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The dimeric Vinca alkaloid vinblastine (VLB) undergoes metabolic transformation to three products in a reaction catalyzed by the human serum copper oxidase ceruloplasmin. The enzyme reaction requires chlorpromazine as a shuttle oxidant, and the course of the oxidation reaction appears to be subject to the nature of the shuttle oxidant used. Preparative-scale incubations have resulted in the isolation of three products, which were characterized by chemical and spectral analyses. The metabolites were identified as the ring fission product catharinine, obtained by oxidation of the Iboga ring system; an enamine/ether derivative obtained by oxidation of the Aspidosperma portion of VLB; and a metabolite embodying the same structural changes in both parts of the vinblastine dimeric structure. Catharinine is identical with the product of VLB oxidation obtained by peroxidase oxidation. The other two products are new metabolites and are derivatives of VLB. All of the metabolites are less active than VLB when tested in vitro vs the human T-cell leukemic cell line (CRFF-CEM).

The microbial transformation of the sesquiterpene lactone arreannuin B [3] using Aspergillus flavipes produced dihydroarteannuin B [4] as the main transformation product. Preparative-scale fermentation of 3 with Beauveria bassiana, on the other hand, has resulted in the production of two metabolites, 3 beta-hydroxyarteannuin B [5] and 13-hydroxy-11-epi-dihydroarteannuin B [6]. The structure of these metabolites, all of which are new compounds, was established using chemical and spectroscopic techniques. The isomeric dihydrocompound, 11-epi-dihydroarteannuin B [7] and an isomer of arteannuin B [8] were also prepared chemically. All compounds were subjected to 2D-nmr experiments and full 1H- and 13C-nmr assignments were made.

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More than three decades after their discovery and implementation in medicine, essentially nothing is known about the metabolism or the implications of metabolism in mechanism of action or toxicity of the Catharanthus alkaloids. The frustrating paucity of information about pathways of metabolism has limited a major source of structure-activity relationship information and has blocked a critical avenue necessary for the logical development of new and more useful Catharanthus alkaloids. Microbial transformations, peroxidases, copper oxidases, mouse and rat cytochrome P-450 systems, and mouse brain and bovine liver monoamine oxidase (MAO) preparations have been explored in the study of Catharanthus alkaloid metabolism. In this report, we present results which have clarified the involvement of enzymatic and chemically catalyzed one-electron oxidations that yield nitrogen-centered cation radicals, iminium, and carbinolamine intermediates, all of which explain how new carbon-carbon and carbon-oxygen bonds form, or break and rearrange. The dimeric Catharanthus alkaloids are recalcitrant to oxidations catalyzed by monoamine oxidases and to both normal and induced P-450 rat microsomal preparations. However, the Catharanthus alkaloids appear to be selective reversible inhibitors of MAO-B. Chemical and biochemical aspects of the metabolic transformations of dimeric Catharanthus alkaloids are reviewed together with the implications of our findings.