Carbonic anhydrase inhibitors. Synthesis of heterocyclic 4-substituted pyridine-3-sulfonamide derivatives and their inhibition of the human cytosolic isozymes I and II and transmembrane tumor-associated isozymes IX and XII

• A series of novel 4-heterocyclic-3-pyridinesulfonamide have been synthesized.
• All compounds were tested as inhibitors of four human CA isozymes.
• Some of them has CA IX inhibition constant in range of clinically used sulfonamides.
• Selectivity ratios CA IX/CA II was higher (0.9–6.9) than reference (0.23–0.8).
• Also anticancer in vitro evaluation have been performed at NCI.

A series of novel heterocyclic 4-substituted pyridine-3-sulfonamides 2–13, 15–20 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA.EC 4.2.1.1), that is the cytosolic CA I and II, and tumor-associated isozymes CA IX and XII. Against the human isozymes hCA I the new compounds showed KI values in the range 169–5400 nM, toward hCA II in range 58.5–1238 nM, against hCA IX in range 19.5–652 nM and against hCA XII in the range of 16.8–768 nM. Compounds 15–19 representing 4-(1H-pyrazol-1-yl)-3-pyridinesulfonamide derivatives showed good hCA IX inhibitory efficacy with KI = 19.5–48.6 nM comparable or more effective than clinically used sulfonamides: AAZ, MZA, EZA, DCP, IND (KI = 24–50 nM). Anticancer evaluation at a single dose 10 μM, against a panel of 60 human tumor cell lines, was performed at the US National Cancer Institute, on compounds 2, 3, 5–13, 16, 17, 19, 20. Among them 6 bearing 4-(3,4,-dichlorophenyl)piperazine moiety showed broad spectrum of growth inhibition in the range 25–89% over 26 cell lines representing all tumors subpanels.

A series of novel heterocyclic 4-substituted pyridine-3-sulfonamides have been synthesized. Some of them showed good carbonic anhydrase CA I, II, IX and XII inhibitory efficiency, and promising in vitro anticancer activity.Figure optionsDownload as PowerPoint slide