期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 23, 页码 10860-10874出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01504
关键词
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资金
- Ente Cassa di Risparmio di Firenze, Italy [ECR 2016.0774]
- National Center for Advancing Translational Sciences of the National Institutes of Health under University of Florida [TL1TR001428, UL1TR001427]
Human carbonic anhydrases (CA, EC, 4.2.1.1) IX and XII are overexpressed in cancer cells as adaptive response to hypoxia and acidic conditions characteristic of many tumors. In addition, hypoxia facilitates the activity of specific oxido-reductases that may be exploited to selectively activate bioreductive prodrugs. Here, new selective CA IX/XII inhibitors, as analogues of the antitumor phase II drug SLC-0111 are described, namely ureido-substituted benzenesulfonamides appended with a nitro-aromatic moiety to yield an antiproliferative action increased by hypoxia. These compounds were screened for the inhibition of the ubiquitous hCA I/II and the target hCA IX/XII. Six X-ray crystallographies with CA II and IX/mimic allowed for the rationalization of the compounds inhibitory activity. The effects of some such compounds on the viability of HT-29, MDA-MB-231, and PC-3 human cancer cell lines in both normoxic and hypoxic conditions were examined, providing the initiation toward the development of hypoxia-activated antitumor CAIs.
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