Synthesis of 6-aryl-substituted sulfocoumarins and investigation of their carbonic anhydrase inhibitory action

• Published in: Bioorganic & medicinal chemistry Vol. 23; no. 7; pp. 1430 - 1436
• Main Authors: Grandane, Aiga, Tanc, Muhammet, Žalubovskis, Raivis, Supuran, Claudiu T.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2015; Elsevier
• Subjects: Biochemistry & Molecular Biology; Carbonic anhydrase; Carbonic Anhydrase Inhibitors - chemical synthesis; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Coumarins - chemical synthesis; Humans; Inhibitor; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Sulfocoumarin; Sulfur Compounds - chemical synthesis; Tumor-associated enzyme; Inhibitor; Carbonic anhydrase; Tumor-associated enzyme; Sulfocoumarin; MECHANISM; ZINC-COMPLEXES; SULFONAMIDES; COUMARINS; IX; POTENT; BENZENESULFONAMIDES; PATENT; SELECTIVE INHIBITORS; ISOZYME-II
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.02.023

Ar=Ph; 2-, 3- and 4-substituted-phenyls with Me, CF3, halogens, alkyl, alkoxy, etc. KI (hCA I)>10μM; KI (hCA II)>10μM; KI (hCA IX)=9.0–95.3nM; KI (hCA XII)=3.5–14.2nM. [Display omitted] A series of 6-aryl-substituted 1,2-benzoxathiine 2,2-dioxides was obtained by reacting 6-iodo-sulfocoumarin with arylboronic acids in Suzuki cross-coupling conditions. The new sulfocoumarins incorporating various substituted phenyl moieties in position 6 of the heterocyclic ring were investigated for the inhibition of four human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms with medicinal chemistry applications, the cytosolic hCA I and II, and the transmembrane, tumor-associated hCA IX and XII. The aryl-substituted sulfocoumarins did not inhibit the ubiquitous, off-target cytosolic isoforms hCA I and II (KIs>10μM) but showed effective inhibition against the two transmembrane CAs, with KIs ranging from 9.0 to 95.3nM against hCA IX, and between 3.5 and 14.2nM against hCA XII. As hCA IX and XII are validated anti-tumor targets, such sulfocoumarin, isoform-selective inhibitors may be useful for identifying suitable drug candidates for further clinical trials of this class of pharmacologic agents.