ASPECTS OF THE MODE OF ACTION OF MITOMYCIN C

PAUL JOSEPH KELLER, Purdue University

Abstract

The Streptomycete metabolite mitomycin C is a clinically useful antitumor antibiotic which has been shown to cross-link DNA after chemical reduction, and after exposure to acidic conditions. The present work, which was not concerned with any aspects of acid catalyzed reactions, had three objectives.^ The first objective was the structure elucidation of novel reaction products arising upon reduction of mitomycin C in the presence of potassium ethyl xanthate in neutral aqueous solution. This work led to the characterization of four 1,2-cis-disubstituted-10-ethylxanthyl-7-aminodecarbamoyl-mitosenes which possess the following substituents at C(,1) and C(,2): (a) 1,2-cis-fused-1'-ethoxy-1'-mercaptothiazolidine, (b) 1-mercapto-2-thio-O-ethylcarbamate, (c) a fused epithiotrithiazocine, and tentatively (d) a 1-ethylxanthyl and a 2-amino group respectively. Two 1,2-trans-disubstituted mitosene products of the same reaction were reported earlier (Hornemann, U.; Keller, P. J.; Kozlowski, J. F.; 1979; J. Amer. Chem. Soc., 101, 7121). It was observed that the 1,2-cis/trans ratio of the overall reaction is approximately 1:1. On the basis of high field ('1)H-NMR analysis, a theoretical framework for the determination of the conformation and for the assignment, in favorable cases, of the relative stereochemistry in the saturated five-membered ring of mitosenes was developed in conjunction with the structure elucidation work.^ The second objective was the confirmation or reassignment of the ('13)C-NMR spectrum of mitomycin C. The previous assignments for this spectrum (Lown, J. W.; Begleiter, A.; 1974; Can. J. Chem., 52, 2331) were reasonable but not unambiguous. In the present work, several techniques were employed to arrive at unambiguous assignments for mitomycin C, thus revising those published by Lown and Begleiter for carbons 5, 6, 8, 8a and 9a.^ The third objective was the investigation of the interaction of mitomycin C with DNA. It was found that mitomycin C - DNA cross-links are stable to attack by potassium ethyl xanthate under reducing conditions. Additionally, an initial attempt to alkylate the self-complementary hexanucleotide d(ApTpGpCpApT) with a ('14)C-labeled mitomycin is reported, which affords alkylated products which await to be studied indetail. ^

Degree

Ph.D.

Subject Area

Chemistry, Pharmaceutical

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