Development of novel carbonic anhydrase inhibitors as anticancer agents from tubulin assembly scaffolds

Carbonic anhydrases (CAs) are ubiquitous metalloenzymes that catalyse the reversible conversion of carbon dioxide and water to bicarbonate and a proton via a coordinated metal ion. Hence, CAs activity is pivotal to the metabolism regulation under both physiological and pathological conditions.1 The human CA (hCA) isoforms have been an ever-growing focus of attention as a therapeutic strategy for the design of new agents to treat a variety of diseases, including cancer.2 Herein, in an effort to identify novel carbonic anhydrase inhibitors as anticancer agents, we designed and synthesised a series of structurally related indole and pyrrole compounds by modulating the scaffold of the most active tubulin assembly inhibitors reported in our previous work.3 Among the tested derivatives, we discovered that compounds 1 and 2, characterised by the presence of both N1-(4-benzenesulfonamide) and 3-(3,4,5-trimethoxyphenyl) moieties, showed a strong hCA inhibition (Figure 1). These latter demonstrated to be equipotent to 5-FU as inhibitors of HCT116 cells, and to be remarkably more potent against the SW480 and SW620 cell lines. Noteworthy, compound 1 proved to be a novel dual-targeting drug, with activity against hCA and Wnt/-catenin. Finally, molecular modeling studies highlighted docking poses, in the binding sites of the four hCA isoforms, consistent with the observed Ki values of this novel class of compounds. References 1. Supuran, C.T. Biochem J 2016, 473, 2023-2032. 2. La Regina, G.; Puxeddu, M.; Nalli, M.; Vullo, D.; Gratteri, P.; Supuran, C.T.; Nocentini, A.; Silvestri, R. ACS Med. Chem. Lett. 2020, 11, 633- 637. 3. Puxeddu, M.; Shen, H.; Bai, R.; Coluccia, A.; Bufano, M. ; et al. Eur J Med Chem. 2021, 221, 113-532.