Identification of 3,4-Dihydroisoquinoline-2(1H)-sulfonamides as Potent Carbonic Anhydrase Inhibitors: Synthesis, Biological Evaluation, and Enzyme−Ligand X-ray Studies

Abstract

Following previous studies we herein report the exploration of the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects and enzyme selectivity of a small class of 1-(cyclo)alkylisoquinolines containing a sulfonamide function considered a key feature for inhibiting CA. The results of enzymatic assays against human (h) CA isoforms, hCA I and hCA II (cytosolic, ubiquitous enzymes), hCA IX (transmembrane, tumor-associated), and hCA XIV (transmembrane), suggested that the presence of C-1 small substituents on isoquinoline scaffold controls both inhibitory potency and selectivity. Some derivatives showed potent hCA IX and hCA XIV inhibitory effects at nanomolar concentrations as well as low affinity for the ubiquitous hCA II. Moreover, we report the X-ray crystal structure of one of these derivatives in complex with dominant human isoform II, thus confirming the sulfonamide--zinc interactions. Finally, the results of docking experiments suggested the hypothetic interactions in the catalytic binding site for the most active and selective hCA IX and hCA XIV inhibitor.

Structure, function and applications of carbonic anhydrase isozymes

“…One is metal complex forming anions and others are sulfonamides and their isosteres. 125,126 Structural data show that the inhibitors ionize upon binding with the enzyme to yield an NH À group that relocates the zinc hydroxide ion and shares a hydrogen bond with Thr199. 64 Approximately 25 clinically used drugs have been developed against CAs that used as diuretics, antiglaucoma drugs, anticonvulsants and anticancer agents.…”

One Pot Synthesis of Some Novel Sulfonamide Derivatives Containing -NH2 Group: Spectral Characterization and Biological Evaluation

“…So sulfonamides and their derivatives are used as antibiotics medicines [2]. Apart from this application as an antibacterial agent, various sulfonamide derivatives are known to inhibit many enzymes such as Serine protease [3][4][5], cyclooxygenase [6], matrix metalloproteinase [7] and carbonic anhydrase [8][9][10][11]. Moreover their widespread potential values have led to discovery of various therapeutic applications in cancer chemotherapy, hypoglycemia, diuretics [12] and anti-impotence agent Viagra [13].…”

Quinazoline-sulfonamides as potential antitumor agents: synthesis and biological testing

“…In our study, they showed activity comparable to that of the standard drug (with IC 50 of 0.012 µM) against the four selected cell lines. Free sulfonamide group was a common Scheme 3 feature in these two compounds; such moiety was reported to play a crucial role in CA inhibition and antitumor activity [7][8][9][10][11][12][13][14][15] . Condensing the sulfonamide moiety with different isocyanates produced the disubstituted sulfonylureido derivatives 9-11 and 22-24 of which compounds 10, 22 and 23 exhibited good antitumor activity against the tested cell lines, but they were less active than the parent sulfonamide derivative; compound 16 displayed moderate antitumor activity against hepatoma cancer cell line and good activity against the other cell lines, compound 17 was active against human beast as well as colon cancer cell lines and moderate activity against human cervix cell line.…”

“…In that context, several quinazoline derivatives have been shown to exhibit high affinity for receptor tyrosine kinases, as well as other oncogenic targets 5,6 . Many new sulfonamide derivatives, such as E7070 (indisulam), have shown substantial antitumor activity via different mechanisms [7][8][9][10][11][12][13][14][15][16][17] . It was also reported to selectively accumulate within cancerous cells.…”