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New approaches to the structural modification of olean-type pentacylic triterpenes via microbial oxidation and glycosylation
Abstract
Microbial transformation of 4 olean-type pentacyclic triterpenes (OPTs), 3-oxo oleanolic acid (1), 3-acetyl oleanolic acid (2), oleanolic acid (3), and esculentoside A (4) was studied. After the screening of 12 strains of microbes, preparative biotransformation by two strains of Streptomyces griseus ATCC 13273 and Aspergillus ochraceus CICC 40330 resulted in the isolation of 10 metabolites. The microbial catalyzed high efficient regio-selective methyl oxidation and glycosylation were discovered, which could be provided as an alternative method to expand the structural diversity of OPTs. All the structures of the metabolites were elucidated unambiguously by ESI-MS, 1H NMR, 13C NMR, and 2D-NMR spectroscopy.
... Hydroxylation at C21 was shown to increase the anti-inflammatory activity of OA derivatives [128]. Using the same strain, biotransformation of OA (approximately 0.05 g/L) with the formation of derivatives 94 and 96 was previously described by Y. Zhu et al. [129]. ...
... Hydroxylation at C21 was shown to increase the anti-inflammatory activity of OA derivatives [128]. Using the same strain, biotransformation of OA (approximately 0.05 g/L) with the formation of derivatives 94 and 96 was previously described by Y. Zhu et al. [129]. Trichothecium roseum (M 95.56) OA, 0.08 g/L 7β,15α-dihydroxy-3-oxo-olean-12-en-28-oic acid (51), 7.5% Anti-inflammatory [114] 15α-hydroxy-3-oxo-olean-12-en-28-oic acid (52), 6.25% -Circinella muscae AS 3.2695 OA, 0.02 g/L 7β,15α-dihydroxy-3-oxo-olean-12-en-28-oic acid (51), 6.1% Anti-inflammatory [15] 7β-hydroxy-OA (53), 5.8% Anti-inflammatory 7β,21β-dihydroxy-OA (54), 4.2% -7α,21β-dihydroxy-OA (55), 3.1% -7β,15α-dihydroxy-OA (56), 4.9% ...
... Hydroxylation at C21 was shown to increase the anti-inflammatory activity of OA derivatives [128]. Using the same strain, biotransformation of OA (approximately 0.05 g/L) with the formation of derivatives 94 and 96 was previously described by Y. Zhu et al. [129]. In addition to OA, S. griseus ATCC 13273 cells can also transform UA (0.04 g/L) by catalyzing site-selective oxidation of the C30 methyl group to the carboxyl one and C24-hydroxylation within 3 days to produce 3β-hydroxy-urs-12-ene-28,30-dioic acid (97) and 3β,24-dihydroxy-urs-12-ene-28,30dioic acid (98), with the product yield exceeding 30.0%. ...
Oleanane and ursane pentacyclic triterpenoids are secondary metabolites of plants found in various climatic zones and regions. This group of compounds is highly attractive due to their diverse biological properties and possible use as intermediates in the synthesis of new pharmacologically promising substances. By now, their antiviral, anti-inflammatory, antimicrobial, antitumor, and other activities have been confirmed. In the last decade, methods of microbial synthesis of these compounds and their further biotransformation using microorganisms are gaining much popularity. The present review provides clear evidence that industrial microbiology can be a promising way to obtain valuable pharmacologically active compounds in environmentally friendly conditions without processing huge amounts of plant biomass and using hazardous and expensive chemicals. This review summarizes data on distribution, microbial synthesis, and biological activities of native oleanane and ursane triterpenoids. Much emphasis is put on the processes of microbial transformation of selected oleanane and ursane pentacyclic triterpenoids and on the bioactivity assessment of the obtained derivatives.
... Ye et al. reported the biotransformation of 25 by Cunninghamella elegans AS 3.1207, Syncephalastrum racemosum AS 3.264 and Doratomyces stemonitis AS 3.1411 [26]. Biocatalytic fermentations of 25 with C. elegans AS 3.1207 for 6 days afforded several regioselective hydroxylated metabolites presented in Figure 12, (20R,24S)-2α,3β,6α,16β,25-pentahydroxy-20,24-epoxycycloartane (34), (20R,24S)-3β,6α,12α,16β,25-pentahydroxy-20,24-epoxy-cycloartane (35), (20R,24S)-3β,6α,16β, 25,28-pentahydroxy-20,24-epoxy-cycloartane (36), (20R,24S)-3β,6α,16β,25,29-pentahydroxy-20, 24-epoxy-cycloartane (37), (20R,24S)-3β,6α,16β,25-tetrahydroxy-20,24-epoxy-cycloartan-28-carbaldehyde (38), (20R,24R)-3β,6α,25,28-tetrahydroxy-16β,24:20,24-diepoxy-cycloartane (39) and (20R,24S)-3β, 6α,16β,19,25-pentahydroxy-ranunculan-9(10)-ene (26) [26]. [28]. ...
... Figures 26-30). These highly efficient and regioselective methyl oxidation and glycosylation provided an alternative approach to expand the structural diversity of OPTs [38]. The two interesting reactions observed during fermentation of four synthetic pentacyclic triterpenoids (3)(4) The pentacyclic triterpene maslinic acid (2α,3β-dihydroxyolean-12-en-28-oic acid, 73) is a natural pentacyclic triterpenoid compounds which is present in abundant amount in the surface wax on the fruits and leaves of Olea europaea. ...
... Fermentation of 72 with S. griseus ATCC 13273 yielded two more polar metabolites, serratagenic acid (96) and 3β,24-dihydroxy-olean-12-en-28,29-dioic acid (97). Incubation of 72 with A. ochraceus CICC 40330 afforded another polar metabolite, 78 (Figure 26)[38].Incubation of 3-oxo oleanolic acid (93) with S. griseus ATCC 13273 produced two polar metabolites, 3-oxo-olean-12-en-28,29-dioic acid (98) and 24-hydroxy-3-oxo-olean-12-en-28,29-dioic acid (99). On the other hand, incubation of 93 with A. ochraceus CICC 40330 afforded a different polar metabolite 28-O-β-D-glucopyranosyl 3-oxo-olean-12-en-28-oate (100)(Figure 27). ...
Microbial-catalyzed biotransformations have considerable potential for the generation of an enormous variety of structurally diversified organic compounds, especially natural products with complex structures like triterpenoids. They offer efficient and economical ways to produce semi-synthetic analogues and novel lead molecules. Microorganisms such as bacteria and fungi could catalyze chemo-, regio- and stereospecific hydroxylations of diverse triterpenoid substrates that are extremely difficult to produce by chemical routes. During recent years, considerable research has been performed on the microbial transformation of bioactive triterpenoids, in order to obtain biologically active molecules with diverse structures features. This article reviews the microbial modifications of tetranortriterpenoids, tetracyclic triterpenoids and pentacyclic triterpenoids.
... The 13 C-NMR data of 3 (Table 2) indicated the presence of six methyl groups, two carboxylic carbons at δC 180.1 and 179.5, one carbonyl carbon at δC 216.3, and two olefinic carbons (one quaternary at δC 144.8 and one methane at δC 122.8, suggesting the presence of a double bond), 10 sp 3 methylenes, three sp 3 methines, and seven sp 3 quaternary carbon atoms. The NMR data of 3 were very similar to those of 3-oxo-olean-12-en-28,29-dioic acid [11], implying that 3 was also an oleanane triterpenoid. ...
... Therefore, the structures of 6 and 7 were determined to be 16- (10.5, 9.9) 67.0 4.36 m 3.74 dd (11.2, 10.3) 67 . Based on 13 C-NMR data (Table 4) and HRESIMS, the molecular formulae of glinusopposides D-G (8)(9)(10)(11) were deduced to be C43H70O13, C45H72O13, C47H74O14, and C44H70O13, respectively. By comparing their NMR data ( Table 4) with those of spergulagenin A 3-O-β-D-xylopyranoside (31) [13], saponins 8-11 were deduced to be disaccharide glycosides of spergulagenin A. The presence of trans-2-butenoyl (crotonyl) group in 9 was confirmed by the 1 H-NMR signals at δH 7.06 (m), 6.02 (dq, J = 15.6, 1.6 Hz), and 1.66 (3H, d, J = 6.8 Hz), along with COSY correlations of H-2′′′/H-3′′′ and H-3′′′/H-4′′′ (Supplementary Materials). ...
: Four new triterpenoids, 3β,12β,16β,21β,22-pentahydroxyhopane (1), 12β,16β,21β,22-tetrahydroxyhopan-3-one (2), 3-oxo-olean-12-ene-28,30-dioic acid (3), and 3β-hydroxyoleana-11,13(18)-diene-28,30-dioic acid 30-methyl ester (4); 21 new triterpenoid saponins, glinusopposides A–U (5–25); and 12 known compounds (26–37) were isolated from the whole plants of Glinus oppositifolius. The structures of the new compounds were elucidated based on the analysis of one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) and mass spectrometry (MS) data. All compounds from the plants were measured for antifungal activities against Microsporum gypseum and Trichophyton rubrum. Glinusopposide B (6), glinusopposide Q (21), glinusopposide T (24), and glinusopposide U (25) showed strong inhibitory activities against M. gypseum (MIC50 7.1, 6.7, 6.8, and 11.1 μM, respectively) and T. rubrum (MIC50 14.3, 13.4, 11.9, and 13.0 μM, respectively). For those active compounds with an oleanane skeleton, glycosylation (21–26) or oxidation (3) of 3-OH was helpful in increasing the activity; replacement of the 30-methyl group (29) by a carboxymethyl group (26) enhanced the activity; the presence of 11,13(18) double bonds (20) decreased the activity.
... However, a preliminary study of the antimicrobial activity of lupeol acetate, 31-norlanostenol and euphorbol against several fungal and bacterial phytopathogens did not show any noticeable activity. Several studies reported that modification of triterpenes through enzymatic or chemical synthesis often resulted in enhanced biological activities [12][13][14][15][16]. In this study we attempted to enhance the activity of lupeol acetate and 31-norlanostenol through chemical modification. ...
... Supplementary data: 1 H, 13 C and DEPT NMR data, as well as details on the inhibition of radial growth of Verticillium dahlia, are also available. ...
This study evaluated the in vitro antimicrobial effect of 3β-acetoxy-norlup-20-one (1) and 3-chloro-4a,14a-dimethyl-5a-cholest-8-ene (2), triterpene derivatives from Euphorbia officinarum latex against fungal and bacterial phytopathogens. Results showed that although mycelial growth of several strains of Vericillium dahlia, and Fusarium oxysporum fsp. melonis and Penicillium expansum was affected only moderately, the two compounds were able to reduce highly conidia formation and germination, suggesting that they act as fungistatic compounds. Their antibacterial activity was tested against Pseudomonas syringae pv. syringae (Pss), P. syringae pv. tabacci (Pst), Erwinia amylovora (Ea) and Agrobacterium tumefaciens (At) using disc diffusion method. Results showed that compound 2 was more effective in inhibiting the growth of Pss, Pst and Ea than compound 1.
... However, a preliminary study of the antimicrobial activity of lupeol acetate, 31-norlanostenol and euphorbol against several fungal and bacterial phytopathogens did not show any noticeable activity. Several studies reported that modification of triterpenes through enzymatic or chemical synthesis often resulted in enhanced biological activities [12][13][14][15][16]. In this study we attempted to enhance the activity of lupeol acetate and 31-norlanostenol through chemical modification. ...
... Supplementary data: 1 H, 13 C and DEPT NMR data, as well as details on the inhibition of radial growth of Verticillium dahlia, are also available. ...
This study evaluated the in vitro antimicrobial effect of 3β-acetoxy-norlup-20-one (1) and 3-chloro-4α,14α-dimethyl-5α-cholest-8-ene (2), triterpene
derivatives from Euphorbia officinarum latex against fungal and bacterial phytopathogens. Results showed that although mycelial growth of several strains of
Verticillium dahlia, and Fusarium oxysporum fsp. melonis and Penicillium expansum was affected only moderately, the two compounds were able to reduce
highly conidia formation and germination, suggesting that they act as fungistatic compounds. Their antibacterial activity was tested against Pseudomonas
syringae pv. syringae (Pss), P. syringae pv. tabacci (Pst), Erwinia amylovora (Ea) and Agrobacterium tumefaciens (At) using disc diffusion method. Results
showed that compound 2 was more effective in inhibiting the growth of Pss, Pst and Ea than compound 1
... Thus, further analysis and exploration on their application in food and human health, post-modification of triterpenes could serve as a major interest of the natural products sector. Post-modification of triterpenes can be achieved through the enzymatic biosynthesis such as P450 monooxidases (Seki et al., 2008;Zhu et al., 2011), glycosyl transferases (Zhu et al., 2011) as well as chemical synthesis (Yu et al., 2013;Huang et al., 2014). Oxygenated and glycosylated triterpenes often associated with improved functionality in biological mediums as well as foods (Agustin et al., 2011). ...
... Thus, further analysis and exploration on their application in food and human health, post-modification of triterpenes could serve as a major interest of the natural products sector. Post-modification of triterpenes can be achieved through the enzymatic biosynthesis such as P450 monooxidases (Seki et al., 2008;Zhu et al., 2011), glycosyl transferases (Zhu et al., 2011) as well as chemical synthesis (Yu et al., 2013;Huang et al., 2014). Oxygenated and glycosylated triterpenes often associated with improved functionality in biological mediums as well as foods (Agustin et al., 2011). ...
The study aimed to isolate and elucidate the chemical compounds that are found in banana (Musa balbisiana cv. Saba) inflorescences. Banana inflorescence buds were extracted using methanol and the resulted methanolic extract was partitioned using chloroform, ethyl acetate and butanol against deionized water. The chloroform partition was further separated into fractions using column chromatography assisted by thin layer chromatography. The structure elucidation was performed using nuclear magnetic resonance spectrometry (NMR). Three triterpenes were isolated namely 31-norcyclolaudenone (1), cycloartenol (2) and (24R)-4a,24- trimethyl-5a-cholesta-8,25(27)-dien-3b-ol (3). This is the first report on the isolation of these triterpenes from Musa balbisiana inflorescence. The discovery of new triterpenes from banana inflorescence should be further explored to open a new perspective that banana by-products might serve as new source of natural products for food and pharmaceutical applications.
... So far, GTs from bacteria, plants and animals have been extensively studied. Despite the great potential of fungi as whole-cell biocatalysts for the glycosylation of various substances [28][29][30][31][32][33][34], only a few fungal GTs, such as MhGT1 from Mucor hiemalis, UGT58A1 from Rhizopus japonicus, UGT59A1 from Absidia coerulea and BbGT86 from Beauveria bassiana, have been isolated and characterized [35][36][37]. ...
Quercetin is the most abundant flavonoid in food products, including berries, apples, cauliflower, tea, cabbage, nuts, onions, red wine and fruit juices. It exhibits various biological activities and is used for medical applications, such as treating allergic, inflammatory and metabolic disorders, ophthalmic and cardiovascular diseases, and arthritis. However, its low water solubility may limit quercetin’s therapeutic potential. One method of increasing the solubility of active compounds is their coupling to polar molecules, such as sugars. The attachment of a glucose unit impacts the stability and solubility of flavonoids and often determines their bioavailability and bioactivity. Entomopathogenic fungi are biocatalysts well known for their ability to attach glucose and its 4-O-methyl derivative to bioactive compounds, including flavonoids. We investigated the ability of cultures of entomopathogenic fungi belonging to Beauveria, Isaria, Metapochonia, Lecanicillium and Metarhizium genera to biotransform quercetin. Three major glycosylation products were detected: (1), 7-O-β-D-(4″-O-methylglucopyranosyl)-quercetin, (2) 3-O-β-D-(4″-O-methylglucopyranosyl)-quercetin and (3) 3-O-β-D-(glucopyranosyl)-quercetin. The results show evident variability of the biotransformation process, both between strains of the tested biocatalysts from different species and between strains of the same species. Pharmacokinetic and pharmacodynamic properties of the obtained compounds were predicted with the use of cheminformatics tools. The study showed that the obtained compounds may have applications as effective modulators of intestinal flora and may be stronger hepato-, cardio- and vasoprotectants and free radical scavengers than quercetin.
... A 10% inoculum derived from 24 h old stage I cultures was used to initiate stage II cultures, which were incubated for 24 h before receiving 10 mg of the substrate in 1 mL of ethanol, and incubation was conducted as before. 15 2.3. Extraction, Isolation, and Purification. ...
Pentacyclic triterpenoids are considered to be the potential HMGB1 inhibitors, but due to the limited number of hydrogen bond donors and the number of rotatable bonds in the rigid skeletons, their further chemical biology research with this target was restricted. To improve these profiles, microbial-catalyzed Baeyer-Villiger oxidation of the primary ursane and oleanane-type triterpenoids including uvaol (1), erythrodiol (2), oleanolic acid (3), and ursolic acid (4) was performed by Streptomyces olivaceus CICC 23628. As a result, ten new and one known A-ring cleaved metabolites were obtained and the possible biogenetic pathways were also discussed based on the HPLC-MS analysis. Furthermore, the direct interactions between compounds 1d, 2b, and HMGB1 were observed by the biolayer interferometry technique. Molecular docking revealed that the newly introduced vicinal diol at C-4, C-24, and the hydroxyl group at C-21 of compound 1d are crucial for binding with HMGB1. The cellular assay showed that co-treatment of 1d could significantly block HMGB1-activated nitric oxide release with an IC50 value of 9.37 μM on RAW 264.7 cells. Altogether, our research provides some insights into 3,4-seco-triterpenes as potential anti-inflammatory candidates for the discovery of novel HMGB1 inhibitors.
... (90-92, 94-101). The microbial catalyzed high efficient regio-selective methyl oxidation and glycosylation were discovered, which could be provided as an alternative method to expand the structural diversity of OPTs (Fig. 9) [22]. ...
... (90-92, 94-101). The microbial catalyzed high efficient regio-selective methyl oxidation and glycosylation were discovered, which could be provided as an alternative method to expand the structural diversity of OPTs (Fig. 9) [22]. ...
Natural products are structurally and biologically interesting metabolites, but they have been isolated in minute amounts. The syntheses of such natural products help in obtaining them in bulk amounts. The recognition of microbial biotransformation as important manufacturing tool has increased in chemical and pharmaceutical industries. In recent years, microbial transformation is increasing significantly from limited interest into highly active area in green chemistry including preparation of pharmaceutical products. This is the first review published
... (90-92, 94-101). The microbial catalyzed high efficient regio-selective methyl oxidation and glycosylation were discovered, which could be provided as an alternative method to expand the structural diversity of OPTs (Fig. 9) [22]. ...
Natural products are structurally and biologically interesting metabolites, but they have been isolated in minute amounts. The syntheses of such natural products help in obtaining them in bulk amounts. The recognition of microbial biotransformation as important manufacturing tool has increased in chemical and pharmaceutical industries. In recent years, microbial transformation is increasing significantly from limited interest into highly active area in green chemistry including preparation of pharmaceutical products. This is the first review published on the usage of microbial biocatalysts for some natural product classes and natural product drugs.
... [80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95], 5[89,[95][96][97][98][99][100][101][102][103][104][105], 6 [81-83,88,89,91-95,103], 7 [51,89,95,99, 100,104-109]) have been assayed (see ...
Gymnema sylvestre R. Br., one of the most important medicinal plants of the Asclepiadaceae family, is a herb distributed throughout the World, predominantly in tropical countries. The plant, widely used for the treatment of diabetes and as a diuretic in Indian proprietary medicines, possesses beneficial digestive, anti-inflammatory, hypoglycemic and anti-helmentic effects. Furthermore, it is believed to be useful in the treatment of dyspepsia, constipation, jaundice, hemorrhoids, cardiopathy, asthma, bronchitis and leucoderma. A literature survey revealed that some other notable pharmacological activities of the plant such as anti-obesity, hypolipidemic, antimicrobial, free radical scavenging and anti-inflammatory properties have been proven too. This paper aims to summarize the chemical and pharmacological reports on a large group of C-4 gem-dimethylated pentacyclic triterpenoids from Gymnema sylvestre.
... In all cases, a more polar metabolite, a 28-O-b-D-glucopyranosyl derivative (67, 73, and 74), was isolated. This highly efficient and regio-selective glucosylation of the carboxyl group at C-28 from A. ochraceus will have great advantages over other chemical methods (Zhu et al. 2011) (Fig. 17). ...
A significant number of terpenoid compounds are glycosides with the sugars linked to the active groups. Sometimes, the glycosidic residue is crucial for their activity, but in other cases glycosylation only improves pharmacokinetic parameters. Enzymatic glycosylation of terpenoids is a useful tool due to the high selectivity and the mildness of the reaction conditions, in comparison with chemical methods. Several types of biocatalysts have been used in the enzymatic glycosylation of terpenoids. These include the use of glycosyltransferases, trans-glycosidases, and whole-cell biotransformation systems capable of regenerating the cofactor, such as fungi, bacteria, plant-cell cultures, etc. Many biosynthesized terpenoid glycosides display medicinal and pharmacological properties and can be used as pro-drug substances. These terpenoid glycosides have also been employed as food additives (e.g. low-caloric sweetener compounds) and cosmetics, and even have applications as controlled-release fragrances.
... Biotransformation methods can be used as an alternative to the traditional chemical synthesis in search of new production routes for fine chemical, pharmaceutical, and agrochemical compounds. Several biotransformations of oleanolic acid (1), using different microorganisms, have been published (Hikino et al., 1969(Hikino et al., , 1971(Hikino et al., , 1972aZhang et al., 2005;Wang et al., 2006;Choudhary et al., 2008;Sun et al., 2010;Capel et al., 2011;Liu et al., 2011;Zhu et al., 2011). Recently, the first biotransformation of maslinic acid by Cunninghamella blakesleana has been described (Feng et al., 2012). ...
Microbial transformation of oleanolic acid by Rhizomucor miehei produced three metabolites. A known compound, a 30-hydroxyl derivative (queretaroic acid), and two 7β,30- and 1β,30-dihydroxylated metabolites, respectively. The action of the same fungus (R. miehei) on maslinic acid produced an olean-11-en-28,13β-olide derivative, a metabolite hydroxylated at C-30, an 11-oxo derivative, and two metabolites with an 11α,12α-epoxy group, hydroxylated or not at C-30. Their structures were elucidated by extensive analyses of their spectroscopic data, and also by chemical correlations.
Actinobacteria are one of the most intriguing bacterial phyla in terms of chemical diversity and bioactivities of their reported biomolecules and natural products, including various types of chiral molecules. Actinobacterial genera such as Detzia, Mycobacterium, and Streptomyces are among the microbial sources targeted for selective reactions such as asymmetric biocatalysis catalyzed by whole cells or enzymes induced in their cell niche. Remarkably, stereoselective reactions catalyzed by actinobacterial whole cells or their enzymes include stereoselective oxidation, stereoselective reduction, kinetic resolution, asymmetric hydrolysis, and selective transamination, among others. Species of actinobacteria function with high chemo‐, regio‐, and enantio‐selectivity under benign conditions, which could help current industrial processing. Numerous selective enzymes were either isolated from actinobacteria or expressed from actinobacteria in other microbes and hence exploited in the production of pure organic compounds difficult to obtain chemically. In addition, different species of actinobacteria, especially Streptomyces species, function as natural producers of chiral molecules of therapeutic importance. Herein, we discuss some of the most outstanding contributions of actinobacteria to asymmetric biocatalysis, which are important in the organic and/or pharmaceutical industries. In addition, we highlight the role of actinobacteria as microbial cell factories for chiral natural products with insights into their various biological potentialities.
Several 2,2-bipyridyl-based d-f heterobinuclear [GdCuL1-5(bpy)2(NO3)2] complexes are present, where (Ligand 1) (9E)-N¹-(2-Hydroxy-5-methylbenzylidene)–N²-((E)-2-(2-hydroxy-5-methyl benzylideneamino)ethyl)ethane-1,2-diamine. (Ligand 2) N¹,N¹-bis((E)-2-(2-hydroxy-5-methylbenzylideneamino)ethyl)ethane-1,2-diamine. (Ligand 3) (9E)-N¹-(2-((E)-2-(2-hydroxy-5-methylbenzylideneamino)ethylamino)ethyl)–N²-(2-hydroxy-5-methylbenzylidene)ethane-1,2-diamine. (Ligand 4) (9E)-N¹-(2-((E)-3-(2-hydroxy-5- methylbenzylideneamino) propylamino) ethyl)–N³-(2-hydroxy-5-methylbenzylidene)propane-1,3-diamine and (Ligand 5) (9E)-N-(2-hydroxy-5-methylbenzylidene)-3-(4-((E)-3-(2-hydroxy-5-methylbenzylideneamino)propyl)piperazin-1-yl)propan-1-amine. These compounds were described using spectroscopy and the elemental analysis method. Researches were conducted into the luminous, Genetic code, catalytic, magnetism, and breaking attributes of the [GdCuL1-5(bpy)2(NO3)2] complexes. In DMF with 0.1 M tetra-n-butylammonium perchlorate, the binuclear [GdCuL1-5(bpy)2(NO3)2] network complexes exhibit two one electron irreversible reduction events. VSM was used to calculate the complexes' magnetic susceptibility. There is ferromagnetic coupling in the [GdCuL1-5(bpy)2(NO3)2] complexes. The [GdCuL1-5(bpy)2(NO3)2] complexes' excited state lifetimes lengthen in the following order: [GdCuL5(bpy)2] [GdCuL1(bpy)2(NO3)2] [GdCuL3(bpy)2(NO3)2] [GdCuL4(bpy)2] and [GdCuL2(bpy)2(NO3)2]. The binuclear [GdCuL1-5(bpy)2(NO3)2] complexes' inceptive rate of progress for oxidizing 1,2-benzenediol to cyclohexa-3,5-diene-1,2-dione are longer chains with higher activity. Both the [GdCuL5(bpy)2(NO3)2] and [GdCuL4(bpy)2(NO3)2] complexes have strong DNA genetic code properties in the calf genus thymus. The complexes exhibit considerable singlet oxygen-mediated oxidative rift of circular recombinant plasmid pBR322 cloning vector in the existence of 2-sulfanylethanol.
Selective oxidation reactions represent a challenging task for conventional organic chemistry. Whole-cell biocatalysis provides a very convenient, easy to apply method to carry out different selective oxidation reactions including chemo-, regio-, and enantio-selective reactions. Streptomyces species are important biocatalysts as they can catalyze these selective reactions very efficiently owing to the wide diversity of enzymes and enzymatic cascades in their cell niche. In this review, we present and analyze most of the examples reported to date of oxidative reactions catalyzed by Streptomyces species as whole-cell biocatalysts. We discuss 33 different Streptomyces species and strains and the role they play in different oxidative reactions over the past five decades. The oxidative reactions have been classified into seven categories that include: hydroxylation of steroids/non-steroids, asymmetric sulfoxidations, oxidation of aldehydes, multi-step oxidations, oxidative cleavage, and N-oxidations. The role played by Streptomyces species as recombinant hosts catalyzing bio-oxidations has also been highlighted.
Flavonoids, terpenoids, and polyketides are structurally diverse secondary metabolites used widely as pharmaceuticals and nutraceuticals. Most of these molecules exist in nature as glycosides, in which sugar residues act as a decisive factor in their architectural complexity and bioactivity. Engineering glycosylation through selective trimming or extension of the sugar residues in these molecules is a prerequisite to their commercial production as well to creating novel derivatives with specialized functions. Traditional chemical glycosylation methods are tedious and can offer only limited end-product diversity. New in vitro and in vivo biocatalytic tools have emerged as outstanding platforms for engineering glycosylation in these three classes of secondary metabolites to create a large repertoire of versatile glycoprofiles. As knowledge has increased about secondary metabolite–associated promiscuous glycosyltransferases and sugar biosynthetic machinery, along with phenomenal progress in combinatorial biosynthesis, reliable industrial production of unnatural secondary metabolites has gained momentum in recent years. This review highlights the significant role of sugar residues in naturally occurring flavonoids, terpenoids, and polyketide antibiotics. General biocatalytic tools used to alter the identity and pattern of sugar molecules are described, followed by a detailed illustration of diverse strategies used in the past decade to engineer glycosylation of these valuable metabolites, exemplified with commercialized products and patents. By addressing the challenges involved in current bio catalytic methods and considering the perspectives portrayed in this review, exceptional drugs, flavors, and aromas from these small molecules could come to dominate the natural-product industry.
Glycosylation endows both natural and synthetic small molecules with modulated physico-chemical and biological properties. Plant and bacterial glycosyltransferases capable of decorating various privileged scaffolds have been extensively studied, but those from kingdom Fungi still remain underexploited. Here, we use a combination of genome mining and heterologous expression techniques to identify four novel glycosyltransferase-methyltransferase (GT-MT) functional modules from Hypocreales fungi. These GT-MT modules display decent substrate promiscuity and regiospecificity, methylglucosylating a panel of natural products such as flavonoids, stilbenoids, anthraquinones, and benzendiol lactones. Native GT-MT modules can be spilt up and regrouped into hybrid modules with similar or even improved efficacy as compared with native pairs. Methylglucosylation of kaempferol considerably improves its insecticidal activity against the larvae of oriental armyworm Mythimna separata (Walker). Our work provides a set of efficient biocatalysts for the combinatorial biosynthesis of small molecule glycosides that may have significant importance to pharmaceutical, agricultural, and food industries.
Colchicinoids and their derivatives are of great importance in pharmaceutical applications, and colchicine is usually used as the first choice for the treatment of gout. To expand the structural diversities and clinical application of colchicinoids, many attempts have been established for the derivatives with better activity or less toxicity. Herein, in this paper, we report a direct microbial transformation of colchicine into 2-O-demethyl-colchicine (M1) and 3-O-demethl-colchicine (M2) by Streptomyces griseus ATCC 13273. It is noteworthy that when DMF was used as co-solvent, the yield of M1 and M2 could reach up to 51 and 31%, respectively. All the structures of the metabolites were elucidated unambiguously by ESI-MS, ¹H–NMR, ¹³C–NMR, and 2D–NMR spectroscopy.
The oxidization of unactivated C–H bonds is of great interests in the structural modification of pentacyclic triterpenes. Herein we discovered the unique capability of Streptomyces griseus ATCC 13273 to catalyze the site-selective oxidation of C-29 methyl group to carboxyl group over a range of oleanane triterpenes, oleanolic acid (1), hederagenin (2), echinocystic acid (3), quillaic acid (4) and senegenin (5). Along with this reaction the hydroxylation on C-24 and C-21 were also discovered on some substrates. As a result, eight new compounds (1c, 2a∼5a and 2b∼4b) among the ten metabolites were isolated. The anti-inflammatory activities of these compounds were evaluated against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages, and the products with hydroxyl group on C-21 (1c, 2b and 5a) showed significantly enhanced activities with the IC50 values of 1.230, 0.078 and 0.015 μM, respectively. Thus S. griseus ATCC 13273 was further proved as a useful biocatalyst to expand the structural diversity of oleanane triterpenes for medicinal chemistry research.
The oxidization of unactivated C–H bonds of pentacyclic triterpenes (PTs) is of great interest for the structural modification of PTs. Herein, we discovered the unique capability of Streptomyces griseus ATCC 13273 to catalyze the site-selective oxidation of the C-30 methyl group to the carboxyl group and hydroxylation of the C-24 methyl group over a range of ursane triterpenes, including ursolic acid (1), 3-oxo ursolic acid (2), and corosolic acid (3). It is noteworthy that while using asiatic acid (4) and madasiatic acid (5), which bear one hydroxyl group on C-23 as substrates, the hydroxylation on C-24 was blocked. As a result, eight new compounds (1a–3a, 5a, 1b–3b and 5b) of the metabolites were isolated and their structures were elucidated based on 1D and 2D NMR and HR-MS data. In addition, the cytotoxicity of substrates and transformed products was preliminarily evaluated by an MTT assay.
Microbial transformation of ursolic acid (1) by Bacillus megaterium CGMCC 1.1741 was investigated and yielded five metabolites identified as 3-oxo-urs-12-en-28-oic acid (2); 1β, 11α-dihydroxy-3-oxo-urs-12-en-28-oic acid (3); 1β-hydroxy-3-oxo-urs-12-en-28, 13-lactoe (4); 1β, 3β, 11α-trihydroxyurs-12-en-28-oic acid (5) and 1β, 11α-dihydroxy-3-oxo-urs-12-en-28-O-β- D- glucopyranoside (6). Metabolites 3, 4, 5 and 6 were new natural products. Their nitric oxide (NO) production inhibitory activity was assessed in lipopolysaccharide (LPS) - stimulated RAW 264.7 cells. Compounds 3 and 4 exhibited significant activities with the IC50 values of 1.243 and 1.711 μM, respectively. A primary structure-activity relationship was also discussed.
To discover new inhibitors on tissue factor procoagulant activity, 20 pentacyclic triterpenes were semi-synthetized through microbial transformation and assayed on the model of human THP-1 cells stimulated by lipopolysaccharide. In the biotransformation two types of reactions were observed, regio-selective hydroxylation and glycosylation. The bioassay results showed that most of tested compounds were significant effective on this model and two of the biotransformation products 23-hydroxy-28-O-β-D-glucopyranosyl betulinic acid (3d) and 28-O-β-D-glucopyranosyl oleanic acid (1a) exhibited most potential activites with the IC50 values of 0.028, 0.035nM respectively. The preliminary structure and activity relationship analysis revealed that the aglycones with single free hydroxyl group on the skeleton (1, 1j) were less effective than that with more free hydroxyl groups (1d, 1f, 2), mono-glycosylation can significantly enhance their inhibitory effects. Our findings also provide some potential leading compounds for tissue factor-related diseases, such as cancer and cardiovascular diseases.
A series of new simplified oleanolic acid saponins with a glycosyl ester moiety at C28, were efficiently prepared. Furthermore, the effect of nasal administration of the synthetic oleanolic acid saponins on the nasal anti-influenza virus antibody titer against secondary nasal inoculation of the influenza split vaccine was examined. The result revealed cinnamoyl saponin as a suitable candidate vaccine adjuvant.
Background:
Panacis Japonici Rhizoma (PJR) is one of the most famous Chinese medical herbs that is known for exhibiting potential anti-cancer effects.
Purpose:
This study aims to isolate and investigate the anti-cancer potential of saponins from PJR in ovarian cancer cells.
Methods:
The compounds were separated by comprehensive chromatographic methods. By comparison of the 1H- and 13C NMR data, as well as the HR-ESI-MS data, with the corresponding references, the structures of compounds were determined. MTT assay was performed to evaluate cell viability, along with flow cytometry for cell cycle analysis. JC-1 staining, Annexin V-PI double staining as well as Hoechst 33; 342 staining were used for detecting cell apoptosis. Western blot analysis was conducted to determine the relative protein level. Transwell assays were performed to investigate the effect of the saponin on cell migration and invasion and zymography experiments were used to detect the enzymatic activities.
Results:
Eleven saponins were isolated from PJR and their anti-proliferative effects were evaluated in human ovarian cancer cells. Chikusetsusaponin IVa methyl ester (1) exhibited the highest anti-proliferative potential among these isolates with the IC50 values at less than 10 µM in both ovarian cancer A2780 and HEY cell lines. Compound 1 induced G1 cell cycle arrest accompanied with an S phase decrease, and down-regulated the expression of cyclin D1, CDK2, and CDK6. Further study showed that compound 1 effectively decreased the cell mitochondrial membrane potential, increased the annexin V positive cells and nuclear chromatin condensation, as well as enhanced the expression of cleaved PARP, Bax and cleaved-caspase 3 while decreasing that of Bcl-2. Moreover, compound 1 suppressed the migration and invasion of HEY and A2780 cells, down-regulated the expression of Cdc42, Rac, RohA, MMP2 and MMP9, and decreased the enzymatic activities of MMP2 and MMP9.
Conclusion:
These results provide a comprehensive evaluation of compound 1 as a potential agent for the treatment of ovarian cancer.
The most recent results about the products of microbial transformation of pentacyclic triterpenes of the lupan, olean, and ursan families are reviewed, with some of the available informations about their biological activities.
Biotransformation studies of harmine by S. griseus ATCC 13273 were conducted. S. griseus ATCC 13273 catalyzed the microbial transformation process of harmine into two metabolites (H1 and H2). The two metabolites were isolated and identified as harmol and N-hydroxyl-harmine by MS, H-NMR and C-NMR analysis. The optimization of harmine biotransformation conditions was carried out and the optimal conditions were determined as follows:pH value 8.0, substrate concentration 0.25mmoL/L, fermentation time 5 d, addition time 48 h, inoculums concentration 4%, and addition mode dissolved in DMF. Under this optimized condition, the yield of harmol and N-hydroxyl-harmine was 8.70% and 12.76%, respectively. This study enriches the range of substrate S. griseus ATCC 13273 catalysis providing a new approach to synthesize harmol and N-hydroxyl-harmine.
Four new oleanane-type triterpenoid saponins, schefflesides I-L (1-4), were isolated from the aerial parts of Schefflera kwangsiensis. Their structures were established as oleanolic acid 3-O-β-d-glucopyranosyl (1 → 2) [α-l-arabinopyranosyl (1 → 4)]-β-d-(6-O-methyl) glucuronopyranoside (1), 22α-hydroxyoleanolic acid 3-O-α-l-arabinopyranosyl (1 → 4)-β-d-glucuronopyranoside (2), hederagenin 3-O-α-l-arabinopyranosyl (1 → 4)-β-d-glucuronopyranoside (3) and oleanolic acid 28-O-β-d-glucopyranosyl (1 → 2)-β-d-glucuronopyranosyl ester (4) by spectroscopic analyses (HRESIMS, 1D and 2D NMR) and chemical methods.
A new fatty acid, (5E,7E)-9-oxooctadeca-5,7-dienoic acid (1), was isolated from the leaves and stems of Clerodendron trichotomum. The structure of the new compound was elucidated by analysis of spectrometric data.
American ginseng is a widely used natural product. Ginseng products are usually taken orally, and human intestinal microflora may metabolize ginsenosides. Existing publications report the metabolite fates of ginsenosides. However, investigations on the comprehensive metabolic profile of American ginseng extract are absent because of the chemical complexity and limitation of analytical methods. In this work, we studied the biotransformation and metabolic profile of American ginseng extract by human intestinal microflora. Human fecal microflora was prepared from a healthy Chinese man and then anaerobically incubated with American ginseng sample at 37°C for 24h. A rapid and simple liquid-liquid extraction method was used for sample pretreatment. A highly sensitive and selective liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) method was used to characterize ginsenosides and related metabolites in the reaction samples. The LC-Q-TOF-MS provides superior data quality and advanced analytical capabilities for profiling, identifying, and characterizing complex metabolites in matrix-based biological samples. A total of 25 metabolites were detected, 13 of which were undoubtedly assigned by comparison with reference compounds, and 12 others were tentatively identified. The three most abundant metabolites are 20S-ginsenoside Rg3, ginsenoside F2 and compound K. The main metabolic pathways of ginseng saponins are deglycosylation reactions by intestinal microflora through stepwise cleavage of sugar moieties. Subsequent dehydration reactions also occur. Protopanaxadiol- and oleanane-type triterpenoids are easy to metabolize. The intestinal microbiota may play an important role in mediating the metabolism bioactivity of American ginseng.
Microbial transformation of triterpenoids has provided new derivatives that are potentially useful for pharmacological studies. In these biotransformation processes, several reactions that are difficult to achieve by chemical means have been accomplished, such as: introduction of hydroxyl groups into remote positions of the molecules; selective cleavage of the side chains of tetra-cyclic terpenoids to produce C19 steroids; regioselective glycosidic transfer reactions; selective ring cleavage through a Baeyer-Villiger-type oxidation to ren-der seco-triterpenoids; and carbon skeleton rearrangements involving a methyl group migration. These biotransformations have also been used as in vitro models to mimic and predict the mammalian metabolism of biologically active triterpenoids.
In order to establish the possible relationship between their chemical structures and pharmacological properties, the oral and topical anti-inflammatory activities of ten triterpenoids belonging to the lupane, oleanane, and ursane series, were evaluated. All triterpenoids were remarkably active against the edema produced by TPA. While the basic carbon skeleton has no influence on the activity, the presence of a C-28 or C-30 carboxylic group and an alcoholic group at C-28 increases the activity in carrageenan- and EPP-induced edemas, respectively.
Twenty-five naturally occurring pentacyclic triterpenes, 15 of which were synthesized in this study, were biologically evaluated as inhibitors of rabbit muscle glycogen phosphorylase a (GPa). From SAR studies, the presence of a sugar moiety in triterpene saponins resulted in a markedly decreased activity ( 7, 18- 20) or no activity ( 21, 22). These saponins, however, might find their value as potential natural prodrugs which are much more water-soluble than their corresponding aglycones. To elucidate the mechanism of GP inhibition, we have determined the crystal structures of the GPb-asiatic acid and GPb-maslinic acid complexes. The X-ray analysis indicates that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Pentacyclic triterpenes represent a promising class of multiple-target antidiabetic agents that exert hypoglycemic effects, at least in part, through GP inhibition.
Six pentacyclic triterpene acids, ursolic acid, oleanolic acid, betulinic acid, 23-hydroxybetulinic acid, glycyrrhetinic acid, and senegenin, were metabolized by the microbe Nocardia sp. NRRL 5646 to selectively furnish their corresponding 28-methyl esters. Notably, ursolic acid (1) was converted to oleanolic acid methyl ester (4) via two intermediates, oleanolic acid (2), and ursolic acid methyl ester (3), which are formed by participation of ‘retro-biosynthetic’ methyl migration from C-19 to C-20. Senegenin (11) was selectively converted to a nortriterpene methyl ester, senegenic acid methyl ester (12), via an unprecedented C–C bond cleavage. The stereochemical assignments of compounds 11 and 12 were made unambiguously for the first time using 2D NMR spectroscopy.
Preparative-scale biotransformation of quercetin (1), fisetin (7), and (+)-catechin (12) with Streptomyces griseus (ATCC 13273) resulted in the isolation and characterization of nine known hydroxylated and/or methylated (2-6, 8, 9, 11, 13a) metabolites and two previously unknown (10 and 14) metabolites. S. griseus catalyzed aromatic hydroxylations of rings A and B of quercetin and fisetin. Mono- and dimethoxy ring-B metabolites were obtained with all three substrates. Methylation appeared to occur only when catechol functional groups were present. Metabolite structures were established by FABMS, EIMS, and 1D and 2D NMR analysis.
Gleditsia saponin C [1] and gymnocladus saponin G [2] were isolated from Gleditsia japonica and Gymnocladus chinensis, respectively, as anti-HIV principles. Compounds 1 and 2 demonstrated inhibitory effects against HIV replication in H-9 cells with EC(50) values of 1.1 and 2.7 mu M, respectively. Evaluation of the anti-HIV activities of the prosapogenins of 1 and 2 suggested chat the unusual monoterpenyl moieties in 1 and 2 are essential for their anti-HIV activity. Derivatives of echinocystic acid [8], the aglycone of compound 1, were also prepared and evaluated for inhibitory activity against HIV replication 3,16-Di-O-acetylechinocystic acid [12] was shown to be an anti-HIV agent with an EC(50) value of 2.3 mu M.
Twelve triterpene saponins were detected (by TLC) in root cultures of Phytolacca acinosa. Seven were isolated in 0.5–1 g quantities and identified by TLC, 13C, 1H NMR and mass spectra. Among these, esculentoside B, S, A and H, and phytolaccoside F have been detected previously in roots or leaves of P. acinosa and/or P. americana: phytolaccoside F (3-O-α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranosyl-(1 → 2)-β-d-xylopyranosyl-phytolaccagenic acid) has been identified for the first time in P. acinosa. Esculentoside L1 (3-O-β-d-glucopyranosyl-(1 → 2)-β-d-xylopyranosyl-28-O-β-d-glucopyranosyl-phytolaccagenic acid) is an isomer of the earlier described esculentoside L, having an altered linkage of the sugar moiety. Esculentoside R has been isolated for the first time. It has been identified as a bidesmoside of phytolaccoside F with an additional glucose, ester glycosidic linked with C-28.
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Microbial transformation of betulonic acid by Nocardia sp. NRRL 5646 in preparative scale resulted in the isolation of one unexpected asymmetric alpha-hydroxylation product, methyl 2 alpha-acetoxy-3-oxo-lup-20(29)-en-28-oate, and one known compound methyl 3-oxo-lup-20(29)-en-28-oate. The structures of metabolites were elucidated unambiguously by ESI-MS, 2D-NMR spectroscopy. This is the first successful microbial transformation of ketone alpha-hydroxylation of lupane-type pentacyclic triterpenes.
Streptomyces griseus NRRL 8090 catalyzed the biotransformation of naphthalene (1) to 4-hydroxy-1-tetralone (4) in good yield. The bioconversion pathway from 1 to 1-naphthol (2) and 1-tetralone (3) was surmised by feeding 2 and 3 as substrates and measuring 4 formation by gas chromatography. Tetralin and 1, 4-naphthoquinone were not biotransformed by S. griseus. 2-Methyl-1,4-naphthoquinone (5) was converted to 2-methyl-4-hydroxytetralone (6) while 2-methylnaphthalene was not a substrate for S. griseus. All products were isolated by solvent extraction, chromatographically purified and characterized by gas chromatography/mass spectrometry (GC/MS) and 1H- and 13C-NMR spectroscopy. Unlike previous work in fungi, 4 is the major naphthalene metabolite, and the pathway for S. griseus conversion of naphthalene is different.
Echinocystic acid (3β,16α-dihydroxy-olean-12-en-28-oic acid 1) is a complex compound with many bioactivities. Microbial transformation of echinocystic acid (1) by Nocardia corallina CGMCC4.1037 has been studied. Incubation of echinocystic acid with N.corallina CGMCC4.1037 afforded three metabolites: 3-oxo-16α-hydroxy-olean-12-en-28-oic acid (2), 3β,16α-dihydroxy-olean-12-en-28-oic acid 28-O-β-d-glucopyranoside (3), and 3-oxo-16α-hydroxy-olean-12-en-28-oic acid 28-O-β-d-glucopyranoside (4). Product (4) was a new product. Their structure elucidation was mainly based on the HRMS and NMR data. The possible mechanism of the regio-selective oxidation of the 3-OH and a probable sequence of these transformations were also discussed. This is the first report on the microbial transformation of echinocystic acid (1). This method may open a new route to the future modification of echinocystic acid (1).
Myriceric acid A (1) is an oleanane triterpene that is a potent and specific endothelin A receptor antagonist. A practical procedure for large-scale synthesis of myriceric acid A (1) has been developed starting from oleanolic acid 4. The conversion of oleanolic acid 4 to the key intermediate myricerone 3 was achieved in an efficient manner employing a photochemical reaction (the Barton reaction) of nitrite 7. Our synthetic procedure alleviated several difficulties of the original Barton's procedure with regard to yields and large-scale operation. Myricerone 3 afforded Horner−Wadsworth−Emmons (HWE) type phosphonate 2 which has proved to be a versatile precursor of 1. The preparation of phosphonate 2 on a scale of several hundred grams is described. The synthesis was completed by condensation of 2 with 3,4-bis[(diphenylmethyl)oxy]benzaldehyde (21), giving α,β-unsaturated ester 22, which was deprotected to afford 1. The whole synthetic sequence is efficient (14 steps, 31% yield) and requires no chromatographic purification except to obtain the final product 1.
Microbial transformation of one oleane-type pentacyclic triterpene aglycone, phytolaccagenin (2β,3β,23-trihydroxy-olean-12-ene-28,30-dioic acid 30-methyl ester) by Streptomyces griseus ATCC 13273 was investigated for developing new bioactive derivatives. A new oxidized metabolite, through the regio-specific hydroxylation on the C-29 methyl group, was obtained from the preparative-scale biotransformation with a standard two-stage fermentation protocol. The metabolite was identified as 2β,3β,23,29-tetrahydroxy-olean-12-ene-28,30-dioic acid 30-methyl ester by mass and 2D-NMR spectra.
In connection with structure studies on triterpenoid glycosides fromPhytolacca plants, full assignments of13C-NMR signals of phytolaccagenin and its glycosides, phytolaccoside B and E, have been presented.
Triterpenoids isolated and characterized from various sources are reviewed. The newer spectroscopic techniques used in their structure elucidation, the new skeleta characterized, their total chemical synthesis, and their biosynthesis are discussed. A compilation of the triterpenoids isolated during the period 1990–1994 along with their occurrence, physical data, spectroscopy and X-ray analysis used for their characterization, is included. The biological activities of the triterpenoids are also discussed.
Synthesis and biological evaluation of glucoconjugates of oleanolic acid, linked by either a triazole moiety or an ester function, as novel inhibitors of glycogen phosphorylase have been described. Several triterpene-glycoside conjugates exhibited moderate-to-good inhibitory activity against rabbit muscle GPa. Compound 12 showed the best inhibition with an IC(50) value of 1.14 microM. Structure-activity relationship (SAR) analysis of these inhibitors is also discussed. Possible binding modes of compound 12 were explored by molecular docking simulations.
Oleanolic acid, a natural product, possesses an anti-osteoclast formation activity. Targeting at discovery of novel and potent anti-bone resorption agents, 22 glycosides of oleanolic acid derivatives (including d-galactopyranosides, d-glucopyranosides, d-xylopyranoses, d-arabopyranoses and d-glycuronic acids) were synthesized at phase-transfer-catalyzed conditions (K(2)CO(3), Bu(4)NBr, CH(2)Cl(2)-H(2)O) and their inhibitory activity on the formation of osteoclast-like multinucleated cells (OCLs) induced by 1alpha, 25-dihydroxy vitamin D(3) was evaluated in a co-culture assay system. The structure-activity relationships of these compounds were also discussed.
Microbial transformations have been employed as a method for producing quantities of a potentially active metabolite of the antitumor alkaloid acronycine. More than 40 microorganisms were screened for their abilities to convert acronycine to metabolites in small-scale fermentations. Ten cultures were found to accumulate one or more acronycine derivatives in culture media. In larger scale fermentations, Cunninghamella echinulata (NRRL 3655) converted acronycine to the phenolic metabolite, 9-hydroxyacronycine, in 30% yield. The extremely insoluble metabolite was acetylated and its structure established by spectral methods. The potential of microbial transformations as a tool for producing synthetically difficult derivatives of antitumor agents is discussed.
Three new triterpenoid saponins were isolated from the alcoholic extract of the bark of Nothopanax davidii. Their structures have been determined on the basis of spectral and chemical data as 3-O-alpha-(4'-O-acetyl)-L-arabinopyranosyl-3 beta-hydroxyolean-12-ene- 28,29-dioic acid-28-O-[alpha-L-rhamnopyranosyl(1-->4)-beta-D-glucopyranosyl (1-->6)-beta-D-glucopyranosyl]ester, named yiyeliangwanoside IX; 3-O-alpha-(2'-O-acetyl)-L-arabinopyranosyl-3 beta-hydroxyolean-12-ene-28,29- dioic acid-28-O-[alpha-L-rhamnopyranosyl(1-->4)-beta-D-glucopyranosyl(1-->6)- beta-D-glucopyranosyl] ester, named yiyeliangwanoside X; and 3-O-beta-d-xylopyranosyl-3 beta-hydroxyolean-12-ene-28,29-dioic acid-28-O-[alpha-L-rhamnopyranosyl(1-->4)-beta-D-glucopyranosyl(1-->6)-b eta-D - glucopyranosyl] ester, named yiyeliangwanoside XI.
Two new oleanene-type triterpenoids, dillenic acids D and E, have been isolated from the leaves and stems of Dillenia papuana together with the new natural product 3-oxoolean-12-en-30-oic acid. Together with these compounds, the known compound, betulinic acid (3 beta-hydroxy-20(29)-lupen-28-oic acid) was isolated as the major component of the fractions studied. Dillenic acids D and E were characterized as 2,3-seco-2-oxoolean-12-en-3-methylester-30-oic acid and 1 alpha,3 beta-dihydroxyolean-12-en-30-oic acid and their nuclear magnetic resonance data were unambiguously assigned using two-dimensional nuclear magnetic resonance techniques. A comparison of antibacterial activities of these compounds with the earlier reported dillenic acids A-C indicated that, aside from a double bond in gamma- or delta-position to a carboxylic group, a ketone function in ring A of an oleanene-skeleton may be required for the observed activity.
As the first non-peptide endothelin receptor antagonist from a higher plant, a new triterpenoid, myriceric acid A (50-235) (1) was isolated from the bayberry, Myrica cerifera. Myriceric acid A (1) inhibited not only an endothelin-1-induced increase in cytosolic free Ca2+ concentration (IC50 = 11 +/- 2 nM) but [125I]endothelin-1 binding in rat aortic smooth muscle cells (Ki = 66 +/- 15 nM). Two new related triterpenoids, myriceric acid C (6), and myriceric acid D (8), were also isolated. Furthermore, the chemical modification of these natural products led to the synthesis of sulfated derivatives (13, 14, 15) which showed 1.5 to 20 times higher affinity for endothelin receptors. The structure activity relationships of myriceric acids and their derivatives are discussed.
We have designed and synthesized 16 new olean- and urs-1-en-3-one triterpenoids with various modified rings C as potential antiinflammatory and cancer chemopreventive agents and evaluated their inhibitory activities against production of nitric oxide induced by interferon-gamma in mouse macrophages. This investigation revealed that 9(11)-en-12-one and 12-en-11-one functionalities in ring C increase the potency by about 2-10 times compared with the original 12-ene. Subsequently, we have designed and synthesized novel olean- and urs-1-en-3-one derivatives with nitrile and carboxyl groups at C-2 in ring A and with 9(11)-en-12-one and 12-en-11-one functionalities in ring C. Among them, we have found that methyl 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oate (25), 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) (26), and methyl 2-carboxy-3,12-dioxooleana-1,9(11)-dien-28-oate (29) have extremely high potency (IC(50) = 0.1 nM level). Their potency is similar to that of dexamethasone although they do not act through the glucocorticoid receptor. Overall, the combination of modified rings A and C increases the potency by about 10 000 times compared with the lead compound, 3-oxooleana-1,12-dien-28-oic acid (8) (IC(50) = 1 microM level). The selected oleanane triterpenoid, CDDO (26), was found to be a potent, multifunctional agent in various in vitro assays and to show antiinflammatory activity against thioglycollate-interferon-gamma-induced mouse peritonitis.
One of the best known bioactive triterpenoids is oleanolic acid, a widespread 3-hydroxy-17-carboxy oleanane-type compound. In order to determine whether further oxidation of carbon 3 affects anti-inflammatory activity in mice, different tests were carried out on oleanolic acid and its 3-oxo-analogue oleanonic acid, which was obtained from Pistacia terebinthus galls. The last one showed activity on the ear oedema induced by 12-deoxyphorbol-13-phenylacetate (DPP), the dermatitis induced by multiple applications of 12-O-tetradecanoyl-13-acetate (TPA) and the paw oedemas induced by bradykinin and phospholipase A2. The production of leukotriene B4 from rat peritoneal leukocytes was reduced by oleanonic acid with an IC50 of 17 microM. Negligible differences were observed in the response of both triterpenes to DPP, bradykinin, and phospholipase A2, while oleanonic acid was more active on the dermatitis by TPA and on the in vitro leukotriene formation. In conclusion, the presence of a ketone at C-3 implies an increase in the inhibitory effects on models related to 5-lipoxygenase activity and on associated in vivo inflammatory processes.
This review covers the isolation and structure determination of triterpenoids including squalene derivatives, protostanes, lanostanes, holostanes, cycloartanes, dammaranes, euphanes, tirucallanes, tetranortriterpenoids, lupanes, oleananes, friedelanes, ursanes, hopanes, isomalabaricanes and saponins; 574 references are cited.
[reaction: see text] Quinovic acid glycosides were microbially deglycosylated by a Nocardia sp. to their aglycon quinovic acid and its biogenetic counterpart, cincholic acid (3), via an unprecedented carbon skeleton rearrangement involving a methyl group migration. The structures of the metabolites were established by ESI-LC/MS and 2D-NMR techniques.
Two series of oleanolic acid derivatives were synthesized and their inhibitory activity on the formation of osteoclast-like multinucleated cells (OCLs) induced by 1alpha,25-dihydroxy vitamin D3 was evaluated in a co-culture assay system. The structure-activity relationships, together with electronic structure based on the frontier molecular orbitals, for example, HOMO and LUMO, related to different amino acid substituents were studied. Derivatives with proline or phenylalanine showed a tendency to enhance the inhibitory activity.
Oleanolic acid (3beta-hydroxy-olea-12-en-28-oic acid, OA) exists widely in plant kingdom and possesses various pharmacological activities. In recent years, it was found that it had marked anti-tumor effects and exhibited cytotoxic activity towards many cancer cell lines in culture. In this article, the anti-tumor and differentiation-inducing effects of a derivative of OA modified at C-3, 3-oxo oleanolic acid (3-oxo-olea-12-en-28-oic acid, 3-oxo-OA, 3-7-1) was reported. In vitro, 3-7-1 were found to inhibit significantly the growth of cancer cells derived from different tissues. And 3-7-1 had inhibitory effect on melanoma in vivo. This selection may relate to the differentiation induced by 3-7-1. The inhibition of 3-7-1 on B16-BL6 suggests that 3-7-1 may be a useful anti-cancer agent for melanoma.
Five pentacyclic triterpenoids isolated from Campsis grandiflora were tested for insulin-mimetic and insulin-sensitizing activity. The compounds enhanced the activity of insulin on tyrosine phosphorylation of the IR (insulin receptor) beta-subunit in CHO/IR (Chinese-hamster ovary cells expressing human IR). Among the compounds tested, CG7 (ursolic acid) showed the greatest enhancement and CG11 (myrianthic acid) the least. We characterized the effect of CG7 further, and showed that it acted as an effective insulin-mimetic agent at doses above 50 mug/ml and as an insulin-sensitizer at doses as low as 1 mug/ml. Additional experiments showed that CG7 increased the number of IRs that were activated by insulin. This indicates that a major mechanism by which CG7 enhances total IR auto-phosphorylation is by promoting the tyrosine phosphorylation of additional IRs. CG7 not only potentiated insulin-mediated signalling (tyrosine phosphorylation of the IR beta-subunit, phosphorylation of Akt and glycogen synthase kinase-3beta), but also enhanced the effect of insulin on translocation of glucose transporter 4 in a classical insulin-sensitive cell line, 3T3-L1 adipocytes. The results of the present study demonstrate that a specific pentacyclic triterpenoid, CG7, exerts an insulin-sensitizing effect as an IR activator in CHO/IR cells and adipocytes. The enhancement of insulin activity by CG7 may be useful for developing a new class of specific IR activators for treatment of Type 1 and Type 2 diabetes.