Cardiovascular disease is a major health concern in the United States. Older medications, though effective against cardiovascular disease, are problematic to prescribe. A recently isolated natural product, clavatadine A, selectively inhibits human blood coagulation factor XIa. As a result, the synthesis and biological testing of clavatadine A and synthetic clavatadine A analogues that target factor XIa would represent a new direction in cardiovascular disease research. A potent and selective factor XIa inhibitor has the potential to be a safer replacement for current anticoagulants, such as Warfarin®, Pradaxa®, Eliquis®, and Xarelto®. We recently completed the first total synthesis of clavatadine A and will use our rapid, general approach to prepare synthetic clavatadine A analogues. Because clavatadine A binds irreversibly to the active site of factor XIa, we hoped to design and synthesize a selective and reversible factor XIa inhibitor as a potential treatment for blood clotting disorders. To do this, we prepared analogues of clavatadine A that we believe will be less likely to form a covalent bond with a nucleophilic serine residue (Ser-195) in the active site of factor XIa. We then tested the binding activity and selectivity of each analogue toward factor XIa and several other coagulation factors. In the future, we hope to use these results to design a potent, selective, and reversible synthetic clavatadine A derivative as a factor XIa inhibitor for anticoagulant therapy.

Total synthesis of clavatadine A analogs to produce a viable reversible inhibitor for factor XIa

249th National Meeting (2015)

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