Synthesis of Novel N-{[4-(1,2,3-Triazol)pyridin-3-yl]sulfonyl}urea Derivatives With Potential Anticancer Activity

Sulfonylureas have been commonly used since the 1950s as antihypoglycemic (e.g., tolbutamide, glipizide, glimepiride) and diuretics drugs (torasemide). Preclinical studies towards antineoplastic activity of sulfonyloureas led to recognize among them a group of diarylsulfonylureas (DSU) (e.g. LY-181984, Sulofenur and LY‑295501) with activity against a broad spectrum of syngeneic rodent solid tumors and human tumor xenografts [1]. Continuing our previous studies, in which we have shown a significant potential for antitumor activity of 1-(4-substituted pyridine-3-sulfonyl)-3-phenylureas [2], we have undertaken the synthesis and evaluation of cytostatic activity of novel series of N-{[4-(1,2,3-triazol)pyridin-3-yl]sulfonyl}urea derivatives. To provide easy functionalization of substituent at the position 4 of the pyridinesulfonamide scaffold, which have a significant influence on the antitumor activity [2.3], we started from 4-(2-propyn-1-ylthio/amino)pyridine-3-sulfonamides and, using the copper-catalyzed azide-alkyne cycloaddition (CuAAC), introduced 1,4-disubstituted 1,2,3-triazole ring. The primary sulfonamides thus obtained were next treated with various isocyanates to give a series of desired sulfonylurea derivatives. The structures of all compounds were confirmed with IR and NMR spectroscopy and elemental analyses. All compounds were submitted to test their effects on growth of human cancer cell lines: colon cancer HCT-116, breast cancer MCF-7 and cervical cancer HeLa. Cell viability was measured using MTT assay after 72 h of incubation with tested compound in concentration 1 – 100 μM. References: Pasello G, et al. Oncologist 2013; 18: 1118–1125. Szafranski K, Slawinski J. Molecules. 2015; 20; 12029–12044. Slawinski J, et al. Eur J Med Chem. 2013;69:701–10.