Tyoloindicines--Potent Antitumor Compounds

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Description (provided by applicant): Tyloindicines are a class of alkaloids that show profound antitumor activity. Tyloindicines F and G (NSC-650393 and -650394) are compounds that appear among the most potent compounds ever screened at the National Cancer Institute, showing G150 values <1 0-10 M against 54 human-derived tumors in the NCI's primary screen. Furthermore, these compounds show activity against certain melanomas and lung cancers for which there are few, if any, effective drugs. Tyloindicines H and I (NSC-650395 and -650396), while slightly less potent, are also promising leads and represent targets that may be easier of synthesis and of enhanced stability. The P1 in preliminary work in this area has synthesized two G analogues, NSC-71 6802 and -717335, that show potent activity. The former is scheduled for advanced in vivo evaluation (hollow fiber assay) at the NCI, and the second is presently under consideration for advanced evaluation. Clearly from the natural product examples, as well as from the two active synthetic analogues, the tyloindicines represent a structural skeleton that is amenable to design and modification for the development of a line of potent antitumor compounds. The proposed work brings together the laboratories of Prof. David C. Baker at the University of Tennessee (drug design, synthetic and structural chemistry) and those of Prof. Yeung-Chi Cheng at the Yale University School of Medicine (tumor biology, cell culture studies, mode of action studies, in vivo evaluation). Specific aims include the following: (1) Synthesis of tyloindicines F, G, H, and I; (2) Synthesis of selected analogues for structure-activity studies; (3) Supporting syntheses; (4) Studies of the mode of action in cell culture; (5) Studies of the potential as anticancer drugs in vivo; (6) Exploration of the mechanism of action for tyloindicines F and G and their analogues; (7) Preparation and evaluation of prodrugs of selected drug candidates.