Open saccharin-based secondary sulfonamides as potent and selective inhibitors of cancer-related carbonic anhydrase IX and XII isoforms

Abstract

A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (Kis > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with Kis ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Kis ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors.

Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one

“…Their inhibition mechanism is unknown due to the fact that no X‐ray crystal structure of their adducts with any CA isoform has been obtained so far . Structurally similar secondary/tertiary sulfonamides and sulfamates derived from saccharin 53 , acesulfame 54 , and probenecid 55 (Figure ) were reported by Carradori's group to possess potent CA IX/XII inhibitory potency, but again their mechanism of action is poorly understood at this moment due to the lack of X‐ray crystal structures . These large series of derivatives incorporate a variety of substitution patterns (R groups in 53–55 ), which allowed for a detailed understanding of the structure–activity relationship governing their CA IX/XII inhibitory properties …”

“…[255][256][257][258][259] Structurally similar secondary/tertiary sulfonamides and sulfamates derived from saccharin 53, acesulfame 54, and probenecid 55 (Figure 16) were reported by Carradori's group to possess potent CA IX/XII inhibitory potency, but again their mechanism of action is poorly understood at this moment due to the lack of X-ray crystal structures. [260][261][262][263][264][265][266] These large series of derivatives incorporate a variety of substitution patterns (R groups in 53-55), which allowed for a detailed understanding of the structure-activity relationship governing their CA IX/XII inhibitory properties. [260][261][262][263][264][265][266] The protein tyrosine kinase inhibitors imatinib and nilotinib were also reported to inhibit CAs, including the tumorassociated isoforms CA IX and XII in the nanomolar range, although their inhibition mechanism is unknown for the moment.…”

“…[260][261][262][263][264][265][266] These large series of derivatives incorporate a variety of substitution patterns (R groups in 53-55), which allowed for a detailed understanding of the structure-activity relationship governing their CA IX/XII inhibitory properties. [260][261][262][263][264][265][266] The protein tyrosine kinase inhibitors imatinib and nilotinib were also reported to inhibit CAs, including the tumorassociated isoforms CA IX and XII in the nanomolar range, although their inhibition mechanism is unknown for the moment. 267…”

Potent and Selective Carboxylic Acid Inhibitors of Tumor-Associated Carbonic Anhydrases IX and XII

“…Targeting specific CA isoforms has been indeed exploited in the therapy of different diseases. Human CA II (hCA II), hCA IV, and hCA XII are usually referred as anti-glaucoma drug targets [ 3 , 12 , 13 , 14 ], hCA IX and hCA XII are well-known tumor-associated isoforms [ 15 , 16 , 17 , 18 ], hCA VA is a promising drug target for the treatment of obesity [ 19 , 20 , 21 ], while hCA VII is a drug target for the treatment of neuropathic pain and epilepsy [ 1 , 22 , 23 , 24 ]. Coupled with ubiquitous expression and with their critical role in cell homeostasis, indiscriminate inhibition of many hCA isoforms at the same time may lead to detrimental side effects.…”

Design, Synthesis, Molecular Docking Analysis, and Carbonic Anhydrase IX Inhibitory Evaluations of Novel N-Substituted-β-d-Glucosamine Derivatives that Incorporate Benzenesulfonamides

“…The attachment of sugar hydrophilic moiety provides the opportunities to specifically target CA IX due to the membrane impermeability of the inhibitor [ 20 ]. In addition, secondary sulfonamide moiety has been used in numerous clinical drugs [ 21 ], and it has also been described in the literature as a potent and specific inhibitor for CA IX [ 12 , 22 , 23 , 24 , 25 ]. For example, compounds B and C , incorporating a secondary sulfonamide rather than a primary one, showed low Ki values and excellent selectivity to CA IX ( Figure 1 ) [ 24 , 25 ].…”