Carbonic anhydrase IX (CA IX) is an extra-cellular membrane-bound isoform of the α-CA enzyme family. Upregulation of CA IX has been associated with tumor growth and proliferation, and identified as a potential anticancer drug target. Currently there are over 20 clinically used CA inhibitors, but to date none show CA IX isoform selectivity over other α-CA isoforms. Cyclic secondary sulfonamides, such as saccharin (SAC), can inhibit CA IX with up to 60-fold isoform selectivity.  Application of the “tail-approach” to develop inhibitors with higher CA IX selectivity have been achieved by connecting SAC (anchor) to a β glucoside (tail) with a methylene triazole linker, generated by copper mediated cycloaddition of acetylenic glycons and SAC derived azides. The selectivity towards CA IX was increased by up to 1000-fold for the SAC derivatization. When designing and synthesizing new inhibitors for CA IX, we found a problem in the final deprotection step of the existing synthetic scheme, which involved acid-catalyzed removal of a t-butyl protecting group of the SAC nitrogen. Therefore, we developed an improved synthetic approach for these compounds with a mild “one pot” deprotection and SAC ring formation in the final step. In this route, we utilized a ring-opened version of SAC with a sulfonamide nitrogen that was amenable to the required copper mediated cycloaddition.  We also applied this method to the synthesis of new galactosyl and glucosyl conjugates.<br/>With this approach, we are not only able to succeed in the click reaction with 76-95% yields, but also cleave the acetyl protecting groups and cyclize the SAC ring under mild conditions in good yields (71-85%).

Improved synthetic approach to CA IX selective inhibitors featuring one-pot cyclization/deprotection

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.