Carbonic anhydrase inhibitors. Synthesis, and molecular structure of novel series N-substituted N'-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines and their inhibition of human cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII

Eur J Med Chem. 2014 Jan:71:135-47. doi: 10.1016/j.ejmech.2013.10.081. Epub 2013 Nov 10.

Abstract

A series of novel N-substituted N'-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines 9-41 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 cancer-associated isozymes CA IX and XII. Against the human CA I investigated compounds showed KI in the range of 87-6506 nM, toward hCA II ranging from 7.8 to 4500 nM, against hCA IX in the range of 4.7-416 nM and against hCA XII at range of 0.96-540 nM. Compounds 10, 12-14, 16, 18-20, 24-26, 31 and 32 exhibited a powerful inhibitory potency toward hCA IX (K(I) = 4.7-21 nM) in comparison to the reference sulfonamides AAZ, MZA, EZA, DCP and IND (K(I) = 24-50 nM). Compound 14 was the most potent inhibitor of hCA I (K(I) = 87 nM), hCA IX (K(I) = 4.7 nM) and hCA XII (K(I) = 0.96 nM), while 26 was the most effective inhibitor of hCA II (K(I) = 7.8 nM). The most promising compound 32 exerted the highest selectivity ratios toward hCA IX versus hCA I (hCA I/hCA IX = 261) and hCA II (hCA II/hCA IX = 26). The in vitro antitumor activity of compounds 10, 13, 14, 21, 22, 25, 32, 38 and 41 was evaluated at the US National Cancer Institute (NCI) against a panel of 60 human tumor cell lines. The most active antitumor agents 21 and 25, inhibiting 32-35 human tumor cell lines with GI₅₀ in the range of 2.1-5.0 μM also showed relatively high inhibitory activity toward hCA IX and XII with KI from 18 to 40 nM.

Keywords: Anticancer activity; Carbonic anhydrase isozymes I, II, IX and XII inhibitors; Sulfonamide; Sulfonylguanidine; Synthesis.

MeSH terms

  • Antigens, Neoplasm / metabolism
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Carbonic Anhydrase I / antagonists & inhibitors
  • Carbonic Anhydrase I / metabolism
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase IX
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Cell Line, Tumor
  • Cytosol / drug effects
  • Cytosol / enzymology
  • Guanidines / chemistry
  • Guanidines / pharmacology
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Models, Molecular
  • Neoplasms / drug therapy
  • Neoplasms / enzymology*
  • Structure-Activity Relationship

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Carbonic Anhydrase Inhibitors
  • Guanidines
  • Isoenzymes
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • carbonic anhydrase XII