule-based, similarity-based, shape-based, pharmacophore-based, and network-based approaches and docking and machine learning methods are discussed.
Exposure to gamma irradiation (γ-IR) causes cellular alterations (CA) in animals. Extract of Adansonia digitata and Corchorus olitorius leaves (ADCOL) have been shown to protect against γ-IR-induced CA in rats. Traditionally, the leaves are consumed as part of diets, however, there is paucity of scientific information on the use of ADCOL based-diet (BD) against CA. Thus, the study investigated the effects of ADCOL BD in cellular system of irradiated rats. The objectives of the study were to determine the secondary metabolites in ADCOL, induce cellular alterations in rats and evaluate the protective, ameliorative and toxicity of ADCOL BD on rats. A total of 72 rats (186 ± 4.90g) were used in the 2 phases of this study. In the ameliorative phase, 36 rats were assigned into 6 groups of 6 each; Group I were fed with rat chow and distilled water only, all other groups were irradiated, such that, Groups II III, IV, V & VI were fed rat chow only, 80% inclusion of ADBD, 80% inclusion of COBD, 80% inclusion of combined ADCOLBD and Vitamin-C-BD respectively. Similar design was adopted for protective phase, except that, the rats were initially fed the inclusion diet before irradiation. Micronuclei status were viewed by automated electron microscope, p53 level was determined by enzyme linked immunosorbent assay and antioxidant status of rat were determined by standard methods. Data were analysed using Duncan multiple range test at p<0.05. The findings in this study, were that; secondary metabolites constituents of A. digitata and C. olitorius were alkaloids (78.76 and 72.36g/dl) terpenoids (42.45 and 21.25 g/dl) flavonoids (13.42 and 104.81g/dl) polyphenols and (147.90 and 203.14 g/dl) respectively; γ-irradiation significantly (p<0.05) increased mean number of micronuclei and decreased p53, superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) level in rats; 80% inclusion of A. digitata and C. olitorius leaf-BD significantly (p<0.05) reduced mean number of micronuclei and increased p53, SOD, CAT and GSH level in irradiated rats. The study concluded, that A. digitata and C. olitorius protected cellular damage induced by radiation. Thus, recommending their use against cellular damage.
Introduction: The main objective of this research was to investigate the antimalarial therapeutic potential of the ethanolic extract of the leaves and roots of Alstonia boonei, a West African medicinal plant that is used for the traditional treatment of malaria, fever, and other parasitic diseases. There is a need to scientifically evaluate various plants utilized in the ancient treatment of diseases as they might be potential sources of new modern drugs; thus, the importance of this study is obvious. Methods: The extracts were subjected to in vivo antimalarial tests in mice in order to determine their efficacy against malaria infection. These materials exhibited dose–dependent antimalarial activity (P<0.05), as indicated by suppressive and curative effects on mice infected with doses of 100, 200, and 400 mg/kg body weights of the Plasmodium berghei malaria parasite. Results: The suppressive test of the extracts revealed a significant dose–dependent early infection suppression at P<0.05. Conclusion: Based on the results, the plant should be further examined to analyze its bioactive compounds and position it as a potential source of new and novel molecules for antimalarial drug development.
Background: This study aims to compare the information recorded in the three provinces of Jerada, Nador, and Al Hoceima in the Northeastern part of Morocco, in order to evaluate variability of medicinal plant knowledge in these provinces. Methods: All the data were gathered through conducting open-ended semi-structured interviews with randomly selected individuals between 2017 and 2019. The study targeted people belonging to a specific ethnic category: The Berber tribes Aït Waryaghel in the province of Al Hoceima, the tribes Guelaya in the province of Nador, and the Arabs in the province of Jerada. Results: Information on 241 taxa were collected through ethnobotanical surveys conducted with a total of 1,177 persons across the three targeted provinces. In Jerada, 200 taxa were documented based on responses from 380 participants, of which 52% were women. In Al Hoceima, 179 taxa were identified through interactions with 410 persons, with 68% being men, while in Nador 131 taxa were recorded from interviews with 387 interviewees, with 53% being women. The analysis of the results revealed a total of 790 medicinal uses recorded across the provinces: 232 in the province of Al Hoceima, 172 in the province of Nador, and 386 therapeutic uses in the province of Jerada. Additionally, 474 other uses were recorded, with 166 in the province of Al Hoceima, 120 in the province of Nador, and 188 in the province of Jerada. Conclusions: Ethnicity indeed has an important role in the common knowledge of the population; it is even one of the imposing factors that forge it, making the comparison between different regions necessary in order to promote an adequate strategy to preserve biodiversity in a given region. Keywords: Ethnobotanical knowledge, Ethnicity, Medicinal plants, North-East Morocco.
Natural products (NPs) produced as metabolites are derived from various plants, microbes, and marine organisms. They have long been shown to contain bioactive compounds having beneficial effects on humans and other living organisms. Recent advancements in the omics and bioinformatics field have to fasten the process of the traditional way of extraction and characterization of those bioactive compounds along with their qualitative and quantitative analyses. This chapter discusses the steps followed in one of the omics techniques – metabolomics to identify the unknown and quantify the already known bioactive metabolites sourced from NPs. Metabolomics workflow includes the identification of appropriate sources, harvesting, storage, extraction, identification, analytical and statistical analyses, and deposition in the appropriate database. It also summarizes the importance of using various techniques along with their respective advantages and disadvantages used in the metabolomic workflow. Finally successful applications of metabolomics in the discovery of NP and demonstrating the use of NP as potent drug have also been briefly discussed.
Metal-organic frameworks (MOFs) have several benefits over crystalline materials, but they can have environmental concerns and expensive synthesis costs. Utilizing a green preparation approach would lower manufacturing costs, as well as ecological expenses, energy consumption, and the usage of hazardous organic solvents. Therefore, to minimise negative effects on the environment and the economy, the most favoured method of synthesis involves replacing toxic organic solvents with aqueous solutions. This book chapter summarizes the origin of MOFs and their brief classification based on porosity. The various green methods have been presented for the sustainable development of MOFs, emphasizing water-based routes for MOF synthesis. There are a plethora of applications shown by MOF; however, few important applications have been briefly discussed. There is also an overview of future challenges and outlooks associated with the commercialization of MOFs. Our study aims to provide information necessary for future industrial applications of MOFs that will be green, sustainable, and industrially acceptable.
The process of discovering new medications is called as drug discovery. From the ancient period to modern age, there has been a significant improvement in the drug development. Different methodologies have been applied in drug discovery time to time.
Drug discovery has started with the usage of herbal extracts for different ailments, which were termed as traditional medicine. The knowledge, skills and practice of holistic health care, recognized and accepted for its role in the maintenance of health and the treatment of diseases, are defined as traditional medicine. Over the centuries, traditional medicine holds its prime place, and more than 80% of the population of developing countries are still depending upon traditional medicine. Later on, bioactivity-guided fractionation and identification of bioactive molecules (secondary metabolites) approach came into limelight and have been at forefront over the decades. Bioassay-guided fractionation and isolation are still the basic procedures for identifying new natural product-based scaffolds with defined biological activity. Historically, drugs were discovered serendipitously through the accidental identification of active ingredients from the traditional herbal extracts without knowing their targets. After the identification of an active substance, their targets and mechanism of action have been discovered. This approach of drug discovery is defined as classical pharmacology, forward pharmacology or phenotypic drug discovery. Natural products with their structural diversity and drug likeness have significantly contributed to drug discovery. More than 70% of the marketed medications are discovered either directly from natural sources or inspired by natural products. Natural products are still being treated as frontline ligands in the modern target-based drug discovery methods. As the natural products exert remarkable structural diversity, they have been the primary source of drug development. After being overlooked for twenty years, natural product research has regained its importance and is assuming new prominence.
In this chapter, a detailed study of the bioactivity-guided fractionation and identification of bioactive ligands, a basic approach in drug discovery, has been overviewed.
Natural products (NPs) will continue to provide humans with an unrivaled source of innovative medication leads and inspiration for non-natural drug synthesis. Because our scientific understanding of nature is continuously developing, it would be useful to acquaint the scientific community and the general public with the pharmacological characteristics of NPs. Flavonoids have long attracted scientists interest due to their structural diversity and biological activities. Biochanin A, a bioactive isoflavone ingredient derived from Trifolium pratense (red clover) and a variety of other legumes, has grabbed researchers’ interest in recent years due to its broad range of pharmacological effects including neuroprotective, antioxidant, osteogenic, antihyperglycemic, anti-inflammatory, anticancer, and antihyperglycemic properties. Biochanin A targets numerous signal transduction pathways involved in cell proliferation, cell differentiation, and apoptosis to demonstrate its molecular activities. Moreover, it inhibits Akt and mitogen-activated protein kinases (MAPKs) activity in cancer cells. This review highlights the source, chemistry, structural modifications, and therapeutic potential of biochanin A, as well as the molecular targets via which it displays various biological functions.KeywordsBiochanin APharmacological activitiesMedicinal plantsNatural productsDrug discoveryClinical trials
This study characterizes the bioactive molecules from the bulb of Calotropisprocera and investigates the antimicrobial activities of the crude extracts. Theoretical studies on the two isolated compounds in the crude extract were also accomplished.The bulbs were air dried, pulverized, and subjected to extraction procedures by maceration using 500 mL each of normal-hexane, ethyl acetate and methanol. The crude extracts were further tested onmicroorganisms and phytochemical screening using standard procedures. In addition, the bioactive compounds in the extract were screened against DNA gyrase of two Gram negative bacterial species; Escherichia coli and Salmonella typhiusing Molecular Docking simulation techniques and further subjected to ADMET profiling,using the Swiss ADME online server. The Crude ethyl acetate extract has the highest effective activity against Escherichia coli (MIC 2.5mg / mL and MBC/MFC 5mg / mL), Staphylococcus aureus (MIC 2.5mg/mL), Candida albicans, Salmonella typhiand Candida stellafoidea (MIC 5mg/mL). beta-Amyrin acetate and Taraxasterol are the two phytochemicals in the purified white crystalline fractions and were found to fasten to the active sites of DNA gyrase of the Gram negative bacterial species via hydrophobic and hydrogen bond interactions, with binding activity value of -9.6 kcal/mol and -9.5 kcal/mol, respectively. Also, ADMET investigations of the compounds revealed their sound oral bioavailability and excellent pharmacokinetic and toxicity profiles. The findings of this study could provide a platform for discovering safe and potent antibiotics against pathogenic microbes ravaging our society.
Las macrobióticas son establecimientos de gran distribución en el territorio costarricense con una regulación laxa en el ordenamiento jurídico sanitario costarricense. Se presenta la legislación que abarca a estos establecimientos, enfatizando en que su característica permite actividades que pueden potencialmente causar una lesión a la salud pública. Se evidencia relativo descuido u omisión en el cumplimiento de las normas tendientes a proteger la salud en estos lugares.
Background and Objectives: Periodontal pocket treatment must be carried out with the aim of eliminating
or reducing the microbial population and biomechanically removing necrotic tissue in the gingival sulcus
which is a medium for microbial growth and preventing re-infection so that periodontal pockets or gingivitis
can occur. Indonesia is a tropical country that has a high diversity of plants that must be utilized properly, one
of which is widely used as a dental material. This study was to determine the examination of Sarang Semut
(Myrmecodia Pendens) extract as a basic antimicrobial ingredient for periodontal pocket therapy and gingivitis.
Methodology: The experimental animals that were given treatment were 20 male Wistar rats which were
divided into 5 groups; 1 positive control group was given 0,02 % chlorhexidine (CHX), 1 negative control group
was given equates and 3 experimental group were given Sarang Semut extract with dose 1 mg, 10 mg, 100
mg.
Results: Histopathological results of test animal organs given test preparations and autopsied 24 hours
after treatment showed abnormalities in the form of renal tubular epithelial degeneration, peribronchiolitis.
Perivasculitis and hydropic degeneration of the liver. The histopathological results of the test animals that were
autopsied on the 14th day after treatment showed foci of inflammation in the liver.
Conclusions: These results of examination of Sarang Semut extract can be used as a basic antimicrobial
ingredients for periodontal pocket therapy at a dose of less than 100 mg.
Keywords
Sarang Semut, Myrmecodia Pendens, Wistar Rats, Antimicrobial, Periodontal Pocket
The study investigated the cytoactivities of methanolic leaf extract (MLE) and fractions of Senecio biafrae, profiled, and elucidated their metabolites. Hydromethanolic extract of S. biafrae obtained by maceration was partitioned and subjected to cytotoxicity using brine shrimp lethality assay (BSLA), human cervical adenocarcinoma (HeLa) and prostate cancer cell (PC3) lines. The bioactive principles of most active fractions were profiled using GC-MS. The dichloromethane fraction (DMF) was purified using column and high-performance liquid chromatography to afford compounds 1 and 2 identified by 1H and 13C, DEPT-90, DEPT-135, COSY, NOESY and EIMS spectra. The MLE and its fractions exhibited good toxicity on nauplii brine shrimp. The HF exhibited a pronounced cytoactivity on PC-3 cell line with 92.8% followed by DMF. The GC-MS profiling of HF and DMF identified 17 and 6 constituents respectively comprising saturated and unsaturated fatty acids, diterpenoidal alcohol, phytol and aromatic compounds. Hexadecanoic acid, cis, cis, cis-9, 12, 15-octadecatrienoic acid, and phytol accounted for the highest percentage of the constituents in both fractions. Structure elucidation confirmed compounds 1 and 2 as stigmasterol and ergosterol with cytoactivity which compared favourably with doxorubicin. The study revealed that S.biafrae contains cytotoconstituents evidenced by proliferation inhibition of HeLa and PC-3 cell lines. The cyto-activities and bioconstituents indicate that S.biafrae has the potential to be considered as a candidate for drug development in the management of cancer-related conditions. Further investigation into the specific bioactive compounds and their mechanisms of action could provide valuable insights into the therapeutic potential of S.biafrae in cancer treatment.
Viral diseases are the most notorious infective agent(s) causing morbidity and mortality in every nook and corner for ages; viruses are active in host cells, and specific anti-virus medicines’ developments remain uncanny. In this century of the biological era, human viruses act predominantly as versatile spreaders. The infection of the present COVID-19 virus is up in the air; blithely, the integument of medicinal chemistry approaches, particularly bioactive derived phytocompounds could be helpful to control those human viruses, recognized in the last 100 years. Indeed, natural products are being used for various therapeutic purposes. The major bioactive phytocompounds are chemically containing coumarin, thiosulfonate, steroid, polysaccharide, tannin, lignin, proanthocyanidin, terpene, quinone, saponin, flavonoid, alkaloid, and polyphenol, that are documented for inhibitory action against several viral infections. Mostly, about 20–30% of plants from tropical or temperate regions are known to have some antiviral activity. This comprehensive analysis of bioactive-derived phytocompounds would represent a significant impact and might be helpful for antiviral research and the current state of viral treatments.
Background: Sodium fluoride (NaF) causes testicular toxicity via an oxidative stress mechanism. Solanum aethiopicum (SAE) contains abundant antioxidant and androgenic properties. This study investigated the ameliorating potential of SAE extract against NaF-induced testicular damage in rats. Methods: Forty-eight (48) adult male Sprague Dawley rats (130–180 g, 7–9 weeks old) were randomized into six groups of eight rats (n = 8) each. A: Control received only deionized water, B: 20 mg/kg body weight (bw) NaF. C: 500 mg/kg bw SAE. D: 20 mg/kg bw NaF + 500 mg/kg bw SAE. E: 20 mg/Kg bw NaF + 30 mg/kg bw vitamin C (Vit. C). F: 20 mg/kg bw NaF + 500 mg/kg bw SAE + 30 mg/kg bw Vit. C orally for 8 weeks. Testicular histology, histomorphometry parameters, sperm parameters, luteinizing hormone, follicle-stimulating hormone, testosterone, reduced glutathione, glutathione peroxidase, catalase, superoxide dismutase, malondialdehyde (MDA) and inflammation markers were analyzed. Results: Sodium fluoride significantly decrease sperm quality, hormones, antioxidants concentrations, and general body weights and significantly increased MDA, and cause disorientation of seminiferous tubules with a nearly empty lumen and vascular hemorrhage but was attenuated with SAE and Vit. C. Conclusion: Solanum aethiopicum possesses pro-fertility properties capable of ameliorating oxidative stress-induced testicular damage with the profound significance that comes with Vit. C combination.
Natural compounds have been used to treat a range of diseases and illnesses throughout history. Using traditional natural compound chemistry approaches, a significant number of biologically active secondary metabolites originated from global sources were discovered. Several natural compounds are now being researched as potential medications. The introduction to natural compounds aims to highlight historically significant bioactive natural chemicals as well as their applications. Furthermore, the natural compounds chemistry has led to in the identification of various therapeutic applications. In the near future, the use of metabolomic profiling and dereplication techniques for the detailed investigation of different natural product extracts will be explored at molecular level.
The antidermatophytic activity of methanol extract of the leaf of Anogeissus accuminata was evaluated against three species of dermatophytes viz. Trichophyton mentagrophytes (MTCC8476), T. Rubrum (MTAA8477) and Microsporum gypseum (MTCC8469) by minimum inhibitory concentration (MIC) and zone of inhibition (ZOI) study.The extract shows a varying degree of potential inhibitory effect against the tested pathogens. T. mentagrophytes was found to be the most sensitive while M.gypseum was the least sensitive among the tested pathogens.Important bioactive constituents like tannin and flavonoids are detected in the methanol extract of leaf which may be responsible for the observed antimicrobial activity of the plant.
Background: The present ethnobotanical study was conducted to identify plant species used by Burundians to treat
malaria and to repel mosquitoes, to compare this with existing literature, identify species which could be further
investigated and discuss potential future promotion or cultivation.
Methods: Surveys were conducted between April and October 2018 in seven provinces representing the five
ecological zones of Burundi. A semi-structured questionnaire was administered to 341 randomly selected
respondents (between 25 and 50 household heads in each province).
Results: A total of 44 plant species were reported in this study: 32 as antimalarial, two as mosquito repellents and
10 for both purposes. For antimalarial plants (84%) and mosquito repellent plants (88%), leaves were the most
commonly used plant part. According to the respondents, 28 plant species were being cultivated and 16 were
mostly collected from the wild. An examination of the literature on some of the plant species mentioned in this
study revealed that eight of them had never been studied before.
Conclusions: The use of antimalarial and mosquito repellent plants in Burundi was highlighted in this study. Its goal
is to create a database of antimalarial and mosquito repellent plants. This will aid decision-making in the
development of traditional medicine and the conservation of medicinal plants.
Keywords: Ethnobotany; antimalarial activity; mosquito repellents; plants cultivation; Eco-climatic zones.
Muğla ili Köyceğiz ilçesi tıbbi ve aromatik bitki çeşitliliği yönünden oldukça zengindir. Bu çeşitliliğin topoğrafik ve iklimsel özeliklerin bir ürünü olduğu düşünülmektedir. Ancak, kontrolsüz bir şekilde yapılan toplama ve aşırı faydalanmalar sonucunda tıbbi bitki türlerinin önemli bir bölümünün geleceği tehlike altına girmiştir. Bu nedenle, gerek yöre insanının kullandığı bitkisel drogların kayıt altına alınması gerekse yetiştirme koşulları göz önünde bulundurularak nesli tehlikede olan türlerin kültüre alınmasına yönelik farkındalığın artırılması çalışmanın ana amacı olmuştur. Bu çalışmada, Köyceğiz yöresinde yaşayan yerel halkın bitkisel ürünler ve bu ürünlerin bazı hastalıklardaki uygulama şekline yönelik görüş ve önerileri incelenmiştir. Elde edilen veriler normal dağılım göstermemesi sebebiyle Mann Whitney U testi ve Kruskal Wallis testleri ile istatiksel olarak değerlendirilmiştir. Çalışma sonucunda tıbbi ve aromatik bitkilerin yöre halkı tarafından tedavide yaygın bir şekilde kullanıldığı, özellikle yörede yetişen kekik, adaçayı, dağ çayı ve ıhlamur bitkilerini demleme şeklinde sığla yağı, kantaron gibi bitkileri ise yaraların tedavisinde kullandıkları belirlenmiştir. Soğuk algınlığı, öksürük, yara tedavisi ve ağrı giderici gibi rahatsızlık durumlarında katılımcıların ilk başvurdukları yöntemin bitkisel tedavi olduğu tespit edilmiştir.
Inserted in the bioeconomy context, the carbohydrate-based market has the main objective to develop products based on carbohydrate material, in their most diverse forms and sources, and not depend on costly and exhaustible inputs. This chapter discusses possibilities of carbohydrate-based products and market insertion opportunities, covering biofuel, enzymatic biocatalyst, biomaterial, food agents, and bioactive ingredients from fungi cultivated in carbohydrate sources with pathogen biocontrol purpose. Furthermore, industrial trends from the operational and environmental point of view are covered up, bringing perspectives from the fourth and fifth industrial revolution to the carbohydrate-based technologies in the circular bioeconomy context.
Fungal pathogens are commonly opportunistic to human society and cause different superficial as well as systemic infections which are responsible for morbidity and mortality of mainly immunocompromised patients such as organ transplants, diabetes, burn, chemotherapy, cancer, and HIV. The infections caused by nonfilamentous fungi (Candida albicans and non-albicans) are responsible for 50–70% of all infections and cause the fourth leading bloodstream infection worldwide every year. The filamentous fungi (i.e., Aspergillus species) mainly affect respiratory system infection. There are only four classes of clinically approved antifungal drugs (i.e., polyene, azoles, allylamines, and echinocandins) used to treat fungal infection. However, in recent decades, widespread and prolonged usage of antibiotics against opportunistic fungal infections led to a significant increase in the emergence of multidrug resistance globally. The main mechanism of antifungal resistance includes alternation of cell wall biosynthesis pathway (ergosterol pathway), overexpression of membrane transporters (Cdr1p and CaMdr1p), modification of enzymatic pathway, and overexpression of genetic material. Further, due to the steep growth of fungal infection in immunocompromised patients and a limited number of well-known antifungal drugs having several side effects urgently demands for the identification of new compounds with potent antifungal activity. In this regard, the search for new antifungal agents from medicinal plants is an attractive alternative to providing new remedies that can be combined with currently available antifungal agents. The medicinal plants of Himalayan regions have a diverse group of medicinal plants having novel bioactive compounds with unique properties. So, this chapter primarily focuses on the therapeutic properties of Himalayan medicinal plants and their antifungal activity against various fungal pathogens.
Natural products harbor great therapeutic potential and represent nearly 50% of FDA approved drugs. However, because of their structural diversity and complexity, many natural products cannot be chemically synthesized efficiently. Natural product biosynthesis pathways, especially the polyketide synthases (PKS) that condense acyl groups to form polyketides, are seen as powerful, chemoenzymatic tools to synthesize chemically challenging compounds. To harness the chemoenzymatic potential of PKS pathways, it is important to investigate their biochemical mechanisms and structural details. Saxitoxin interacts with the voltage-gated sodium channels and is one of the most potent neurotoxic alkaloids known. Saxitoxin derivatives have potential for development as selective neuropathic pain treatments. Through X-ray crystallography, biochemical assays, and mutagenesis, we further study the enzymes involved in the starter module of the saxitoxin biosynthesis pathway and expand their enzymatic capabilities. Three catalytic domains are found in the saxitoxin starter module: C-methyltransferase (C-MT), decarboxylase (DC) and 8-amino-7-oxonanoate synthase (AONS). The SAM- and metal-dependent SxtA MT initiates the biosynthesis. Structural and biochemical studies revealed essential catalytic residues and features that control the methylation extent in SxtA MT. Through a few simple amino acid substitutions, this monomethylating SxtA MT is converted into a dimethyltransferase. Interestingly, the two downstream enzymes, DC and AONS can process this MT product with an additional methyl group (dimethylmalonyl-ACP) to yield a methylated version of the saxitoxin precursor. This may be used to alter the chemical outcome of the saxitoxin pathway via domain modification, potentially resulting in the development of saxitoxin analogs with reduced toxicity and high selectivity as a pain medicine. SxtA DC was thought to be a gatekeeper because it does not act on MT methylation substrate (malonyl-ACP) and decarboxylates only the methylation product (methylmalonyl-ACP). Further investigation of SxtA DC demonstrates that it may not evolve a mechanism to filter another chemical group (such as dimethylmalonyl-ACP) that is uncommon in its biosynthesis environment. Substrate modeling with the structures of SxtA, CurA and GphF DCs from the saxitoxin, curacin, and gephyronic acid biosynthesis pathways, respectively, reveals that the size of the malonyl-binding pocket determines their substrate preference. A DC with a large pocket would prefer a bulkier malonyl-substrate and vice versa. Structural analysis of the final catalytic domain, AONS, was initiated with an AlphaFold prediction. The AONS performs condensation between an arginine and an acyl group to yield a propionylated arginine-like SxtA precursor. This structure and the AONS’s behavior in solution have suggested that AONS functions as a dimer. Characterization of MT, DC and AONS advances the understanding of the biosynthesis of chemically diverse natural products and provides valuable insights towards harnessing the biocatalytic potential of enzymes in PKS pathways.
Dos nuevos withanolidos, Larnaxolida A (1) y Larnaxolida B (2), fueron aislados del extracto en etanol de las hojas de Larnax glabra (Standl.) Sawyer. Las estructuras de los compuestos fueron establecidas con base en RMN (HMQC, HMBC y COSY) y aspectos biogenéticos. Estos compuestos muestran una actividad leishmanicida promisoria y una toxicidad reducida en comparación con otros withanolidos ya reportados.
Native American people developed a sophisticated plant-based medical system in the ten milennia before the European conquest of America. Many of the plants they used are familiar medicinal species, and have taken a role in modern medicinal treatments. Many others, even though not commonly in use at present, are interesting plants worthy of close study. The intellectual process by which non-literate peoples systematized such a mass of useful knowledge is still unclear. Some of the clues they used to find useful plants may be visible in the study of the aggregate of their knowledge. This paper reviews recent research in this area.
Organoselenium resins 1–4 were prepared from polystyrene via lithiation and quenching with MeSeSeMe, and shown to react with a variety of substrates, aiding in useful functionalizations.
The maytansinoid drug DM1 is 100- to 1000-fold more cytotoxic than anticancer drugs that are currently in clinical use. The immunoconjugate C242-DM1 was prepared by conjugating DM1 to the monoclonal antibody C242, which recognizes a mucin-type glycoprotein expressed to various extents by human colorectal cancers. C242-DM1 was found to be highly cytotoxic toward cultured colon cancer cells in an antigen-specific manner and showed remarkable antitumor efficacy in vivo. C242-DM1 cured mice bearing subcutaneous COLO 205 human colon tumor xenografts (tumor size at time of treatment 65-130 mm3), at doses that showed very little toxicity and were well below the maximum tolerated dose. C242-DM1 could even effect complete regressions or cures in animals with large (260- to 500-mm3) COLO 205 tumor xenografts. Further, C242-DM1 induced complete regressions of subcutaneous LoVo and HT-29 colon tumor xenografts that express the target antigen in a heterogeneous manner. C242-DM1 represents a new generation of immunoconjugates that may yet fulfill the promise of effective cancer therapy through antibody targeting of cytotoxic agents.
Three cytotoxic peptides, Jaspamide (1) and the two new peptides hemiasterlin (2) and geodiamolide TA (3), have been isolated from the sponge Hemiasterella minor. The structures of the three were determined by interpretating the NMR and mass spectra. Hemiasterlin (2) is a novel linear tripeptide embodying two unique, new natural aminoacids and geodiamolide TA (3) is a higher homologe of geodiamolides A–F.
The heterologous production of epothilone D in Myxococcus xanthus was improved by 140-fold from an initial titer of 0.16 mg/L with the incorporation of an adsorber resin, the identification of a suitable carbon source, and the implementation of a fed-batch process. To reduce the degradation of epothilone D in the basal medium, XAD-16 (20 g/L) was added to stabilize the secreted product. This greatly facilitated its recovery and enhanced the yield by three-fold. The potential of using oils as a carbon source for cell growth and product formation was also evaluated. From a screen of various oils, methyl oleate was shown to have the greatest impact. At the optimal concentration of 7 mL/L in a batch process, the maximum cell density was increased from 0.4 g dry cell weight (DCW)/L to 2 g DCW/L. Product yield, however, depended on the presence of trace elements in the production medium. With an exogenous supplement of trace metals to the basal medium, the peak epothilone D titer was enhanced eight-fold. This finding demonstrates the significant role of metal ions in cell metabolism and in epothilone biosynthesis. To further increase the product yield, a continuous fed-batch process was used to promote a higher cell density and to maintain an extended production period. The optimized fed-batch cultures consistently yielded a cell density of 7 g DCW/L and an average production titer of 23 mg/L. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 78: 280–288, 2002.
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Extracts of the sponge Cymbastela sp. have yielded the novel cytoloxic peptides geodiamolide G (II), hemiasterlin A (12), hemiasterlin B (13), criamide A (14) and criamide B (15). The structures of the new compounds were solved via speciroscopic analysis and chemical degradation.
Antimitotic agents have generated considerable interest among cytotoxic agents due to the tremendous success of the taxanes and the widespread use of the Vinca alkaloids in clinical oncology. Renewed interest in tubulin polymerisation inhibitors has been generated by the hope that non-multi-drug resistance (MDR) substrates that interact with tubulin at sites near to, overlapping with or different from those of the taxanes or Vinca alkaloids can be discovered. In this article, new antimitotic agents that inhibit tubulin polymerisation for the treatment of cancer are reviewed, with greater emphasis being focused on the small molecule colchicine site binders. Compounds that induce metaphase arrest, by other novel mechanisms, are summarised. Results of clinical trials of drug candidates that fall into these classes are also briefly discussed. The patent literature was surveyed from January 1998 through May 2002.
Page 4912. The relative stereochemistry of the structures 1 and 2 was transposed incorrectly from the URANUS drawing. The correct relative stereochemistry of the structures 1 and 2 are given below.
Bioactivities of 42 didemnin congeners, either isolated from the marine tunicates Trididemnun solidum and Aplidium albicans or prepared synthetically and semisynthetically, have been compared. The growth inhibition of various murine and human tumor cells and plaque reduction of HSV-1 and VSV grown on cultured mammalian cells were used to assess cytotoxicity and antiviral activity. Biochemical assays for macromolecular synthesis (protein, DNA, and RNA) and enzyme inhibition (dihydrofolate reductase, thymidylate synthase, DNA polymerase, RNA polymerase, and topoisomerases I and II) were also performed to specify the mechanisms of action of each analogue. Immunosuppressive activity of the didemnins was determined using a mixed lymphocyte reaction (MLR) assay. These assays revealed that the native cyclic depsipeptide core is an essential structural requirement for most of the bioactivites of the didemnins, especially for cytotoxicities and antiviral activities. The linear side-chain portion of the peptide can be altered with a gain, in some cases, of bioactivities. In particular, dehydrodidemnin B, tested against several types of tumor cells and in in vivo studies in mice, as well as didemnin M, tested for the mixed lymphocyte reaction and graft vs host reaction in murine systems, showed remarkable gains in their in vitro and in vivo activities compared to didemnin B.
As described in the preceding two papers, our interest in the construction of natural and natural product-like libraries for chemical biology studies led to the development of a new solid-phase cycloloading strategy for the construction of substituted benzopyrans. Herein, we report a parallel solution-phase method that facilitates the enhancement of both the size and diversity of these non-oligomeric benzopyran libraries using the “libraries from libraries” principle. We examine the rationale behind the use of this tandem strategy to construct discrete small molecule libraries, and describe the development of a polymer-assisted solution-phase (PASP) methodology necessary to effect the required transformations. Once developed, this chemistry is applied to two demonstration libraries.
Having developed a reliable and versatile solid-phase strategy for the split-and-pool synthesis of naturally occurring and designed derivatives of the benzopyran template (see preceding paper), we now report the construction of a 10 000-membered natural product-like compound library for chemical biology studies. Concomitantly, we report an early application of the IRORI NanoKan optical encoding system for the high throughput nonchemical tagging and sorting of library members during split-and-pool synthesis. The overall synthetic strategy for library construction is discussed and the individual reaction pathways are examined in the context of specific library members, illustrating reaction conditions as well as yields and purities. The issues of building block selection and quality control of library members are also addressed and, finally, potential applications of the library to chemical biology are discussed.
Herein we report a novel strategy for the design and construction of natural and natural product-like libraries based on the principle of privileged structures, a term originally introduced to describe structural motifs capable of interacting with a variety of unrelated molecular targets. The identification of such privileged structures in natural products is discussed, and subsequently the 2,2-dimethylbenzopyran moiety is selected as an inaugural template for the construction of natural product-like libraries via this strategy. Initially, a novel solid-phase synthesis of the benzopyran motif is developed employing a unique cycloloading strategy that relies on the use of a new, polystyrene-based selenenyl bromide resin. Once the loading, elaboration, and cleavage of these benzopyrans was established, this new solid-phase method was then thoroughly validated through the construction of six focused combinatorial libraries designed around natural and designed molecules of recent biological interest.
Equitable sharing of benefits from pharmacological development of biodiversity has been the topic of much discussion, but few concrete examples of recent plant-derived pharmaceuticals exist. The discovery of prostratin as an anti-viral phorbol isolated from healer preparations of the rain forest tree Homalanthus nutans in Samoa illustrates the importance of careful liaison between western scientists and indigenous leaders. Development of prostratin as an anti-AIDS drug candidate was based on a carefully negotiated covenant between the chiefs and orators of Falealupo village and western researchers, with the concurrence of the Samoan Prime Minister and members of parliament. Since, like all drug candidates, potential commercial development of prostratin still remains uncertain, the case of prostratin indicates the importance of providing benefits to indigenous peoples in advance of royalty or license income. To date, over US$ 480,000 have been supplied to Falealupo village for schools, medical clinics, water supplies, trails, an aerial rain forest canopy walkway, and an endowment for the rain forest based on the Falealupo Covenant. And, in August 2001 the AIDS Research Alliance (ARA) signed an agreement with the Prime Minister of Samoa guaranteeing a total of 20% of all ARA profits from the development of prostratin to be returned to Samoa.
Extracts of Homalanthus nutans, a plant used in Samoan herbal medicine, exhibited potent activity in an in vitro, tetrazolium-based assay which detects the inhibition of the cytopathic effects of human immunodeficiency virus (HIV-1). The active constituent was identified as prostratin, a relatively polar 12-deoxyphorbol ester. Noncytotoxic concentrations of prostratin from greater than or equal to 0.1 to greater than 25 microM protected T-lymphoblastoid CEM-SS and C-8166 cells from the killing effects of HIV-1. Cytoprotective concentrations of prostratin greater than or equal to 1 microM essentially stopped virus reproduction in these cell lines, as well as in the human monocytic cell line U937 and in freshly isolated human monocyte/macrophage cultures. Prostratin bound to and activated protein kinase C in vitro in CEM-SS cells and elicited other biochemical effects typical of phorbol esters in C3H10T1/2 cells; however, the compound does not appear to be a tumor promoter. In skin of CD-1 mice, high doses of prostratin induced ornithine decarboxylase only to 25-30% of the levels induced by typical phorbol esters at doses 1/30 or less than that used for prostratin, produced kinetics of edema formation characteristic of the nonpromoting 12-deoxyphorbol 13-phenylacetate, and failed to induce the acute or chronic hyperplasias typically caused by tumor-promoting phorbols at doses of 1/100 or less than that used for prostratin.
This chapter highlights the discovery of marine natural products with therapeutic potential. Deep water collections have been made by dredging and trawling. These are both cost-effective collection methods if the substratum does not cause damage to or snag the gear. There are several disadvantages to these approaches. It is difficult to photograph the organisms in their habitat, and encrusting organisms or organisms that grow in crevices, under ledges, or on steep rock faces cannot be easily collected unless the hard substrate that supports the organism is collected as well; dredging and trawling put all collected samples in close contact with each other and therefore, some organisms may chemically contaminate others because of exudations or secretions of various compounds and the environmental impact of dredging or trawling can be detrimental because the sampling is nonselective and habitats can be damaged or destroyed. A controversial facet of marine-derived microorganisms is their putative role with respect to the origin of bioactive natural products from marine macroorganism–microorganisms associations. Symbiotic microorganisms have been repeatedly suggested as being the direct or indirect sources of bioactive metabolites in marine sponges and other invertebrates, tunicates, and bryozoans.
Over the past 30 years, the National Cancer Institute has been involved in the preclinical and/or clinical evaluation of the majority of those agents approved for the treatment of cancer. Many of the new agents under consideration in the NCI program are either natural products or derivatives of natural product leads, and of critical importance to their development is the issue of drug supply. In responding to the drug supply crisis which emerged with the demonstration of the clinical efficacy of taxol, the NCI has identified several important lessons for those interested in natural product drug discovery and development. As a result, the NCI has developed plans to avert similar supply crisis in the future by initiating exploratory research projects for large-scale production of promising agents at the earliest possible point following the demonstration of confirmed antitumor activity. These plans, together with a review of the development of taxol, are presented in this paper.
The use of antibody-enzyme conjugates directed at tumor-associated antigens to achieve site-specific activation of prodrugs to potent cytotoxic species, termed "antibody-directed enzyme prodrug therapy" (ADEPT), has attracted considerable interest since the concept was first described in 1987. Prodrug forms of both clinically used anticancer agents and novel cytotoxic compounds have been developed to take advantage of potential prodrug-generating technology employing a variety of enzymes with widely differing substrate specificities. A particular advantage of the ADEPT approach is that it may allow the use of extremely potent agents such as nitrogen mustards and palytoxin, which are too toxic to be readily used in conventional chemotherapy. Preliminary studies using an antibody-enzyme conjugate constructed with a bacterial enzyme and a murine monoclonal antibody not only have established the value of the ADEPT technique, but also have highlighted the potential problem of immunogenicity of proteins of nonhuman origin. This problem has been tackled in the first instance by the use of immunosuppressive agents, but long-term solutions are being investigated in the development of second-generation ADEPT systems, including the development of human antibody-human enzyme fusion proteins and catalytic antibodies. Such improvements, coupled with further refinement of the prodrug-drug element of the system and the wide variety of antibody-enzyme-drug combinations available, should mean that ADEPT-based approaches will form an important element of the search for the anticancer drugs of the future.
Microbial diversity is fundamental to maintenance and conservation of global genetic resources. As extreme environments are explored, the richness of microbial diversity is increasingly evident. Measures must be taken to estimate, record, and conserve microbial diversity, not only to sustain human health but also to enrich the human condition globally through wise use and conservation of genetic resources of the microbial world.
Multiple complications associated with venous access ports are a common occurrence. In an effort to define patterns of sequential complications in our community, we undertook a prospective analysis of adult cancer patients in whom a subcutaneous port was inserted.
One hundred nineteen consecutive adult cancer patients in whom a subcutaneous port was inserted were observed prospectively for the development of complications.
Complications were identified in 70 of the 91 evaluable patients, while sequential complications were identified in 35 patients (38%). In aggregate, 121 complications were identified. The ball-valve effect, the most frequently identified problem, was found to occur disproportionately as a primary complication (52 of 70 versus 26 of 51, P <0.02). In contrast, port-related venous thrombosis was identified most frequently as a subsequent complication (11 of 51 versus 4 of 70, P <0.02). The only identified risk factor for the development of port-related complications was the ball-valve effect, found to be associated with the subsequent development of port-related venous thrombosis (9 of 52 versus 2 of 69, P <0.02).
Multiple sequential complications of subcutaneous ports are common and occur in a rather predictable order. The occurrence of port-related venous thrombosis in patients with an earlier, relatively minor vascular complication (ball-valve effect) suggests a cause-effect relationship. Insight into complication sequencing may lead to improved strategies for prevention and therapy.
Many of our present medicines are derived directly or indirectly from higher plants. While several classic plant drugs have lost much ground to synthetic competitors, others have gained a new investigational or therapeutical status in recent years. In addition, a number of novel plant-derived substances have entered into Western drug markets. Clinical plant-based research has made particularly rewarding progress in the important fields of anticancer (e.g. taxoids and camptothecins) and antimalarial (e.g. artemisinin compounds) therapies. In addition to purified plant-derived drugs, there is an enormous market for crude herbal medicines. Natural product research can often be guided by ethnopharmacological knowledge, and it can make substantial contributions to drug innovation by providing novel chemical structures and/or mechanisms of action. In the end, however, both plant-derived drugs and crude herbal medicines have to take the same pharmacoeconomic hurdle that has become important for new synthetic pharmaceuticals.
Amphibian skin has provided a wide range of biologically active alkaloids. During the past 30 years, over 400 alkaloids of over 20 structural classes have been detected. These include the batrachotoxins, which are potent and selective activators of sodium channels, the histrionicotoxins, which are potent noncompetitive blockers of nicotinic receptor-gated channels, the pumiliotoxins and related allo- and homo-pumiliotoxins, which have myotonic and cardiotonic activity due to effects on sodium channels, and epibatidine, which has potent antinociceptive activity due to agonist activity at nicotinic receptors. Further classes of alkaloids from amphibian skin include pyrrolidines and piperidines, decahydroquinolines, pyrrolizidines, various indolizidines, quinolizidines, and tricyclic gephyrotoxins, pyrrolizidine oximes, pseudophrynamines, coccinellines, and cyclopentaquinolizidines. Most alkaloids of amphibian skin appear to be sequestered from dietary arthropods. The source of the batrachotoxins, histrionicotoxins, pumiliotoxins, epibatidine, and certain izidines are unknown.
Recent developments have enhanced the prospects for the discovery of hyperthermophilic enzymes. This is important because the intrinsic basis underlying the extraordinary thermostability of hyperthermophilic enzymes has yet to be revealed, and so engineering this characteristic into less thermophilic enzymes is not possible at this time. Successful efforts to clone and express the genes encoding hyperthermophilic enzymes in mesophilic hosts have improved the availability of high-temperature biocatalysts. The remaining task is the identification of opportunities to make strategic use of the thermoactivity and thermostability of hyperthermophilic enzymes.
Galactose-targeted delivery of macromolecules and drug conjugates to asialoglycoprotein receptor (ASGPR) positive cells has been widely documented in animals, although targeting in humans has never been demonstrated. In this study we report the pharmacokinetics and imaging determined in the first patient enrolled in a phase I clinical study of the poly[N-(2-hydroxypropyl)methacrylamide] copolymer bearing doxorubicin and galactosamine, known as PK2. Gradient high performance liquid chromatography (HPLC) evaluation of plasma and urine has been combined with 123I-based imaging to show biphasic clearance of the drug from the plasma (half-lives of 78+/-1 and 990+/-15), and approximately 30% delivery of the drug to the hepatic region, as determined by planar whole body imaging at 24 h. This patient has a multifocal hepatoma, and single photon emission computed tomography (SPECT) analysis showed a ratio of tumour tissue to normal liver uptake of approximately 1:3, at 24 h. On the basis of this patient, effective hepatic targeting can be achieved following an intravenous dose of 20 mg/m2 doxorubicin as PK2, however the therapeutic usefulness of this targeted drug has yet to be established.
Microorganisms make a wealth of unusual metabolites that have a secondary role in the organism’s ontogeny, such as self-defense, aggression, or even communication as the need arises. These compounds often have biological activity valuable to humankind (1). Nevertheless, as valuable as antibiotics and other naturally occurring drugs have been over the past 60 years, their future use is threatened by now widespread resistance to antibiotics among human, animal, and agricultural pathogens. Despite the fact that microbial metabolites are being found continually by pharmaceutical companies through targeted screening programs, fewer and fewer fundamentally new types of drugs have been found in this way during the past two decades (2).
Epothilones are produced by the myxobacterium Sorangium cellulosum So ce90, and, like paclitaxel (Taxol((R))), they inhibit microtubule depolymerisation and arrest the cell cycle at the G2-M phase. They are effective against P-glycoprotein-expressing multiple-drug-resistant tumor cell lines and are more water soluble than paclitaxel. The total synthesis of epothilones has been achieved, but has not provided an economically viable alternative to fermentation. We set out to clone, sequence and analyze the gene cluster responsible for the biosynthesis of the epothilones in S. cellulosum So ce90.
A cluster of 22 open reading frames spanning 68,750 base pairs of the S. cellulosum So ce90 genome has been sequenced and found to encode nine modules of a polyketide synthase (PKS), one module of a nonribosomal peptide synthetase (NRPS), a cytochrome P450, and two putative antibiotic transport proteins. Disruptions in the genes encoding the PKS abolished epothilone production. The first PKS module and the NRPS module are proposed to co-operate in forming the thiazole heterocycle of epothilone from an acetate and a cysteine by condensation, cyclodehydration and subsequent dehydrogenation. The remaining eight PKS modules are responsible for the elaboration of the rest of the epothilone carbon skeleton.
The overall architecture of the gene cluster responsible for epothilone biosynthesis has been determined. The availability of the cluster should facilitate the generation of designer epothilones by combinatorial biosynthesis approaches, and the heterologous expression of epothilones in surrogate microbial hosts.
The epothilone biosynthetic gene cluster was isolated from Sorangium cellulosum strain SMP44. The gene cluster contains seven genes and spans approx. 56kb. The genes encoding the PKS, epoA, epoC, epoD, epoE, and epoF, are divided into nine modules. The EpoB protein is a non-ribosomal peptide synthetase (NRPS) that catalyzes formation of the thiazole found in the epothilones. EpoK is a P450 enzyme responsible for the epoxidation of epothilones C and D to epothilones A and B, respectively. EpoK was expressed in Escherichia coli, and the purified protein was shown to convert epothilone D to epothilone B in vitro.
Ambuic acid, a highly functionalized cyclohexenone, was isolated and characterized from Pestalotiopsis spp. and Monochaetia sp. these being biologically related endophytic fungi associated with many tropical plant species. This compound was found in representative isolates of these fungal species obtained from rainforest plants located on several continents. The relevance of ambuic acid to the biology of the association of these fungi to their host plants is also discussed.
diversity-oriented synthesis to construct a library based on a natural product, galanthamine (2, Figure 1), with the goal of discovering molecules that exhibit biological effects beyond those previously associated with the natural product. Although 2 is a potent acetylcholinesterase inhibitor, 8 our aim was not to improve this activity. Galanthamine was selected because it offered a range of functionality for diversity-generating reactions, it presented a rigid polycyclic core that might lower the potential entropy penalty associated with protein binding, and it allowed for the use of powerful biomimetic reactions in the synthesis. 9 In this com- munication, we report a biomimetic solid-phase synthesis of 2527 molecules based on the alkaloid natural product galanthamine and the identification of a molecule from the library that perturbs the secretory pathway in mammalian cells 10 sa process unrelated to the acetylcholinesterase inhibitory activity of 2.
The antitumor cryptophycins are synthetic derivatives of the desipeptide cryptophycins isolated from the cyanobacterium Nostoc sp. Cryptophycin 52 that is currently in clinical trial in solid tumors, is prepared by total synthesis of four key fragments that are coupled to form the final product. The mechanism of anticancer activity of the cryptophycins has been associated with their destabilization of microtubules and with their induction of bcl-2 phosphorylation leading to apoptosis. The cryptophycins maintain activity against ovarian and breast carcinoma cells that overexpress the multidrug resistance efflux pump P-glycoprotein. Cryptophycin 52 has demonstrated a broad range of antitumor activity against both murine and human tumors. In the human MX-1 breast carcinoma xenograft cryptophycin 55 produced greater-than- additive tumor response in combination with 5-fluorouracil. In human non-small cell lung carcinoma and human small cell carcinoma xenografts, administration of the cryptophycins along with gemcitabine, cisplatin or carboplatin resulted in antitumor activity greater than either agent alone. The cryptophycins appear to be additive with fractionated radiation therapy in the human H460 non-small cell lung carcinoma. In the human HCT116 colon carcinoma, the cryptophycins resulted in a greater than additive tumor response when administered sequentially with 5-fluorouracil or irinotecan. Treatment of animals bearing intraperitoneal human OVCAR-2 ovarian carcinoma with cryptophycin 52 resulted in survival times that were greater than those achieved with docetaxel or paclitaxel. Cryptophycin 52 is currently in early clinical testing.