ChemInform Abstract: MICROBIAL TRANSFORMATIONS OF NATURAL ANTITUMOR AGENTS. PART 5. THE STRUCTURE OF A NOVEL VINDOLINE DIMER PRODUCED BY STREPTOMYCES GRISEUS

Nabih, Thomas; Youel, Leisa; Rosazza, John P. N.

doi:10.1002/chin.197841300

Cited by 3 publications

(5 citation statements)

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“…Peroxidase is well-known to catalyze oxidations of nitrogenous substrates, and the first oxidation step with this enzyme may involve either the elimination of hydrogen from carbons adjacent to nitrogen or the formation of a cation radical centered at nitrogen (7,33). With leurosine, the generation of a carbon-centered radical (11) at the 21'-position (as in path B, Figure 2) could be influenced Figure 3. The structure of Catharine (15).…”

Section: And Discussionmentioning

confidence: 99%

“…Previous investigations from this laboratory have elaborated the mechanisms of oxidative transformations of monomeric and dimeric Vinca alkaloids catalyzed by different types of enzymes. For example, the Aspidosperma monomeric alkaloid vindoline (6) is transformed through the same oxidative pathway by peroxidase (7), copper oxidases (8,9), cytochrome P-450 (10), and enzyme systems of the bacterium Streptomyces griseus (11). Detailed investigations established that these alkaloid transformations involved one-electron oxidation steps (7,8), which led to the formation of enamine and iminium intermediates in the oxidation pathway.…”

Section: Introductionmentioning

confidence: 99%

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Leurosine biotransformations: an unusual ring-fission reaction catalyzed by peroxidase

Goswami¹,

Macdonald²,

Hubbard³

et al. 1988

Chem. Res. Toxicol.

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The dimeric Vinca alkaloid leurosine undergoes an unusual fission of the piperidine ring of the Iboga substructure when reacted with horseradish peroxidase and hydrogen peroxide. A preparative-scale oxidation of leurosine provided 15'-hydroxycatharinine, which was identified by infrared and proton and carbon-13 NMR spectroscopies and high-resolution mass spectrometry. A proposed pathway for the formation of 15'-hydroxycatharinine involves radical and iminium intermediates and cleavages of a putative diol. The enzymatic transformation product is 3 orders of magnitude less active than leurosine or vinblastine in vitro, in inhibiting the polymerization of tubulin.

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Section: And Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Leurosine biotransformations: an unusual ring-fission reaction catalyzed by peroxidase

Goswami¹,

Macdonald²,

Hubbard³

et al. 1988

Chem. Res. Toxicol.

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“…Vindoline (7) dihydrovindoline ether and the dihydrovindoline ether dimer (11) were characterized by melting points and UV, NMR, and mass spectra.…”

Section: Methodsmentioning

confidence: 99%

“…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).…”

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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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“…Previous work with Streptomyces griseus (Nabih et al, 1978;Gustafson and Rosazza, 1979), copper oxidases including human serum ceruloplasmin and fungal laccases (Eckenrode et al, 1982), the chemical oxidizing agent 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)? (Sariaslani et al, 1984) and horseradish peroxidase (Sariaslani et d., 1985) revealed that the 3,4-positions of Aspidosperma alkaloids are susceptible to oxidation.…”

Section: Introductionmentioning

confidence: 99%

PHOTOCHEMICAL OXIDATION OF VINDOLINE and 16‐O‐ACETYLVINDOLINE

J.Filippelli

Reeg

Sariaslani

et al. 1988

Photochem & Photobiology

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Photooxidation of 16-0-acetylvindoline in methanol using chlorpromazine.HC1 as a photosensitizing agent produces nearly quantitative yields of an iminium derivative. The 16-0-acetylvindoline-iminium product was characterized spectrally by proton NMR and mass spectrometry; and by chemical reduction with sodium borodeuteride. Proton NMR and mass spectral analyses of the reduced product revealed that deuterium was stereospecifically incorporated into the 3-a-position. The iminium product formed by photochemical oxidation is identical to that produced by copper oxidases and peroxidase. Photochemical oxidation provides direct evidence for the involvement of free radicals in Aspidospermu alkaloid transformations.

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ChemInform Abstract: MICROBIAL TRANSFORMATIONS OF NATURAL ANTITUMOR AGENTS. PART 5. THE STRUCTURE OF A NOVEL VINDOLINE DIMER PRODUCED BY STREPTOMYCES GRISEUS

Abstract: Inkubation von o Vindolin (I) mit einer Kultur von Streptomyces griseus (UI 1158) führt zu dem Dihydrovindolinether (II) und einer Verbindung, der anhand spektroskopischer Untersuchungen (13C‐, 1H‐NMR, MS) die Struktur des Dimeren (III) zugeordnet wird.

Cited by 3 publications

References 1 publication

Leurosine biotransformations: an unusual ring-fission reaction catalyzed by peroxidase

Leurosine biotransformations: an unusual ring-fission reaction catalyzed by peroxidase

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

PHOTOCHEMICAL OXIDATION OF VINDOLINE and 16‐O‐ACETYLVINDOLINE

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