Structurally novel classes of natural products serve as leads for this program in that it combines total synthesis, reaction development, drug design, and structural biology. The lead structures for both components of this program are small, uncharged, rigid molecules with few hydrogen bonds and few rotatable bonds. Therefore both should provide attractive scaffolds for libraries of compounds that fulfill the criteria of Veber and Lipinski for solubility and permeability. SNF 4435C and D are natural products that demonstrate both immunosuppressive and multidrug resistance (mdr) reversal activity. SNF4435C is also active in vivo, enhancing the efficacy of vincristine treatment in mice that carry vincristine-resistant P388 leukemia. Our group has completed an asymmetric total synthesis of SNF 4435C and D. We have also prepared simple analogs that have mdr reversal activity in cells that overexpress the multidrug transporter P-glycoprotein. Efforts now will focus on the preparation of more potent mdr reversal agents that lack immunosuppressant activity and more potent immunosuppressants that do not inhibit multidrug transporters. Both molecular modeling and structure-activity approaches will be pursued. Biological activities will be monitored by mdr reversal assays, by drug efflux assays, and by flow cytometric analysis of immunosuppression. We will attempt to identify the mechanism of immunosuppression. Selected synthetic compounds will be examined for their ability to stabilize crystals of P- glycoprotein for x-ray crystallographic studies. The bisabosquals are inhibitors of yeast squalene synthase and have potential as leads for the development of antihypercholesteremics. Completion of the total synthesis will provide ground rules for the preparation of related structures. Molecular modeling will allow the design of candidates for more active drugs. Candidates will be evaluated in the squalene synthase assay. Collaborations for the medicinal chemistry components of the project have been arranged.
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