The goal of this proposal is to develop new chemical methods to rapidly assemble the structurally novel ICT antimalarials, and determine their biological target and structure activity relationships (SARs). Our long-term goal is to develop new methods for the concise synthesis of terpene-based medicines, which have a proven track-record in drug development and account for an annual $12 billion global market. The proposed research comprises the development of a new class of polyene capable of rapid polycyclic terpene synthesis; a new tert-alcohol inversion reaction; and application of this chemistry to short, scalable and modular syntheses of three ICT subfamilies. This chemistry will be used to explore the contours of the ICT binding pocket through SAR discovery and to design photoaffinity labeled probes for identification of the ICT macromolecular target. The first phase of research concerns the development of new polarized dendritic polyenes - Danishefsky dendralenes - which undergo highly regio- and stereoselective Diels-Alder cascade reactions and rapidly build up the di-, tri-, and tetracyclic fused carbocyclic skeletons of the kalihinenes, amphilectenes, and adocianes. Preliminary data from our laboratory indicates that this will be a successful approach with widespread utility to other complex carbocycles. The second phase of research derives inspiration from Scheuer's hypothesis regarding the unique nitrogen incorporating pathways found in ICT biogenesis. We will explore a new chemoselective and stereoselective tert-alcohol inversion reaction, which is uniquely capable of generating the ICT pharmacophore and appears to be generally useful for the synthesis of chiral tert-alkyl amines. The third phase of research, conducted in collaboration with the Winzeler group, involves determination of the mechanism of action associated with the antimalarial activity of the ICTs. We provide preliminary data suggesting a mechanism that differs from the prevailing hypothesis put forth over a decade ago.
Malaria is already one of the leading causes of death in developing countries, and the identification of resistance to standard of care medicines including ACT (artemisinin combination therapies) threatens to worsen this public health crisis. Isocyanoterpenes (ICTs) are tropical sponge derived secondary metabolites that exhibit potencies and selectivities that are comparable to artemisinin and mefloquine, but their biochemical mode of action is poorly understood. The objective of this proposal is to develop new chemical reactions inspired by the logic of ICT biosynthesis to rapidly assemble these medically valuable antimalarials, determine their biological mechanism of action, optimize their activity, and distribute these compounds to the biomedical community.
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