SEMISYNTHETIC PYRROLIZIDINE ALKALOID ANTITUMOR AGENTS

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Our aim is to provide improved antitumor agents, with better therapeutic indices, modeled after indicine N-oxide (INO) (1), of both the retronecine (2) and heliotridine (3) N-oxide families and to study the mechanism of action of these drugs. The necic acid components will be stereospecifically synthesized, while retronecine will be obtained from the readily available monocrotaline and modified to give other necines. Site selective coupling of the chiral necic acids at C-7 and C-9 of the necines will be utilized. Structure activity studies will be developed with the very potent and active family of compounds represented by 4, in order to obtain mechanistic understanding of the effects of substituents and the effects of chiralities of the necic acids and necines. In vitro screening will be utilized, in addition to the in vivo screening previously undertaken. In order to distinguish between various mechanisms of action, the alkylating ability of selected drugs will be measured by the binding of radioactively labeled compound to cellular DNA and protein and the effects of non-labeled compounds on DNA interstrand crosslinking and strand scission will be determined. Direct comparisons will be made of responses, in the same cell systems, between in vitro cytotoxicity and in vitro protein and DNA binding and DNA strand scission.