Photosensitive Probes into the Tubulin Binding Domain of Cryptophycins: Synthesis and Structure-Activity Relationship of C16 Aromatic Side Chain Analogues

摘要

The cryptophycins are potent tumor selective cyclic depsipeptides isolated from Nostoc sp. ATCC 53789. Cryptophycin-24, Arenastatin A, contains one less chiral center than Cryptophycin-I, but demonstrates very similar activity with respect to tubulin binding. Two convergent total syntheses of Cryptophycin-24 are reported. The first modular approach is particularly good for SAR studies of the C16 aromatic side chain. The second approach, via a novel acyl beta-lactam macrolactonization is good for studies at both the C16 aromatic side chain and the C10 tyrosine side chain. The synthesis of a structurally flexible cryptophycin synthon and its application to the synthesis of a potential photolabel as well as others is also discussed.