Microbial transformations of natural antitumor agents. 3. Conversion of thalicarpine to (+)-hernandalinol by Streptomyces punipalus

Nabih, Thomas; Davis, Patrick J.; Caputo, J. F.; Rosazza, John P. N.

doi:10.1021/jm00217a010

Cited by 18 publications

(8 citation statements)

References 8 publications

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“…Those previously documented include N-demethylation, deacetylation, and the formation of a group of related derivatives of dihydrovindoline ether (2a). In the hope of detecting new types of vindoline metabolites, we screened a variety of microorganisms from our own culture collection, many of which have demonstrated high capacity to metabolize alkaloids, steroids, and amino acid derivatives (14,10,15). Cultures obtained by soil enrichment procedures yielded no new vindoline metabolites.…”

Section: Methodsmentioning

confidence: 99%

Microbial Transformations of Natural Antitumor Agents: O -Demethylation of Vindoline by Sepedonium chrysospermum

Nabih

Youel

et al. 1978

Antimicrob Agents Chemother

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Vindoline (la) was transformed to O-demethylvindoline (lb) by Sepedonium chrysospermum ATCC 13378 in 33% yield. Thin-layer and high-pressure liquid chromatographic methods distinguished lb from previously reported microbial metabolites of vindoline. The structural proof of lb was based on its mass spectral fragmentation pattern and on its chemical and nuclear magnetic resonance spectral properties.The Vinca alkaloids vincristine and vinblastine possess significant antitumor activity and are widely used clinically. They have resisted simple syntheses, and their structural complexity has hindered the preparation of other useful derivatives of the alkaloids by chemical methods. Microbial transformations are being examined for their potential to prepare potentially important Vinca alkaloid derivatives.Vindoline (la) is one of the monomeric Vinca alkaloids and one of the most abundant alkaloids in Vinca rosea L. Since it is more readily available than vincristine and vinblastine, it was used in an effort to identify new types of biotransformation products of this group of alkaloids. Previous reports document the production of a variety of metabolites of vindoline by streptomycetes. Known vindoline metabolites include ( Fig. 1): deacetylvindoline (Ic) and deacetyldihydrovindoline ether (2c) (9); dihydrovindoline ether (2a); 3-acetonyldihydrovindoline ether (2b); a ring contraction product known as 16-dehydroxy-14,15-epoxy-14-oxo-3-norvindoline (12); N-demethylvindoline (Id) (13); and a dimer consisting of two dihydrovindoline ether moieties linked through their 3 and 14 positions (11).This report describes selective cleavage of the methyl ether group of vindoline by Sependonium chrysospermum ATCC 13378. The reaction gives lb in 33% yields, and it is not complicated by the formation of other side products. MATERIALS AND METHODSMelting points were determined on a Thomas-Hoover apparatus and are uncorrected. Infrared spectra were determined on a Perkin-Elmer 267 grating infrared spectrophotometer. Nuclear magnetic resonance (NMR) spectra were determined on a VarianAssociates model T-60 spectrometer using tetramethylsilane as an internal standard. Low-resolution mass spectra were obtained on a Finnigan model 3200 spectrometer, and high-resolution mass spectral data were provided by the Department of Chemistry, Massachusetts Institute of Technology, Cambridge. UV spectra were obtained on a Beckman DK-2 instrument. Elemental analyses were determined by Integral Microanalytical Laboratories, Inc., Raleigh, N.C.Vindoline, deacetylvindoline, dihydrovindoline ether, N-demethylvindoline, 3-acetonyldihydrovindoline ether, and 16-dehydroxy-14,15-epoxy-14-oxo-3-norvindoline were obtained as authentic reference standards from Eli Lilly and Co., Indianapolis, Ind.The purity of each compound was verified by thinlayer chromatography (TLC), high-pressure liquid chromatography, and mass spectral analysis. Vindoline (7) dihydrovindoline ether and the dihydrovindoline ether dimer (11) were characterized by melting points and UV, NMR, and...

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Section: Methodsmentioning

confidence: 99%

Microbial Transformations of Natural Antitumor Agents: O -Demethylation of Vindoline by Sepedonium chrysospermum

Nabih

Youel

et al. 1978

Antimicrob Agents Chemother

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“…adiantifolium Hort., and natalamine from Berberis empetrifolia Lam. (Berberidaceae), while others have been prepared from known benzylisoquinoline−aporphine dimers by oxidation. − …”

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confidence: 99%

“…(Berberidaceae), while others have been prepared from known benzylisoquinoline-aporphine dimers by oxidation. [9][10][11][12]…”

mentioning

confidence: 99%

Faurine and O-Methylfaurine, Two Novel Benzyl−Aporphine Dimers from Thalictrum fauriei

Lee

Doskotch

1996

J. Nat. Prod.

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Two new benzyl-aporphine dimers, faurine (1) and its O-methyl ether (2), were obtained from Thalictrum fauriei and their structures determined by spectral and chemical methods. Faurine (1), the first dimer with the diphenyl ether connection at C-1 of the aporphine, did not undergo a Hofmann degradation, yet formed a chiral phenanthrene product (6) with cyanogen bromide. Two nondimeric chiral aporphine alkaloids, O-acetylisocorydine and O-methylisocorydine, gave the corresponding phenanthrene products 7 and 8, respectively, under the same conditions, but only compound 7 was optically active.

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“…This technique has found widespread use, especially in the preparation of therapeutically important agents (7,16). Microbial transformation has been developed as a general means for providing quantities of potentially active metabolites of complex antitumor compounds from nature (1,6,11); for preparing metabolites difficult to synthesize as analytical standards to facilitate mammalian drug metabolism studies; and for determining potentially important pathways of bioactivation, bioinactivation, and cytotoxicity which may also occur in mammalian species (12). This report deals with the microbial transformation of 7,12-dimethylbenz[a]anthracene (DMBA), a carcinogenic polycycic aromatic hydrocarbon.…”

mentioning

confidence: 99%

“…Epoxidation is a commonly observed metabolic pathway for polycycic aromatic hydrocarbons. The cultures were manipulated according to published procedures (1,6,11). The microorganisms grown on Trypticase soy agar slants were transferred to other agar slants and allowed to grow for several days at room temperature.…”

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confidence: 99%

Microbial transformations of 7,2-dimethylbenz[a]anthracene

Wu¹,

Wong²

1981

Appl Environ Microbiol

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Microbial transformations of 7,12-dimethylbenz[a]anthracene, a carcinogenic polycycic aromatic hydrocarbon, in cultures of Pseudomonas aeruginosa and Penicillium notatum were studied by high performance liquid chromatographic separation of metabolic fractions followed by gas chromatographic-mass spectrometric analysis of the metabolites. Two methyl-hydroxylated metabolites were identified in each of the incubations. The metabolic activation of the polycyclic aromatic hydrocarbon suggests a possible involvement of microorganisms in environmental carcinogenesis.

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Microbial transformations of natural antitumor agents. 3. Conversion of thalicarpine to (+)-hernandalinol by Streptomyces punipalus

Cited by 18 publications

References 8 publications

Microbial Transformations of Natural Antitumor Agents: O -Demethylation of Vindoline by Sepedonium chrysospermum

Microbial Transformations of Natural Antitumor Agents: O -Demethylation of Vindoline by Sepedonium chrysospermum

Faurine and O-Methylfaurine, Two Novel Benzyl−Aporphine Dimers from Thalictrum fauriei

Microbial transformations of 7,2-dimethylbenz[a]anthracene

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