Inhibition of Carbonic Anhydrases with Glycosyltriazole Benzene Sulfonamides

Abstract

A library of glycoconjugate benzene sulfonamides have been synthesized and investigated for their ability to inhibit the enzymatic activity of physiologically relevant human carbonic anhydrase (hCA) isozymes: hCA I, II, and tumor-associated IX. Our synthetic strategy directly links the known CA pharmacophore (ArSO 2NH 2) to a sugar "tail" moiety through a rigid 1,2,3-triazole linker unit using the Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction or "click chemistry". Many of the glycoconjugates were potent CA inhibitors and exhibited some isozyme selectivity. In particular, the methyl-D-glucuronate triazoles 6 and 14 were potent inhibitors of hCA IX (K(i)s 9.9 and 8.4 nM, respectively) with selectivity also favoring this isozyme. Other exceptional compounds included the deprotected beta-D-ribofuranosyl triazole 15 and alpha-D-mannosyl triazole 17, which were potent and selective hCA II inhibitors (K(i) 7.5 nM and K(i) 2.3 nM, respectively). Collectively, the results confirm that modification of ring size, stereochemical configuration, and chain length in the sugar tail moiety of glycoconjugate CA inhibitors permits tunable potency and selectivity that may constitute an important avenue for the future development of efficacious and selective CA-based therapeutics.

Synthesis and Evaluation of Antimalarial Properties of Novel 4‐Aminoquinoline Hybrid Compounds

“…All starting materials and reagents were purchased from commercial suppliers. 3‐Azidopropyl‐1‐amine hydrochloride , 4‐ethynylbenzenesulfonamide , 3‐ethynylbenzenesulfonamide , 4‐azidobenzenesulfonamide , and 3‐azidobenzenesulfonamide were synthesized as described earlier. All reactions were monitored by TLC.…”

Carbonic Anhydrase Inhibitors Developed Through ‘Click Tailing’

“…(3). In order to selectively target CA IX and XII isozymes for in vivo applications our group has focused on optimizing both SAR and SPR of CAIs to provide chemical probes and/or drug leads [26][27][28][29][30][31][32][33]. The physical barrier of the cell membrane is central to the behaviour of compounds in vivo.…”

“…In summary, this combined SAR and SPR approach has provided valuable chemical tools and potential drug leads for the study of CAs. The interested reader is directed to the original research papers for more detail [26][27][28][29][30][31][32][33].…”

Carbonic Anhydrase Inhibitors and Activators for Novel Therapeutic Applications

“…n Sugar-containing sulfonamides/sulfamates/ sulfamides, which, due to their highly hydrophilic character, do not easily cross membranes and thus possess enhanced affinity for extracellular CAs such as CA IX and XII [50][51][52][53][54][55][56];…”