Synthesis Of Novel 1,3,5-Triazinyl Aminobenzenesulfonamides As Potent Carbonic Anhydrase Inhibitors

Kód výsledku v IS VaVaI

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Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Synthesis Of Novel 1,3,5-Triazinyl Aminobenzenesulfonamides As Potent Carbonic Anhydrase Inhibitors

Popis výsledku v původním jazyce

Carbonic anhydrases are metalloenzymes that catalyze reversible hydration of CO2, maintaining acid-base homeostasis, pH and related physiological processes in both prokaryotes and eukaryotes. In humans, 15 different isoforms can be found, including two tumor-associated – hCA IX, hCA XII. hCA IX is cell surface protein induced by hypoxia, involved in adaptation to acidosis and responsi-ble for tumor progression. In cooperation with bicarbonate transporters and monocarboxylate transporters, it increases intracellular pH to values necessary for metabolic processes and proliferation. It acts by its extracellular domain, catalyzing conversion of CO2 to protons, which remain outside the cells, and bicarbonate ions, which are transported into the cell. hCA IX also contributes to lactate export. This further extracellular acidification supports invasion of cancer cells to surrounding normal tissue. hCA IX is, therefore, very promising target in treatment of drug resistant tumors.1 The most important molecules inhibiting carbonic anhydrases are sulfonamides. Sulfonamide functional group binds to Zn(II) in active site of carbonic anhydrases, resulting in its inhibition.2 However, the main problem is achieving selectivity of inhibitors towards specific isoenzyme. Structurally diverse sulfonamides can be prepared by nucleophilic substitution of cyanuric chloride. A series of novel potent selective hCA IX inhibitors with 1,3,5-triazinyl benzenesulfonamide structural fragment were synthetized, and their inhibitory activity of towards isoforms hCA II and hCA IX was evaluated.

Název v anglickém jazyce

Synthesis Of Novel 1,3,5-Triazinyl Aminobenzenesulfonamides As Potent Carbonic Anhydrase Inhibitors

Popis výsledku anglicky

Carbonic anhydrases are metalloenzymes that catalyze reversible hydration of CO2, maintaining acid-base homeostasis, pH and related physiological processes in both prokaryotes and eukaryotes. In humans, 15 different isoforms can be found, including two tumor-associated – hCA IX, hCA XII. hCA IX is cell surface protein induced by hypoxia, involved in adaptation to acidosis and responsi-ble for tumor progression. In cooperation with bicarbonate transporters and monocarboxylate transporters, it increases intracellular pH to values necessary for metabolic processes and proliferation. It acts by its extracellular domain, catalyzing conversion of CO2 to protons, which remain outside the cells, and bicarbonate ions, which are transported into the cell. hCA IX also contributes to lactate export. This further extracellular acidification supports invasion of cancer cells to surrounding normal tissue. hCA IX is, therefore, very promising target in treatment of drug resistant tumors.1 The most important molecules inhibiting carbonic anhydrases are sulfonamides. Sulfonamide functional group binds to Zn(II) in active site of carbonic anhydrases, resulting in its inhibition.2 However, the main problem is achieving selectivity of inhibitors towards specific isoenzyme. Structurally diverse sulfonamides can be prepared by nucleophilic substitution of cyanuric chloride. A series of novel potent selective hCA IX inhibitors with 1,3,5-triazinyl benzenesulfonamide structural fragment were synthetized, and their inhibitory activity of towards isoforms hCA II and hCA IX was evaluated.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

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Návaznosti

O - Projekt operacniho programu

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů