6-Substituted sulfocoumarins bearing the carboxamido, trimethylammonium as well as the cyano and methoxy moieties with interesting inhibitory activity/selectivity against the tumor associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA IX and XII are reported. Moieties leading to the best inhibition were tert-butylcarboxamido, phenylcarboxamido, and 4-pyridylcarboxamido, with K(I) values of 2.1-8.1 nM. No inhibition of the off-target hCA II and I was observed. A number of these compounds were evaluated against HT-29 colon cancer cell lines ex vivo. Compounds 9c and 9e revealed effective cytotoxic effects after 72 h of incubation in both normoxic and hypoxic conditions, unlike sulfonamide CA inhibitors that show such effects only in hypoxia. These results may be of particular importance for the choice of future drug candidates targeting hypoxic tumors and metastases, considering the fact that a sulfonamide CA IX inhibitor (SLC-0111) is presently in phase I clinical trials.

6-substituted sulfocoumarins are selective carbonic anhdydrase IX and XII Inhibitors with significant cytotoxicity against colorectal cancer cells / Grandane, Aiga; Tanc, Muhammet; Di Cesare Mannelli, Lorenzo; Carta, Fabrizio; Ghelardini, Carla; Žalubovskis, Raivis; Supuran, Claudiu T.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 58:(2015), pp. 3975-3983. [10.1021/acs.jmedchem.5b00523]

6-substituted sulfocoumarins are selective carbonic anhdydrase IX and XII Inhibitors with significant cytotoxicity against colorectal cancer cells

TANC, MUHAMMET;DI CESARE MANNELLI, LORENZO;CARTA, FABRIZIO;GHELARDINI, CARLA;SUPURAN, CLAUDIU TRANDAFIR
2015

Abstract

6-Substituted sulfocoumarins bearing the carboxamido, trimethylammonium as well as the cyano and methoxy moieties with interesting inhibitory activity/selectivity against the tumor associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA IX and XII are reported. Moieties leading to the best inhibition were tert-butylcarboxamido, phenylcarboxamido, and 4-pyridylcarboxamido, with K(I) values of 2.1-8.1 nM. No inhibition of the off-target hCA II and I was observed. A number of these compounds were evaluated against HT-29 colon cancer cell lines ex vivo. Compounds 9c and 9e revealed effective cytotoxic effects after 72 h of incubation in both normoxic and hypoxic conditions, unlike sulfonamide CA inhibitors that show such effects only in hypoxia. These results may be of particular importance for the choice of future drug candidates targeting hypoxic tumors and metastases, considering the fact that a sulfonamide CA IX inhibitor (SLC-0111) is presently in phase I clinical trials.
2015
58
3975
3983
Grandane, Aiga; Tanc, Muhammet; Di Cesare Mannelli, Lorenzo; Carta, Fabrizio; Ghelardini, Carla; Žalubovskis, Raivis; Supuran, Claudiu T.
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1008880
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