Carbonic Anhydrase Inhibitors. Inhibition of Tumor-Associated Isozyme IX by Halogenosulfanilamide and Halogenophenylaminobenzolamide Derivatives

Abstract

Two series of halogenated sulfonamides have been prepared. The first consists of mono/dihalogenated sulfanilamides, whereas the second one consists of the mono/dihalogenated aminobenzolamides, incorporating equal or different halogens (F, Cl, Br, and I). These sulfonamides have been synthesized from the corresponding anilines by acetylation (protection of the amino group), chlorosulfonylation, followed either by amidation, or reaction with 5-amino-1,3,4-thiadiazole-2-sulfonamide (and eventually deacetylation). All these compounds, together with the six clinically used sulfonamide inhibitors (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, and brinzolamide) were investigated as inhibitors of the transmembrane, tumor-associated isozyme carbonic anhydrase (CA) IX. Inhibition data against the classical, physiologically relevant isozymes I, II, and IV were also obtained. CA IX shows an inhibition profile which is generally completely different from those of isozymes I, II, and IV, with potent inhibitors (inhibition constants in the range of 12-40 nM) among both simple aromatic (such as 3-fluoro-5-chloro-4-aminobenzenesulfonamide) as well as heterocyclic compounds (such as acetazolamide, methazolamide, 5-amino-1,3,4-thiadiazole-2-sulfonamide, aminobenzolamide, and dihalogenated aminobenzolamides). This first detailed CA IX inhibition study revealed many interesting leads, suggesting the possibility to design even more potent and eventually CA IX-selective inhibitors, with putative applications as antitumor agents.

Ethyl 7-Methyl-1-(4-nitrophenyl)-5-phenyl-3-(thiophen-2-yl)-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylate

“…Ethyl 7-methyl-1-(4-nitrophenyl)-5-phenyl-3-(thiophen-2-yl)-1,5-dihydro- [1,2,4]triazolo [4,3-a] pyri-midine-6-carboxylate was synthesized and tested for its in vitro antitumor activity against two human cancer cell lines (A-549 and HepG-2).…”

“…It has been reported in the literature that functionalized thiophene derivatives have received considerable attention over the last two decades because they are endowed with a wide range of anti-tumor activities [1][2][3][4][5]. On the other hand, the synthesis of triazolopyrimidine derivatives has attracted a great deal of attention in view of their potent biological and pharmacological activities, especially their antitumor properties [6][7][8][9][10][11][12][13][14][15][16].…”

“…the growth of a wide range of cancer cell lines including leukemia and prostate and lung cancer at low dose levels [15]. Moreover, pyrido [2,3-d] [1,2,4]triazolo [4,3-a]pyrimidinone derivative II showed relatively potent antitumor activity against PC-3 and A-549 cell lines [16]. In particular, Compound II was able to cause cell cycle arrest at least partly through enhancing the expression level of the cell cycle inhibitor p21 and induced cancer cell apoptosis via a caspase-3 dependent pathway.…”

Carbonic Anhydrases inhibitory effects of new benzenesulfonamides synthesized by using superacid chemistry

“…Inhibitor and enzyme solutions were preincubated together for 15 min at room temperature prior to assay, in order to allow for the formation of the E-I complex. The inhibition constants were obtained by non-linear leastsquares methods using PRISM 3, as reported earlier, and represent the mean from at least three different determinations 16 . CA isofoms were recombinant ones obtained in house as reported earlier 16,17 .…”

Synthesis and antimicrobial activity of some derivatives of acylhydrazine including novel benzenediazasulfonamides

“…[1][2][3][4][5] Secondly, the sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, antifungal, diuretic, anticarbonic anhydrase, antithyroid, hypoglycemic and antitumour activity [6][7][8][9][10] among others. In continuation of our research in the chemistry of sulfonamides 11 and acylhydrazine derivatives, 12 we report herein the synthesis of novel acylhydrazine derivatives including benzenediazasulfonamides (Scheme 1).…”