This renewal application involves synthesis, computer modeling, mechanistic/mode of action, biological and medicinal studies focused on compounds of demonstrated or potential importance in cancer research and chemotherapy. A special emphasis is placed on compounds possessing novel structures, novel or unique modes of action, and significant clinical potential. It is the objective of this program to develop fundamentally new methods and strategies for the synthesis and modification of such compounds, to elucidate the structural basis for their mode of action, and to exploit these new findings in the rational design of novel cancer chemotherapeutic agents or compounds of interest in cancer research and chemotherapy. Section D.1 describes a continuation of studies on the computer assisted design, synthesis, biological evaluation, and pre-clinical advancement of a new and therapeutically promising family of bryostatin analogues that exhibit superior in vitro potency relative to bryostatin, a promising chemotherapeutic agent now in clinical trials. Section D.2 describes studies on the isolation, characterization, derivatization, semi-synthesis, mode of action, and biological evaluation of the apoptolidins, a promising new family of novel therapeutic leads, that exhibit exceptional and therapeutically desirable selectivity in inducing apoptosis in oncogenically transformed cells relative to normal cells. Section D.3 describes studies on the use of new catalyzed reactions to incorporate pharmacophoric subunits into new scaffolds to generate novel cancer therapeutic leads based on the modulation of kinase activity. Section D.4 describes studies on molecular transporters designed to enable or enhance uptake into cells and tissues of drug candidates or drugs that do not enter cells or do so only poorly. These studies will focus on mechanism of uptake with an emphasis on single molecule studies and the synthesis and evaluation of new transporters including their ability to enter cells and tissue (transgenic mice) and release drugs or probes at therapeutic levels. ? ? ?
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