Synthesis of Cryptophycin Affinity Labels and Tubulin Labeling

Abstract

Abstract : Cryptophycins are a potent, tumor-selective class of tubulin-binding antimitotic anti-cancer agents with excellent activity against MDR cancers. For the development of these promising compounds into useful chemotherapeutic agents, detailed information about the binding domain of the cryptophycins is essential. We plan to map the cryptophycin binding through photoaffinity labeling studies. Toward this goal, we have synthesized the C16 side chain benzophenone analogue of cryptophycin-24. The synthesis is convergent and allows for convenient modification to produce various analogues having photoaffinity labels attached at the C16 side chain. The C16-benzophenone photolabeled analogue was active in the tubulin assembly assay and is therefore a suitable candidate for further studies to explore the tubulin binding domain of cryptophycin. Presently, these compounds are being used for photoaffinity labeling studies with tubulin in collaboration with Professor Richard Himes' laboratory.