期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 168, 期 -, 页码 301-314出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.02.044
关键词
carbonic anhydrase; Isoform-selective inhibitors; Periphery groups; Primary sulfonamides; Subnanomolar inhibition; Pyridazinone; Phthalazinone; Cancer cells; Hypoxic environment; Growth inhibition assay
资金
- Russian Federation Government [14.W03.031.0025]
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 mu M concentration narrowed the selection of compounds to the eight which displayed selective growth inhibition toward the cancer cells. More detailed investigation in concentration-dependent 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. (C) 2019 Elsevier Masson SAS. All rights reserved.
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