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Stereoselective hydrogenation on the exocyclic and conjugated double bond of sesquiterpene lactones by Aspergillus versicolor D-1
Abstract
Aspergillus versicolor D-1 was employed to convert dehydrocostuslactone (1) and 3-hydroxy-1(10),3,11(13)-guaiatriene-12,6-olide-2-one (5) stereoselectively. The reactions occurring were specific hydrogenation on the exocyclic alpha,beta-double bond of sesquiterpene lactones with excellent conversion. Products were identified by the analysis of their spectra such as UV, IR, MS, (1)H, (13)C NMR, and NOESY, and the structure of one new compound was elucidated. The characteristic of the stereoselective hydrogenation was also discussed and suggested.
... olide-2-one (296) and (5S,6S,7S,11R)-3-hydroxy-1(10),3-guaiadiene-12,6-olide-2-one (297) were converted from 295, while 11b,13-dihydrodehydrocostuslactone (298) was converted from 294. From the metabolites produced, it was deduced that efficient conversion and specific hydrogenation occurred on the a,b-double bond at exocyclic sesquiterpene lactones [46] (Scheme 47). ...
Sesquiterpenoids have been identified as natural compounds showing remarkable biological activities found in medicinal plants. There is great interest in developing methods to obtain sesquiterpenoids derivatives and biotransformation is one of the alternative methods for structural modification of complex sesquiterpenes structures. Biotransformation is a great drug design tool offering high selectivity and green method. The present review describes a comprehensive summary of biotransformation products of sesquiterpenoids and its structural modification utilizing a variety of biocatalysts including microorganisms, plant tissue culture and enzymes. This review covers recent literatures from 2007 until 2020 and highlights the experimental conditions for each biotransformation process.
Biotransformation is an economically and ecologically viable technology which has been used to modify the structures of many classes of biologically active products. Some fungi may be useful for the biotransformation of sesquiterpene lactones (SLs), leading to unusual structural changes that modify their biological activities, and other transformations mimic their biosynthetic pathways, generating evidences for the proposed biogenesis. Eight filamentous fungi were screened for their ability to transform different SLs (1-9), and microbial reactions yielded compounds 11 -- 18, which in turn have been isolated as natural products, thus mimicking their biosynthesis. Their structures were identified based on NMR and MS spectroscopic analyses. The cytotoxicities of SLs 1, 4, 6, 7 and 9, and their biotransformed produts (10, 14, 15 and 17) against human cancer cell lines U251 (glia), PC3 (prostate), K562 (leukemia), HCT-15 (colon), MCF7 (breast), and SKLU-1 (lung), were determined, confirming that the presence of Michael acceptor is an important feature for the bioactivity. This article is protected by copyright. All rights reserved.
Sesquiterpenes such as curcumol (1) and curdione (2) are the major ingredients of Rhizoma curcumae. Compounds (1) and (2) are isomers of one another and play important roles in Chinese Traditional Medicine. Microbial transformations of naturally occurring curcumol and curdione by Cunninghamella elegans AS 3.2028 were studied. In this research, stereoselective epoxidation at the double bond of curcumol led to 10S,14-epoxycurcumol (3) as the major metabolite, with no detectable 10R,14-epoxycurcumol (4). Epoxidation also occurred at the double bond of curdione, generating both (1S,10S)- and (1R,10R)-1,10-epoxycurdione (5) and (6). The diastereomeric excess (de) of the S diastereomer was 27%. The selectivity of the biotransformation is discussed.
Covering: January 2009 to December 2009. Previous review: Nat. Prod. Rep., 2009, 26, 1125.
The development of novel biocatalytic methods is a continuously growing area of chemistry, microbiology, and genetic engineering due to the fact that biocatalysts are selective, easy-to-handle, and environmentally friendly. A wide range of reactions are catalyzed by microorganisms. Fungi can be considered as a promising source of new biocatalysts, mainly for chiral reactions. Chemo-, regio-, and stereoselective processes are very important in the synthesis of many chemical, pharmaceutical, and agrochemical intermediates; active pharmaceuticals; and food ingredients. This report reviews stereoselective reactions mediated by fungi, such as stereoselective hydroxylation, sulfoxidation, epoxidation, Baeyer–Villiger oxidation, deracemization, and stereo- and enantioselective reduction of ketones, published between 2000 and 2007.
The aerial parts of Tanacetum argyrophyllum var. argyrophyllum yielded in addition to the known compounds a new sesquiterpene lactone, named tanargyrolide. The structure was elucidated by spectral methods. The sesquiterpene lactones showed antibacterial activity against Staphylococcus aureus, Bacillus megaterium, Bacillus subtilis and Escheria coli.
Terpenoids, dehydrocostuslactone (2), costunolide (3), α-, β-, and γ-cyclocostunolides (4∼6), α-santonin (7) and atractylon (8) isolated from the crude drugs and (-)-ambrox (9) from animal origin were biotransformed by Aspergillus niger, A. cellulosae, and Botryospaeria dothidea etc. to afford the structurally interesting metabolites. Their stereostructures were established by a combination of high-resolution NMR spectrum, X-Ray crystallographic analysis and chemical reaction. The metabolic pathways of terpenoids by A. niger resembled those by mammals, but are quite different from those by A. cellulosae.
Total methanol extract of Saussurea lappa radix (Compositae) showed potent inhibitory effect on the production of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, in murine macrophage-like cell (RAW264.7 cells) in our previous screening studies on 120 Korean medicinal plants. The activity-guided purification of the plant resulted in the isolation of three components. The chemical structures of the components isolated were established by spectroscopic analyses as sesquiterpene lactones [cynaropicrin (1), reynosin (2), and santamarine (3)]. These three compounds inhibited TNF-alpha production in a dose-dependent manner. The molar concentrations of cynaropicrin, reynosin, and santamarine producing 50% inhibition (IC50) of TNF-alpha production were 2.86 micrograms/ml (8.24 microM), 21.7 micrograms/ml (87.4 microM), and 26.2 micrograms/ml (105 microM), respectively. However, treatment with sulphydryl (SH) compounds such as L-cysteine, dithiothreitol, and 2-mercaptoethanol abrogated the inhibitory effect of cynaropicrin on TNF-alpha production. Therefore, we conclude that the principal inhibitory component of Saussurea lappa is cynaropicrin and its inhibitory effect is mediated through conjugation with SH-groups of target proteins.
Tandem sulfonium ylide formation and [2,3] sigmatropic rearrangement sequence from allylic sulfides and diazoacetates has been effected by using dirhodium(II) tetrakis[3(S)-phthalimido-2-piperidinonate], Rh2 (S-PTPI)4, as a chiral catalyst, displaying enantioselectivities of up to 58%. It has been demonstrated that the [2,3] sigmatropic rearrangement proceeds through chiral, nonracemic free sulfonium ylides dissociated from the dirhodium(II) complex.
A new compound, 12-methoxydihydrodehydrocostuslactone, has been isolated from the essential oil of Saussurea lappa. The structure and stereochemistry were established by spectroscopic and chemical methods.
The minimum inhibitory concentrations (MIC) against Mycobacteriumtuberculosis and M. avium of parthenolide, costunolide, 1 (10)-epoxycostunolide and other germacranolide-type sesquiterpene lactones and derivatives were determined by use of a radiorespirometric bioassay. Structure-activity relationship studies with natural and semisynthetic sesquiterpene lactones suggested that the α-methylene-γ-lactone moiety is an essential, but not sufficient, structural requirement for significant in vitro activity against M. tuberculosis and M. avium.
This review takes highlights from the 1998 1999 literature to illustrate some of the recent advances in the use of biotransformations in synthetic organic chemistry. The biotransformations of organic functional groups and special techniques used in biotransformations are examined. Yes Yes
Evidence is presented that sesquiterpene lactones or ketones containing the O=CC=CH2 moiety, e.g., tenulin and helenalin, alkylate the thiol group of reduced glutathione and L-cysteine in vitro. A proposal is offered that this mechanism of action is responsible for the observed potent in vivo antitumor activity of these agents in the Ehrlich ascites and Walker 256 carcinosarcoma and to a lesser extent in the P388 leukemic screen. Inhibition of tumor growth is thought to occur due to the O=CC=CH2 system alkylating by rapid Michael addition the SH biological nucleophiles of key regulatory enzymes of nucleic acid and chromatin metabolism. This proposition is in accord with the ability of these agents to inhibit DNA synthesis and gene activity of Ehrlich ascites cells.
Ten sesquiterpene lactones and one sesquiterpene isolated from Tanacetum praeteritum subsp. praeteritum: 1 alpha, 6 alpha -dihydroxyisocostic acid methyl ester (2), 1 alpha-hydroxy-1-deoxoarglanine (3), douglanin (5), santamarin (6), reynosin (7), 1-epitatridin B (8), ludovicin A (10), armexin (12), armefolin (13), armexifolin (14), and 3 alpha-hydroxyreynosin (15) were tested against the human lung carcinoma cell line GLC4 and the colorectal cancer cell line COLO 320 as well as against the bacteria Bacillus subtilis, Staphylococcus aureus, Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus, beta-hemolytic Streptococcus, and the yeast Candida albicans. In addition, two germacranolides tatridin A (16) and tamirin (17) were included in the study. All compounds showed cytotoxic activity (IC50 = 124 microM) but most of them were not effective in the antimicrobial tests.
The minimum inhibitory concentrations (MIC) against Mycobacterium tuberculosis and M. avium of parthenolide, costunolide, 1 (10)-epoxycostunolide and other germacranolide-type sesquiterpene lactones and derivatives were determined by use of a radiorespirometric bioassay. Structure-activity relationship studies with natural and semisynthetic sesquiterpene lactones suggested that the alpha-methylene-gamma-lactone moiety is an essential, but not sufficient, structural requirement for significant in vitro activity against M. tuberculosis and M. avium.
In an attempt to study the structural dependence of antimycobacterial activity of the guaianolide dehydrocostus lactone and its derivatives, m-chloroperoxybenzoic acid oxidations of dehydrocostus lactone (1a) were performed. Three new monoepoxides, one previously synthesized diepoxide, and two new diepoxides were obtained. Two of the monoepoxides are C-10 epimers (3a, 3b), while the 4(15)-monoepoxide (2) has the 4alpha-O-configuration. The known diepoxide (4a) contains a C-10 alpha-epoxide and a beta-epoxide at C-4. The diepoxides 4b and 4c, each with a C-4 alpha-epoxy group, differ in the configuration of the epoxide ring at C-10. Allylic oxidation of dehydrocostus lactone (1a) with selenium dioxide/tert-butyl hydroperoxide afforded the known 3-epizaluzanin C (1b). The relative configurations of compounds 1b-4c were established by 1D and 2D NMR techniques (1H, 13C, COSY, NOESY, HMQC, and HMBC) as well as comparison with literature data. The molecular structures of lactones 1b, 4a, and 4c were determined by single-crystal X-ray diffraction. In radiorespirometric bioassays against Mycobacterium tuberculosis and Mycobacterium avium, dehydrocostus lactone (1a) exhibited minimum inhibitory concentrations of 2 and 16 microgram/mL, respectively. In contrast, its monoepoxides (2, 3a, and 3b) and diepoxides (4a-c), as well as its hydrogenated derivatives and other analogues (1b, 1c, 5, and 6), showed significantly lower activities against M. tuberculosis.
Biotransformation of the fungistatic sesquiterpenoid patchoulol (1) by the fungus Botrytis cinerea affords the 5-, 7- and (8R)-hydroxy (2, 3, and 5) derivatives as the major metabolites, together with a number of minor metabolites (4, 6-9) arising from hydroxylation at C-2, C-3, C-5, C-9, C-13, and C-14.
Incubations of the fungi Cunninghamella echinulata and Rhizopus oryzae with the sesquiterpene lactones (+)-costunolide (1), (+)-cnicin (2), (+)-salonitenolide (3), (-)-dehydrocostuslactone (4), (-)-lychnopholide (5), and (-)-eremantholide C (6) were perfomed. Incubation of 1 with C. echinulata afforded Delta11(13)-dihydrogenation and Delta1(10)-epoxidation products (7-10). C. echinulata also hydrolyzed the side chain of 2, and transformed 4 into (+)-11alpha,13-dihydrodehydrocostuslactone (12), a new natural product. R. oryzae converted 4 into both Delta11(13)-dihydrogenation and Delta10(14)-epoxidation products (16 and 17). Both fungi transformed 5 into (-)-16-(1-methyl-1-propenyl)eremantholanolide (13), providing experimental evidence for the biosynthesis of the eremantholide hemiketal unit. Compounds 3 and 6 were not metabolized by either fungus under the test conditions.
We investigated in vitro anti-inflammatory effects of cynaropicrin, a sesquiterpene lactone from Saussurea lappa, on tumor necrosis factor (TNF)-alpha and nitric oxide (NO) release, and lymphocyte proliferation. Cynaropicrin strongly inhibited TNF-alpha release from lipopolysaccharide-stimulated murine macrophage, RAW264.7 cells, and differentiated human macrophage, U937 cells, proved to produce notable amount of TNF-alpha. It also potently attenuated the accumulation of NO released from lipopolysaccharide- and interferon-gamma-stimulated RAW264.7 cells in a dose-dependent manner. In addition, the immunosuppressive effects of the compound on lymphocyte proliferation in response to mitogenic stimuli were examined. Cynaropicrin also dose-dependently suppressed the proliferation of lymphocytes from splenocytes and interleukin-2-sensitive cytotoxic T lymphocyte, CTLL-2 cells, stimulated by lipopolysaccharide, concanavalin A, phytohemagglutinin and interleukin-2. However, treatment with sulphydryl compound, L-cysteine, abrogated all these inhibitory effects. These results suggest that cynaropicrin may participate in the inflammatory response by inhibiting the production of inflammatory mediators and the proliferation of lymphocytes and its inhibitory effect is mediated through conjugation with sulphydryl groups of target protein(s).
The fixed oil of Laurus novocanariensis (previously L. azorica) contains mostly glycerides together with minor non-saponifiable compounds. The direct identification and quantitative determination of costunolide and dehydrocostuslactone, two sesquiterpene lactones components of the oil that exhibit biological activities, is described. The analysis was carried out using 13C-NMR spectroscopy (signal acquisition with inverse gated decoupling of protons; diglyme as internal standard) without separation, derivatisation or any sample preparation.
A new isolate of Aspergillus sp. hydrogenated the gamma,delta-double bond of securinine (143 mg l(-1)) to give 14,15-dihydrosecurinine at over 98% (w/w) yield after 8 h. It also hydrogenated the C11(13) double bond of 3-hydroxy-1(10),3,11(13)-guaiatriene-12,6-olide-2-one (HGT) (200 mg l(-1)) to give 3-hydroxy-1(10),3-guaiadiene-12,6-olide-2-one with over 98% (w/w) conversion after 24 h.