The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII

Abstract

Human (h) carbonic anhydrase (CAs, EC 4.2.1.1) isoforms IX and XII were recently confirmed as anticancer targets against solid hypoxic tumours. The “three-tails approach” has been proposed as an extension of the forerunner “tail” and “dual-tail approach” to fully exploit the amino acid differences at the medium/outer active site rims among different hCAs and to obtain more isoform-selective inhibitors. Many three-tailed inhibitors (TTIs) showed higher selectivity against the tumour-associated isoforms hCA IX and XII with respect to the off-targets hCA I and II. X-ray crystallography studies were performed to investigate the binding mode of four TTIs in complex with a hCA IX mimic. The ability of the most potent and selective TTIs to reduce in vitro the viability of colon cancer (HT29), prostate adenocarcinoma (PC3), and breast cancer (ZR75-1) cell lines was evaluated in normoxic (21% O 2 ) and hypoxic (3% O 2 ) conditions demonstrating relevant anti-proliferative effects.

Development of Hydrogen Sulfide-Releasing Carbonic Anhydrases IX- and XII-Selective Inhibitors with Enhanced Antihyperalgesic Action in a Rat Model of Arthritis

“…Among the numerous H 2 S-releasing scaffolds reported in the literature, which showed different gasotransmitter releasing properties, the drug design strategy here proposed was initiated with the 4-substituted 3 H -1,2-dithiole-3-thione chemotype ( DTT , Figure ), chosen on the basis of the target therapeutic action and resulting necessary H 2 S release rate. As for including CAI scaffolds into the molecular hybrids, the choice fell on the benzenesulfonamide chemotype which furnishes optimal hCA inhibition potency and was shown to be suitable for drug design strategies aimed at enhancing isoform selectivity. , …”

“…As for including CAI scaffolds into the molecular hybrids, the choice fell on the benzenesulfonamide chemotype which furnishes optimal hCA inhibition potency and was shown to be suitable for drug design strategies aimed at enhancing isoform selectivity. 36 , 37 …”

“…As for including CAI scaffolds into the molecular hybrids, the choice fell on the benzenesulfonamide chemotype which furnishes optimal hCA inhibition potency and was shown to be suitable for drug design strategies aimed at enhancing isoform selectivity. 36,37 The synthesis of the H 2 S releaser�CAI hybrids starts with the preparation of the 3H-1,2-dithiole-3-thione core, which bears a p-COOH-phenyl moiety at position 4 for the subsequent hybridization with the CAI scaffold. Initially, 4isopropylbenzoic acid was protected as ethyl ester 1, using SOCl 2 in dry ethanol (EtOH) (Scheme 1).…”

Five-Membered Heterocyclic Sulfonamides as Carbonic Anhydrase Inhibitors

“…Subsequently, this approach was further developed in the “dual-tail” and “three-tails” approach to increase the possibility of interaction with specific residues of the target isoform and, at the same time, to have the possibility to interact simultaneously with both the polar and the lipophilic area of the binding pocket, presenting a hydrophobic and a hydrophilic tail [ 74 , 75 , 76 , 77 , 78 ].…”

Ibuprofen: a weak inhibitor of carbonic anhydrase II

“…The sulfonamide-based CAIs are termed classical CA inhibitors as they are the most widely studied pharmacophore in CAIs (Supuran, 2016). However, there has been a change in emphasis in the last few decades to develop CA isoform-specific inhibitors for the clinical treatment of a variety of diseases, including certain cancers (Bonardi et al, 2022;Bozdag et al, 2014;Mboge et al, 2021;Vannozzi et al, 2022). A major hurdle in the development of effective CAIs is the similarity between the human CA isoforms, which leads to off-target binding.…”