Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

A central goal of chemical biology is to develop molecular probes that enable fundamental studies of cellular systems. In the hierarchy of bioactive molecules, the so-called ionophore class occupies an unflattering position in the lower branches, with typical labels being "non-specific" and "toxic". In fact, the mere possibility that a candidate molecule possesses "ionophore activity" typically prompts its removal from further studies; ionophores-from a chemical genetics perspective-are molecular outlaws. In stark contrast to this overall poor reputation of ionophores, synthetic chemistry owes some of its most amazing achievements to studies of ionophore natural products, in particular the carboxyl polyethers renowned for their intricate molecular structures. These compounds have for decades been academic battlegrounds where new synthetic methodology is tested and retrosynthetic tactics perfected. Herein, we review the most exciting recent advances in carboxyl polyether ionophore (CPI) synthesis and in addition discuss the burgeoning field of CPI chemical biology.