Synthesis and Biological Evaluation of Unusual Natural Products and Novel Heterocyclic Chemotypes as Carbonic Anhydrase Inhibitors

Abstract

Carbonic anhydrases (CAs) are zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. The zinc cation in the active site of these metalloenzymes is the suggested target for small molecule inhibitors to block the endogenous CA catalysed reaction. Almost all reported CA inhibitors consist of zinc binding group (ZBG) among which the, primary sulfonamide group (-SO2NH2) is the most prominent example. Primary sulfamate (-OSO2NH2) and primary sulfamide (-NH-SO2NH2) groups also serve as zinc binding groups in CA inhibitors, however they are less represented than the primary sulfonamide group. Natural products (NPs) have proven an invaluable source of compounds for drug discovery. NPs containing primary sulfonamide (-SO2NH2) and primary sulfamate (-OSO2NH2) group are rare, while there are no NP primary sulfamides. A literature search of the Dictionary of Natural Products (DNP) database revealed only two primary sulfonamide and five primary sulfamate compounds. This project will focus on the tractable synthesis of these rare natural products, biological evaluation against CA and protein X-ray crystal structures in complex with medicinally important isozymes of CA.