Synthesis of Biologically Active Macrocycle Molecules

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DESCRIPTION (provided by applicant): This project on the synthesis of biologically active macrocyclic molecules aims to invent, develop, and apply synthetic methods (particularly novel metal mediated methods) during the synthesis and study of architecturally complex bioactive natural products. The synthetic methods and strategies developed herein will facilitate the evaluation and study of the biological properties of the targeted and allied molecules. The program will concentrate in three areas: (a) Synthesis of a new class of platelet activating factor (PAF) antagonists known as the phomactins. PAF is a compound ubiquitous to the human body and implicated in respiratory, inflammatory, and cardiovascular diseases. The phomactins are uniquely selective PAF antagonists as they have no effect on adenosine diphosphate, arachidonic acid, or collagen-induced platelet aggregation. (b) Synthesis of amphidinolide A and allied molecules. These structurally striking compounds are deemed active against all 60 NCI cancer screens and exhibit especially acute antileukemic properties, as well as activity towards rabbit skeletal muscle actomysion ATPase. (c) Synthesis of superstolide A, a marine natural product with excellent activity against human bronchpulmonary non-small cell lung carcinoma. Non-small cell lung carcinoma accounts for the large majority of lung cancers. Unfortunately chemotherapy against NSCLC has yet to prove very successful. Superstolide A is also active against resistant murine leukemia cells. Such tremendous biological potential makes superstolide A a very attractive candidate for total synthesis.