Carbonic Anhydrase Inhibitory Effects Research Articles

Design and synthesis of sulfonamides incorporating a biotin moiety: Carbonic anhydrase inhibitory effects, antiproliferative activity and molecular modeling studies

Sulfonamides constitute an important class of classical carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Herein we have accomplished the conjugation of biotin with an ample number of sulfonamide motifs with the aim of testing them in vitro as inhibitors of the human carbonic anhydrase (hCA) isoforms I and II (cytosolic isozymes), as well as hCA IX and XII (transmembrane, tumor-associated enzymes). Most of these newly synthesized compounds exhibited interesting inhibition profiles, with activities in the nanomolar range. The presence of a 4-F-C6H4 moiety, also found in SLC-0111, afforded an excellent selectivity towards the tumor-associated hypoxia-induced hCA isoform XII with an inhibition constant (KI) of 4.5 nM. The 2-naphthyl derivative was the most potent inhibitor against hCA IX (KI = 6.2 nM), 4-fold stronger than AAZ (KI = 25 nM) with very good selectivity. Some compounds were chosen for antiproliferative activity testing against a panel of 3 human tumor cell lines, one compound showing anti-proliferative activity on glioblastoma, triple-negative breast cancer, and pancreatic carcinoma cell lines.

Hypoxia-Activated Prodrugs with Dual COX-2/CA Inhibitory Effects on Attenuating Cardiac Inflammation under Hypoxia.

Cardiac inflammation is generally accompanied by hypoxia, while myocardial injury and an abnormal microenvironment caused by hypoxia tend to suppress the efficacy of common anti-inflammatory drugs. To improve the anti-inflammatory effect under hypoxia, a hypoxia-activated prodrug HAP1 consisting of a cyclooxygenase-2 (COX-2) inhibitor Ind and a carbonic anhydrase (CA) inhibitor Ace was synthesized. HAP1 was found to be activated by nitroreductase (NTR) under hypoxia to release two pharmacophores and achieve the combinatory medication intensively at the hypoxic site, better than Ind or Ace alone. When NTR activity was inhibited by Na2WO4 under hypoxia, no pharmacophores were found to release from HAP1 without exhibiting its activity. However, the efficacy of the Ind and Ace combination group (I&A) was not affected. Furthermore, HAP1 showed advantages over I&A in vivo not only in improving bioavailability but also in reducing side effects. The HAP approach turns out to inhibit cardiac inflammation efficiently and safely under hypoxia.

Investigation of carbonic anhydrase inhibitory effects and cytotoxicities of pyrazole-based hybrids carrying hydrazone and zinc-binding benzenesulfonamide pharmacophores

Pyrazole-based carbohydrazone hybrids have been considered to be a remarkable class of compounds in pharmaceutical chemistry. Here, we reported bioactivities of 4-(3-(2-(arylidene)hydrazin-1-carbonyl)-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamides (1–27) towards CA isoenzymes (hCA I, hCA II, hCA IX) and human oral squamous cell carcinoma cell line. Compounds 19 (Ki = 10.1 nM, hCA I/hCA IX = 749.6), 22 (Ki = 18.5 nM, hCA I/hCA IX = 429.2), 26 (Ki = 14.5 nM, hCA I/hCA IX = 596.9), 27 (Ki = 21.5 nM, hCA I/hCA IX = 413.1) were more potent and selective inhibitors of cancer-associated hCA IX isoenzyme. Compounds 22 and 26 were also found to be approximately three times more selective hCA IX inhibitors over off-target hCA II at low nanomolar. Compounds 19, 22, 23, 24, and 26 with IC50 of 1.6–1.7 μM showed potent cytotoxicity against human oral squamous cell carcinoma cell line as compared with human gingival fibroblast, producing the tumor-specificity value over 100. This was due to its cytostatic growth inhibition accompanied by a slight but significant dose-dependent increase in cell shrinkage and subG1 cell accumulation and marginal activation of caspase 3 substrates. Bioassay results showed that carbohydrazone-based hybrids could be useful candidates to design novel anticancer compounds and selective carbonic anhydrase inhibitors.

Synthesis, cytotoxic, and carbonic anhydrase inhibitory effects of new 2‐(3‐(4‐methoxyphenyl)‐5‐(aryl)‐4,5‐dihydro‐1H‐pyrazol‐1‐yl)benzo[d]thiazole derivatives

Abstract2‐(3‐[4‐Methoxyphenyl]‐5‐aryl‐4,5‐dihydro‐1H‐pyrazol‐1‐yl)benzo[d]thiazoles (1b‐7b) were synthesized for the first time except 1b, and spectral methods such as 1H NMR, 13C NMR and HRMS were utilized to illuminate the chemical structures of the synthesized compounds. Phenyl (1b), 2‐methoxyphenyl (2b), 4‐methoxyphenyl (3b), 4‐methoxy‐3‐hydroxyphenyl (4b), 2,5‐dimethoxyphenyl (5b), 3,4,5‐trimethoxyphenyl (6b), or thiophene‐2‐yl (7b) was used as a aryl part. The inhibitory effects of the compounds were evaluated toward human carbonic anhydrase I and II enzymes (hCA I and hCA II). In vitro cytotoxic effects of the compounds against human oral squamous carcinomas and human normal oral cells were carried out via MTT. The compounds (1b‐7b) had Ki values of 36.87 ± 11.62‐66.24 ± 2.99 μM (hCA I) and 22.66 ± 1.41‐89.95 ± 6.25 μM (hCA II). Compounds 1b (Ki = 36.87 ± 11.62 μM) toward hCA I, 6b (Ki = 22.66 ± 1.41 μM) toward hCA II had significant enzyme inhibitory potency. Compound 6b had the highest tumor selectivity (TS = 29.3) and potency selectivity expression (PSE = 272.3) values. Therefore, compounds 1b and 6b with CAs inhibition effect and compound 6b with the cytotoxicity may be forwarded to further studies as potent compounds.

Anticancer effects of new dibenzenesulfonamides by inducing apoptosis and autophagy pathways and their carbonic anhydrase inhibitory effects on hCA I, hCA II, hCA IX, hCA XII isoenzymes

In this study, new dibenzensulfonamides, 7–9, having the chemical structure 4,4′-(5′-chloro-3′-methyl-5-aryl-3,4-dihydro-1′H,H-[3,4′-bipyrazole]-1′,2-diyl)dibenzenesulfonamide were synthesized in five steps to develop new anticancer drug candidates. Their chemical structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Cytotoxicities of the dibenzensulfonamides were investigated towards HCC1937, MCF7, HeLa, A549 as tumor cell lines and towards MRC5 and Vero as non-tumor cells. Carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory effects of the dibenzensulfonamides 7–9 were also evaluated on the cytosolic human (h) hCA I and II and the tumor-associated hCA IX and XII isoenzymes. Results indicate that both 7 and 8 induced cleavage of poly (ADP ribose) polymerase (PARP), activation of caspases -3, -7 and -9 which are the hallmarks of apoptosis. Meanwhile both compounds induced autophagy in HCC1937 cells which is shown by enhanced expression of LC3 and decreased level of p62 protein. The compounds tested were also effectively inhibited tumor-associated hCA IX and hCA XII isoenzymes in the range of 20.7–28.1 nM and 4.5–9.3 nM, respectively.

Synthesis and carbonic anhydrase inhibitory effects of new N-glycosylsulfonamides incorporating the phenol moiety

A small series of N-glycosylsulfonamides incorporating the phenol moiety has been prepared by Ferrier sulfonamidoglycosylation of d-glycals. N-Glycosides were tested for the inhibition of four isoforms of carbonic anhydrase. In this study, all compounds showed good inhibitory activity against hCA I and II, with selectivity against the cytosolic hCA II versus the tumor associated isozymes. These results confirm that attaching carbohydrate moieties to CA phenol pharmacophore improves and enhances its inhibitory activity.

Synthesis of 4-(2-substituted hydrazinyl)benzenesulfonamides and their carbonic anhydrase inhibitory effects

In this study, 4-(2-substituted hydrazinyl)benzenesulfonamides were synthesized by microwave irradiation and their chemical structures were confirmed by 1H NMR, 13CNMR, and HRMS. Ketones used were: Acetophenone (S1), 4-methylacetophenone (S2), 4-chloroacetophenone (S3), 4-fluoroacetophenone (S4), 4-bromoacetophenone (S5), 4-methoxyacetophenone (S6), 4-nitroacetophenone (S7), 2-acetylthiophene (S8), 2-acetylfuran (S9), 1-indanone (S10), 2-indanone (S11). The compounds S9, S10 and S11 were reported for the first time, while S1–S8 was synthesized by different method than literature reported using microwave irradiation method instead of conventional heating in this study. The inhibitory effects of 4-(2-substituted hydrazinyl)benzenesulfonamide derivatives (S1–S11) against hCA I and II were studied. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized sulphonamide derivatives with Kis in the range of 1.79 ± 0.22–2.73 ± 0.08 nM against hCA I and in the range of 1.72 ± 0.58–11.64 ± 5.21 nM against hCA II, respectively.

Localization of action of chlorothiazide in the nephron of the dog.

Localization of the actions of chlorothiazide in dogs has been studied by the ‘stop-flow’ technique. The compound interfered with the reabsorption within the proximal segment of a portion of the filtered sodium chloride. In this activity it exhibited effects qualitatively similar to those of chlormerodrin, an organic mercurial diuretic. In addition, chlorothiazide diminished H+ and NH4+ excretion while augmenting K+ secretion within the distal segment. These are typical of the carbonic anhydrase inhibitory effects observed previously with acetazoleamide and presented in this study with dichlorphenamide. Probenecid blocked the proximal secretion of chlorothiazide but did not alter its actions on ion transport.