Benzenesulfonamides with pyrimidine moiety as inhibitors of human carbonic anhydrases I, II, VI, VII, XII, and XIII (original) (raw)
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Design of [(2-pyrimidinylthio)acetyl]benzenesulfonamides as inhibitors of human carbonic anhydrases
European journal of medicinal chemistry, 2012
A series of [(2-pyrimidinylthio)acetyl]benzenesulfonamides were designed and synthesized. Their binding affinities as inhibitors of several recombinant human carbonic anhydrase (CA) isozymes were determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). A group of compounds containing a chlorine atom in the benzenesulfonamide ring were found to exhibit higher selectivity but lower binding affinity toward tested CAs. The crystal structures of selected compounds in complex with CA II were determined to atomic resolution. Docking studies were performed to compare the binding modes of experimentally determined crystallographic structures with computational prediction of the pyrimidine derivative binding to CA II. Several compounds bound to select CAs with single-digit nanomolar affinities and could be used as leads for inhibitor development toward a select CA isozyme.
4-AMINO-SUBSTITUTED Benzenesulfonamides as Inhibitors of Human Carbonic Anhydrases
Molecules (Basel, Switzerland), 2014
A series of N-aryl-β-alanine derivatives and diazobenzenesulfonamides containing aliphatic rings were designed, synthesized, and their binding to carbonic anhydrases (CA) I, II, VI, VII, XII, and XIII was studied by the fluorescent thermal shift assay and isothermal titration calorimetry. The results showed that 4-substituted diazobenzenesulfonamides were more potent CA binders than N-aryl-β-alanine derivatives. Most of the N-aryl-β-alanine derivatives showed better affinity for CA II while diazobenzenesulfonamides possessed nanomolar affinities towards CA I isozyme. X-ray crystallographic structures showed the modes of binding of both compound groups.
Bioorganic & Medicinal Chemistry, 2010
A series of 4-[N-(substituted 4-pyrimidinyl)amino]benzenesulfonamides were designed and synthesised. Their binding potencies as inhibitors of selected recombinant human carbonic anhydrase (hCA) isozymes I, II, VII, and XIII were measured using isothermal titration calorimetry and the thermal shift assay. To determine the structural features of inhibitor binding, the crystal structures of several compounds in complex with hCA II were determined. Several compounds exhibited selectivity towards isozymes I, II, and XIII, and some were potent inhibitors of hCA VII.
Novel Sulfamide-Containing Compounds as Selective Carbonic Anhydrase I Inhibitors
Molecules (Basel, Switzerland), 2017
The development of isoform selective inhibitors of the carbonic anhydrase (CA; EC 4.2.1.1) enzymes represents the key approach for the successful development of druggable small molecules. Herein we report a series of new benzenesulfamide derivatives (-NH-SO₂NH₂) bearing the 1-benzhydrylpiperazine tail and connected by means of a β-alanyl or nipecotyl spacer. All compounds 6a-l were investigated in vitro for their ability to inhibit the physiological relevant human (h) CA isoforms such as I, II, IV and IX. Molecular modeling provided further structural support to enzyme inhibition data and structure-activity relationship. In conclusion the hCA I resulted the most inhibited isoform, whereas all the remaining ones showed different inhibition profiles.
Pyridazinone substituted benzenesulfonamides as potent carbonic anhydrase inhibitors
Bioorganic & Medicinal Chemistry Letters, 2016
An expanded set of pyridazine-containing benzene sulfonamides was investigated for inhibition of four human carbonic anhydrase isoforms, which revealed a pronounced inhibition trend toward hCA IX, a cancer-related, membrane-bound isoform of the enzyme. Comparison of antiproliferative effects of these compounds against cancer (PANC-1) and normal (ARPE-19) cells at 50 µM concentration narrowed the selection of compounds to the eight which displayed selective growth inhibition toward the cancer cells. More detailed investigation in concentrationdependent mode against normal (ARPE-19) and two cancer cell lines (PANC-1 and SK-MEL-2) identified two lead compounds one of which displayed a notable cytotoxicity toward pancreatic cancer cells while the other targeted the melanoma cells. These findings significantly expand the knowledge base concerning the hCA IX inhibitors whose inhibitory potency against a recombinant enzyme translates into selective anticancer activity under hypoxic conditions which are aimed to model the environment of a growing tumor.
Bioorganic & Medicinal Chemistry, 2014
A series of benzenesulfonamide derivatives incorporating triazine moieties in their molecules was obtained by reaction of cyanuric chloride with sulfanilamide, homosulfanilamide, or 4-aminoethylbenzenesulfonamide. The dichlorotriazinyl-benzenesulfonamides intermediates were subsequently derivatized by reaction with various nucleophiles, such as water, methylamine, or aliphatic alcohols (methanol and ethanol). The library of sulfonamides incorporating triazinyl moieties was tested for the inhibition of three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic hCA I and II, and the transmembrane, tumorassociated hCA IX. The new compounds reported here inhibited hCA I with K I s in the range of 75-136 nM, hCA II with K I s in the range of 13-278 nM, and hCA IX with K I s in the range of 0.12-549 nM. The first hCA IX-selective inhibitors were thus detected, as the chlorotriazinyl-sulfanilamide and the bis-ethoxytriazinyl derivatives of sulfanilamide/homosulfanilamide showed selectivity ratios for CA IX over CA II inhibition in the range of 166-706. Furthermore, some of these compounds have subnanomolar affinity for hCA IX, with K I s in the range 0.12-0.34 nM. These derivatives are interesting candidates for the development of novel unconventional anticancer strategies targeting the hypoxic areas of tumors. Clear renal cell carcinoma, which is the most lethal urologic malignancy and is both characterized by very high CA IX expression and chemotherapy unresponsiveness, could be the leading candidate of such novel therapies.
Bioorganic & Medicinal Chemistry Letters, 2007
A novel series of benzenesulfonamides that contain ferrocenyl or ruthenocenyl moieties were synthesized and investigated for their ability to inhibit the enzymatic activity of physiologically relevant carbonic anhydrase (CA) isozymes: hCA I, II and tumour-associated IX (h = human). This manuscript describes the regioselective synthesis of both the 1,4-and 1,5-disubstituted-1,2,3-triazole benzenesulfonamides from ethynylmetallocene substrates. This is the first report describing the covalent attachment of organometallic moieties to the arylsulfonamide (ArSO 2 NH 2 ) CA recognition pharmacophore. At hCA I these metallocene derivatives were either nanomolar or low micromolar inhibitors, while against hCA II and IX inhibition in the range of 9.7-80 nM and 10.3-85 nM, respectively, was observed. The ruthenocenyl derivatives gave superior CA inhibition compared to the ferrocenyl compounds across all three CA isozymes. These compounds constitute a new organometallic class of CA inhibitors with promising biological activity.
European Journal of Medicinal Chemistry, 2011
A series of novel 3-pyridinesulfonamide derivatives (2e5, 9e11 and 13e15) have been synthesized and investigated as inhibitors of five isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic ubiquitous CA I and II, and isozymes CA IX and XII (cancer-associated), and XIV. Against the human isozyme hCA I the new compounds showed K I s in the range of 0.089e251 mM, whereas toward hCA II, K I s ¼ 50.5e487 nM. Isozyme hCA IX was inhibited with K I s in the range of 5.2e18.3 nM, while hCA XII with K I s ¼ 6.0e16.4 nM, and hCA XIV with K I s ¼ 76.4e152.0 nM. All of the new compounds 2e5, 9e11 and 13e15 showed excellent hCA IX inhibitory efficacy, with K I s ¼ 5.2e18.3 nM, being much more effective as compared to the clinically used AAZ, MZA, EZA, DCP and IND (K I s ¼ 24e50 nM).