This proposal is a continuation of our synthetic efforts in indole alkaloids that have significant pharmacological activity for clinical use. It describes two projects in syntheses of novel agents with specific anti-cancer activity and one project for generation of anti- addiction agents that are free of tremorigenic toxicity. In one anti-cancer project we continue efforts to optimize our established ability to activate noncytotoxic, atropisomeric pro-drugs by thermal or ultrasound procedures for site-activation chemotherapy. In addition, we extend in this project our initial discovery of vinblastine/vincristine congeners that lack the neurotoxicity of the parent anti-cancer drugs, to establishment of structural requirements for this selective anti-cancer activity. A second project is directed at syntheses of the pauciflorines, a new and structurally novel class of indoline alkaloids that have been shown to be potent inhibitors of melanin biosynthesis in melanoma. Syntheses of close analogues and simplified structures will provide a first indication of structure/activity requirements, which may be exploited for syntheses of melanoma specific targeting agents. For the generation of new anti-addiction drugs, we will isolate receptor proteins for our active coronaridine-type structures through the synthesis of congeners that can be used for affinity chromatography and we will extend our initial successful structure/activity studies. We expect to improve on our initial candidate, 18-methoxycoronaridine (which shows promising long-term effect against morphine, cocaine, nicotine and alcohol addiction in rats, is non-toxic, and is to start in clinical trials this year).
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