Novel 2-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)-1-(1,3,5-triazin-2-ylamino)guanidine derivatives: Inhibition of human carbonic anhydrase cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII, anticancer activity, and molecular modeling studies

• DOI: 10.1016/j.ejmech.2017.11.005
• Publication Date: 2017-11-04T08:31:36Z
• Authors: Beata Żołnowska; Jarosław Sławiński; Krzysztof Szafrański; Andrea Angeli; Claudiu T. Supuran; Anna Kawiak; Miłosz Wieczór; Joanna Zielińska; Tomasz Bączek; Sylwia Bartoszewska
• Keywords: Models, Molecular; 0303 health sciences; Carbonic Anhydrase I; Dose-Response Relationship, Drug; Molecular Structure; Cell Survival; Antineoplastic Agents; Carbonic Anhydrase II; 3. Good health; Isoenzymes; Structure-Activity Relationship; 03 medical and health sciences; Tumor Cells, Cultured; Humans; Drug Screening Assays, Antitumor; Carbonic Anhydrase IX; Carbonic Anhydrase Inhibitors; Anticancer; Benzenesulfonamide; Carbonic anhydrase inhibitors; Molecular dynamics; Synthesis; Guanidine; Carbonic Anhydrases; Cell Proliferation

A series of novel 2-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)-1-(6-substituted-4-chloro-1,3,5-triazin-2-ylamino)guanidine derivatives 9-20 have been synthesized by substitution of chlorine atom at the 1,3,5-triazine ring in compounds 5-8 with 3- or 4-aminobenzenesulfonamide and 4-(aminomethyl)benzenesulfonamide hydrochloride. All the synthesized compounds were evaluated for their inhibitory activity toward hCA I, II, IX and XII as well as anticancer activity against HeLa, HCT-116 and MCF-7 human tumor cell lines. The investigated compounds showed weak inhibitory potency against the human CA I, while activity toward hCA II was differentiated and depended on structure of inhibitor (KI: 5.4-933.1 nM). Compounds containing the 4-sulfamoylphenyl moiety (9-12) exhibited the strongest inhibitory activity against hCA IX with KI values from 37.1 to 42.9 nM, as well as against hCA XII in range of 31-91.9 nM. The most promising compound 12 (KI = 41 nM) showed the highest selectivity toward hCA IX versus hCA I (hCA I/hCA IX = 18) and hCA II (hCA II/hCA IX = 4). Compound 12 displayed prominent cytotoxic effect selectively toward HeLa cancer cells (IC50 = 17 μM) and did not exhibit toxicity to the non-cancerous HaCaT cells. In silico analysis suggested that despite the lack of a single binding pose, the selective affinity is conferred by specific interactions with an arginine moiety, as well as better-defined binding modes within the active site.