Ellipticine alkaloids metabolism

The antitumor alkaloid ellipticine (5,1 l-dimethyl-6//-pyrido[4,3-b]carbazole) has been isolated from many species of Ochrosia and Aspidosperma. Ellipticine and its derivatives are highly active versus several experimental neoplasms, and the compound has been widely subjected to studies devoted to its total synthesis, the preparation of derivatives, and metabolism. Metabolic transformation studies with ellipticines have been conducted, using microorganisms, in vivo and in vitro... 

Microbial transformations of ellipticine (15) and 9-methoxyellipticine (16) were reported by Chien and Rosazza (143, 144). Of 211 cultures screened for their abilities to transform 9-methoxyellipticine (16), several, including Botrytis alii (NRRL 2502), Cunninghamella echinulata (NRRL 1386), C. echinulata (NRRL 3655), and Penicillium brevi-compactum (ATCC 10418), achieved O-demethylation of 16 in good yield (Scheme 9). P. brevi-compactum was used to prepare 9-hydroxyellipticine (22) from the methoxylated precursor, and 150 mg of product was obtained from 400 mg of starting material (37% yield). The structure of the metabolite was confirmed by direct comparison with authentic 9-hydroxyellipticine (143). O-Demethylation is a common microbial metabolic transformation with 16 and many other alkaloids (143). Meunier et al. have also demonstrated that peroxidases catalyze the O-demethylation reaction with 9-methoxyellipticine (145). 

The metabolism of any drug is invariably of theoretical and practical importance, and the metabolic behavior of the ellipticine family of antitumor alkaloids and synthetic derivatives is no exception. A number of new developments have been described since the Suffness and Cordell review 10). The pharmacokinetics of elliptinium (5) have been studied in a human brain tumor clonogenic cell assay (250) and in metastatic breast cancer patients (257). In the latter study, the drug was mainly excreted in the feces ( C-labeled 5)... 

Many of the enzyme/microorganism mediated dealkylation procedures that have been reported have come from the work of Rosazza and his coworkers as a consequence of their studies on Microbial models on Mammalian metabolism. These studies have largely concerned with demethylation of various alkaloids with bacteria and fungi. 0-deethylation reactions with Streptomyces griseus as with dealkylation of 7-ethoxy coumarin gave very poor yields and therefore was not considered a viable synthetic procedure. The quinone imine(I), has been prepared in 64%isolated yield by horseradish peroxidase/hydrogen peroxide O-demethylation of 9-methoxy-ellipticine(II). Studies with H2 0 as a reaction medium demonstrated that the reaction was not a simple demethylation but rather a replacement of the methoxy group by OH from the solvent (as shown in Fig.l)... 

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