Synthetic studies on anti-cancer and anti-HIV compounds

The research discussed in this dissertation focuses on the synthesis and biological evaluation of two families of therapeutic agents. In 1999 a group of scientists at the National Cancer Institute reported that during a screening of their database they had found an active non-nucleoside reverse transcriptase inhibitor. This compound (NSC-108406) was substantially more potent than the other inhibitors identified during their screening with an IC50 of 0.5 ± 0.3 μM. During a cell-based antiviral screen, it was found to provide an EC50 of 1.5 ± 1.0 μM. In an effort to increase the potency of the lead, a set of analogs of NSC-108406 was synthesized in our laboratories, providing a compound with an EC50 of 0.036 μM. Hydramycin is a naturally occurring pluramycinone that is a potent antimicrobial and antitumor agent and whose biological activity has created an interest in its synthesis. Our work began with a model study that established a strategy by which the pyranone system and associated functionality could be realized. The route makes use of a novel alkyne and a fluoride-induced ring closure that provided a molecule consisting of a chromenone with the essential moieties analogous to those of hydramycin. The protocol was applied to a compound containing the hydramycin anthraquinone system via a 2-formyl-1- hydroxy anthraquinone that was coupled with an alkyne.