The synthesis and mechanistic studies of antitumor agents designed from natural products

Natural products, due to competitive environments and millions of years of evolution, prove to be a vast source for the discovery of antitumor agents. Many of these agents contain novel structural attributes, and unique mechanisms of action. Structural features from natural products, isolated from the Fijian sponge Zyzzya cf. marsailis, known as Makaluvamines; and the synthetic (APBIs) 6-acetamidopyrrolo [1,2-a] benzimidazole-based antitumor agents discovered in our laboratory, were combined to create a new class of antitumor agents. These benzimidazole based iminoquinones contain an extended amidine moiety found in many natural products. A library of these extended amidines has been studied at the National Cancer Institutes (NCI) Drug Research and Development branch. Initial screening, against the NCI 60 tumor cell lines, showed the extended amidines to be potent and selective antitumor agents for non-small cell lung cancer and melanoma cell lines. Compounds 7A, 8B, and 8G have been advanced to in vivo toxicity studies at the NCI. COMPARE analysis, a computerized pattern recognition algorithm, revealed a possible molecular target to be proto-oncogene tyrosine kinase.; The natural product CC-1065, isolated from Streptomyces zelensis , has proved to be one of the most studied antitumor antibiotics over the past three decades. There remains much debate with regards to acid dependence, and alkylation of CC-1065 by DNA. pH-Rate studies were carried out on 2-substituted derivatives of the CC 1065 A-ring over the range of pH 5 to 0. Our studies show that the cyclopropyl group undergoes reversible general acid catalyzed trapping of chloride nucleophiles above pH 4. The presence of general acid catalysis is not apparent from direct rate measurements because the chloride trapping occurs in a reversible non-rate determining step. However, the determination of equilibrium constants for chloride trapping as a function of pH confirmed that opening of the A-ring cyclopropyl group is general acid catalyzed. This finding implies that general acid catalyzed alkylation of DNA minor groove by the A-ring is feasible. pH Rate studies also showed the 2-substituent does not influence the pKa of the protonated carbonyl of the A-ring (pKa ∼ 1) and has relatively little effect on the rate of nucleophile trapping.