Maytansinol Functionalization: Towards Useful Probes for Studying Microtubule Dynamics

Abstract

Maytansinoids are a successful class of natural and semisynthetic tubulin binders, known for their potent cytotoxic activity. Their wider application as cytotoxins and chemical probes to study tubulin dynamics has been held back by the complexity of natural product chemistry. Here we report the synthesis of long-chain derivatives and maytansinoid conjugates. We confirmed that bulky substituents do not impact their high activity or the scaffold's binding mode.These encouraging results open new avenues for the design of new maytansine-based probes.

Bridging the maytansine and vinca sites: Cryptophycins target β-tubulin’s T5-loop

“…Furthermore, the close proximity of the βT5-loop site to the vinca and maytansine sites opens up a unique avenue for the design of hybrid ligands targeting multiple major binding sites on β-tubulin: simultaneous binding to these two sites could guide ligands to specifically interact with the βT5-loop to elicit novel effects on tubulin dynamics and assembly. We previously pursued a similar objective by linking maytansinol to guanosine but faced challenges in effectively targeting the nucleotide site on β-tubulin ( 30 ). Our finding that the βT5-loop site acts as a bridge between the maytansine and vinca sites now provides a strong basis for the design of such hybrid molecules.…”