COX-2 Selective Inhibitors, Carbonic Anhydrase Inhibition and Anticancer Properties of Sulfonamides Belonging to This Class of Pharmacological Agents

Supuran, Claudiu T.; Casini, Angela; Mastrolorenzo, Antonio; Scozzafava, Andrea

doi:10.2174/1389557043403792

Cited by 150 publications

(73 citation statements)

References 36 publications

(174 reference statements)

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“…Thus, some sulphonamide CAIs, including the clinically used analgesic celecoxib, can inhibit AE1-mediated HCO 3 -transport at clinically significant concentrations 20 . Celecoxib shows substantial antitumour activity, possibly owing to its cyclooxygenase 2-, CA9-and CA12-inhibiting properties, although other mechanisms of action may also be involved 77,78 . Compounds that specifically inhibit anion exchangers and do not interfere with other enzymes or transport proteins are not yet available.…”

Section: Compound Genericmentioning

confidence: 99%

Interfering with pH regulation in tumours as a therapeutic strategy

Neri¹,

Supuran

2011

Nat Rev Drug Discov

1,382

1,269

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The growth of solid tumours is characterized not only by the uncontrolled proliferation of cancer cells but also by changes in the tumour environment that support the growth of the neoplastic mass and the metastatic spread of cancer cells to distant sites 1 . The formation of new blood vessels from pre-existing ones (angiogenesis) provides oxygen and nutrients to the tumour, which are essential for tumour growth 2 . A complex dynamic interplay exists between the expanding neoplastic mass and the tumour environment, which is affected by the metabolic requirements of cancer cells and by their products, such as secreted proteins (for example, extracellular matrix components and proteases) and metabolites.Upregulated glucose metabolism is a hallmark of invasive cancers 3 . In normal cells glucose is converted to glucose-6-phosphate and subsequently to pyruvate, which is then oxidized in the mitochondria to carbon dioxide and water; this releases 38 moles of ATP per mole of glucose 3 . However, inadequate oxygen delivery to some regions of tumours leads to hypoxia, which restricts oxidative phosphorylation. As a consequence, hypoxic tumour cells shift their metabolism towards glycolysis so that the pyruvate generated in the first step of the process is reduced to lactate, generating only 2 moles of ATP per mole of glucose. This is a less energy-efficient process but it does not depend on oxygen. Furthermore, glycolysis often persists even after reoxygenation because the obtained metabolic intermediates (that is, lactate and pyruvate) can be used for the biosynthesis of amino acids, nucleotides and lipids, thus providing a selective advantage to proliferating tumour cells. This explains Warburg's observation of high glucose consumption and high lactate production in tumour tissues 3-5 (known as the Warburg effect).Oncogenic metabolism also generates an excess of protons and carbon dioxide, which are kept in equilibrium with carbonic acid by the enzyme carbonic anhydrase 3-9 . Thus, increased glucose metabolism in tumour cells leads to enhanced acidification of the extracellular milieu, which is frequently accompanied by various levels of hypoxia. This phenotype confers a substantial Darwinian growth advantage to tumour cells over normal cells, which undergo apoptosis in response to such an acidic extracellular environment 3 .Tumour cells have evolved various mechanisms to cope with the acidic and hypoxic stress mentioned above. They eliminate acidic catabolites by ion transporters and pumps to preserve a slightly alkaline intracellular pH (pH i ), which is optimal for cell proliferation and tumour survival 3-10 . Acid export leads to a reduction in the extracellular pH (pH e ) to values as low as 6.0 (the usual pH e in tumours is in the range of 6.5-7.0) 3 , which is a salient feature of the tumour microenvironment 3-9 . As well as triggering the overexpression of many proteins involved in glucose metabolism -such as the glucose transporter GLUT1 (also known as SLC2A1) and pH-regulating proteins such as carbonic anhyd...

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Section: Compound Genericmentioning

confidence: 99%

Interfering with pH regulation in tumours as a therapeutic strategy

Neri¹,

Supuran

2011

Nat Rev Drug Discov

1,382

1,269

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“…AZA, a well-known CAI, was used as a standard drug for comparison ( Table 5). As in other CAs inhibition assays with sulfonamides and their metal complexes, phenols and thiophenols, the enzymes were incubated for 10-15 min with test compounds for allowing the formation of the enzyme-inhibitor adduct [41][42][43][44][45]49,50 . Working under similar conditions, Hats salts inhibited both hCAs and micro-organisms CAs in the micromolar concentration range, although they exhibited a weaker inhibitory power compared with AZA (Table 5).…”

Section: Ca Inhibitionmentioning

confidence: 99%

Salts of 5-amino-2-sulfonamide-1,3,4-thiadiazole, a structural and analog of acetazolamide, show interesting carbonic anhydrase inhibitory properties, diuretic, and anticonvulsant action

Díaz

Camí

Liu‐González

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Three salts of 5-amino-2-sulfonamide-1,3,4-thiadiazole (Hats) were prepared and characterized by physico-chemical methods. The p-toluensulfonate, the methylsulfonate, and the chlorhydrate monohydrate salts of Hats were evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) and as anticonvulsants and diuretics, since many CAIs are clinically used as pharmacological agents. The three Hats salts exhibited diuretic and anticonvulsant activities with little neurotoxicity. The human (h) isoforms hCA I, II, IV, VII, IX, and XII were inhibited in their micromolar range by these salts, whereas pathogenic beta and gamma CAs showed similar, weak inhibitory profiles.

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“…Furthermore the sulphonamides are the best-known inhibitors of the carbonic anhydrase enzyme, currently used for the treatment of glaucoma in clinical medicine [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%