A Versatile Chemoenzymatic Synthesis for the Discovery of Potent Cryptophycin Analogs
Schmidt JJ, Khatri Y, Brody SI, Zhu C, Pietraszkiewicz H, Valeriote FA, and Sherman DH. A Versatile Chemoenzymatic Synthesis for the Discovery of Potent Cryptophycin Analogs. ACS Chem Biol 2020; 15(2):524-532.
ACS Chem Biol
The cryptophycins are a family of macrocyclic depsipeptide natural products that display exceptionally potent antiproliferative activity against drug-resistant cancers. Unique challenges facing the synthesis and derivatization of this complex group of molecules motivated us to investigate a chemoenzymatic synthesis designed to access new analogs for biological evaluation. The cryptophycin thioesterase (CrpTE) and the cryptophycin epoxidase (CrpE) are a versatile set of enzymes that catalyze macrocyclization and epoxidation of over 20 natural cryptophycin metabolites. Thus, we envisioned a drug development strategy involving their use as standalone biocatalysts for production of unnatural derivatives. Herein, we developed a scalable synthesis of 12 new unit A-B-C-D linear chain elongation intermediates containing heterocyclic aromatic groups as alternatives to the native unit A benzyl group.