Benzenesulfonamides with different rigidity-conferring linkers as carbonic anhydrase inhibitors: an insight into the antiproliferative effect on glioblastoma, pancreatic, and breast cancer cells

Abstract

Among the chemotypes studied for selective inhibition of tumour-associated carbonic anhydrases (CAs), SLC-0111 , a ureido-bearing benzenesulfonamide CA IX inhibitor, displayed promising antiproliferative effects in cancer cells in vitro and in vivo , being in Phase Ib/II clinical development. To explore the structural characteristics required for better discrimination of less conserved regions of the enzyme, we investigate the incorporation of the urea linker into an imidazolidin-2-one cycle, a modification already explored previously for obtaining CA inhibitors. This new library of compounds inhibited potently four different hCAs in the nanomolar range with a different isoform selectivity profile compared to the lead SLC-0111 . Several representative CA IX inhibitors were tested for their efficacy to inhibit the proliferation of glioblastoma, pancreatic, and breast cancer cells expressing CA IX, in hypoxic conditions. Unlike previous literature data on SLC-149 , a structurally related sulphonamide to compounds investigated here, our data reveal that these derivatives possess promising anti-proliferative effects, comparable to those of SLC-0111 .

Imidazole‐hydrazone derivatives: Synthesis, characterization, X‐ray structures and evaluation of anticancer and carbonic anhydrase I–II inhibition properties

“…In light of this, numerous hCA isoforms are regarded as desirable therapeutic targets for various pharmacological uses. [5,6] The precise physiological significance of CA I, which is widely distributed across many tissues and contributes to various pathological conditions such as retinal and brain edema, is poorly unknown. Additionally, abundant in numerous tissues, CA II is important in many disease states, including glaucoma, epilepsy, edema, high altitude condition, and kidney illness.…”

“…Fluctuations in CA expression levels can cause cancer, neuropathic pain, altitude sickness, glaucoma, epilepsy, hypertension, and more. In light of this, numerous hCA isoforms are regarded as desirable therapeutic targets for various pharmacological uses [5,6] . The precise physiological significance of CA I, which is widely distributed across many tissues and contributes to various pathological conditions such as retinal and brain edema, is poorly unknown.…”

Synthesis and biological evaluation of coumarin‐thiazole hybrids as selective carbonic anhydrase IX and XII inhibitors

“…Schrödinger Suite release 2019‐1 was used to perform molecular modeling studies. [ 34 ] The protein crystal structure of the hCA IX receptor in complex with 5‐(1‐naphthalen‐1‐yl‐1,2,3‐triazol‐4‐yl)thiophene‐2‐sulfonamide (PDB ID: 5FL4) [ 35 ] and hCA XII receptor in complex with 4‐propylthiobenzenesulfonamide (PDB ID: 4WW8) [ 36 ] was retrieved from the RCSB Protein Data Bank. Next, proteins were prepared by using the Protein Preparation Wizard of the Maestro.…”

Design and synthesis of some new benzoylthioureido benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors

“…Because of its ability to form many stable hydrogen bonds with targeted protein, the ureido moiety is one of the most prevalent functional groups within medications of synthetic or natural origin 13 , 14 . For N,N-alkylated compounds of the class reported by Zhang 15 and Liguori et al., 16 the significant function of the ureido moiety in promoting the selectivity of carbonic anhydrase inhibitors (CAIs) was clearly demonstrated. On the other hand, Akgul et al.…”