Part 1: Synthesis of a bicyclic pyran for use as a model study in the synthesis of cytotoxic xanthone IB-00208. Part 2: Progress towards the synthesis of a cyclopropyl-constrained isoleucine residue for studying the effects of preorganization in protein-ligand binding.

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Lee, Joseph

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Part 1: Nature is the source of many biologically active molecules that serve as the bases for numerous drugs. One such molecule is IB-00208, a polycyclic xanthone produced by marine bacteria Actinomadura. Despite the prevalence of such xanthones in nature, few have reported syntheses. Because of this paucity of syntheses in the literature and the harsh reactions of reported procedures, the Martin group undertook the synthesis of IB-00208. Since the Martin group had issues oxidizing the hexacyclic core of IB-00208, a bicylic ether was synthesized to perform a model study on the hexacylic core’s oxidation.

Part 2: In drug development, constraining ligands in their biologically active conformation is one method for increasing binding affinity. This strategy is closely associated with the presumption that preorganization will decrease the entropic penalty, resulting in a more favorable ΔG and Ka. The Martin group has investigated the thermodynamic effects of introducing cyclopropyl constrains into various ligands, and has discovered the relationship is complex and unpredictable. This study attempts to synthesize a pYEEI-derived ligand with cyclopropyl constraint for the Src SH2 domain.


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