An expanded set of diversely substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides was synthesized and tested for inhibition of human carbonic anhydrase I, II, IX and XII isoforms. The initial biochemical profiling revealed a significantly more potent inhibition of cancer-related, membrane-bound isoform hCA IX (reaching into submicromolar range), on top of potent inhibition of hCA XII that is another cancer target. The observed structure-activity relationships have been rationalized by molecular modeling. Comparative single-concentration profiling of the carbonic anhydrase inhibitors synthesized for antiproliferative effects against normal (ARPE-19) and cancer (PANC-1) cell lines under chemically induced hypoxia conditions revealed several candidate compounds selectively targeting cancer cells. More in-depth characterization of these leads revealed two structurally related compounds that showed promising selective cytotoxicity against pancreatic cancer (PANC-1) and melanoma (SK-MEL-2) cell lines.

Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment / Krasavin, Mikhail; Shetnev, Anton; Sharonova, Tatyana; Baykov, Sergey; Kalinin, Stanislav; Nocentini, Alessio; Sharoyko, Vladimir; Poli, Giulio; Tuccinardi, Tiziano; Presnukhina, Sofia; Tennikova, Tatiana B; Supuran, Claudiu T. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1768-3254. - ELETTRONICO. - 164:(2019), pp. 92-105. [10.1016/j.ejmech.2018.12.049]

Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment

Nocentini, Alessio;Supuran, Claudiu T
2019

Abstract

An expanded set of diversely substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides was synthesized and tested for inhibition of human carbonic anhydrase I, II, IX and XII isoforms. The initial biochemical profiling revealed a significantly more potent inhibition of cancer-related, membrane-bound isoform hCA IX (reaching into submicromolar range), on top of potent inhibition of hCA XII that is another cancer target. The observed structure-activity relationships have been rationalized by molecular modeling. Comparative single-concentration profiling of the carbonic anhydrase inhibitors synthesized for antiproliferative effects against normal (ARPE-19) and cancer (PANC-1) cell lines under chemically induced hypoxia conditions revealed several candidate compounds selectively targeting cancer cells. More in-depth characterization of these leads revealed two structurally related compounds that showed promising selective cytotoxicity against pancreatic cancer (PANC-1) and melanoma (SK-MEL-2) cell lines.
164
92
105
Krasavin, Mikhail; Shetnev, Anton; Sharonova, Tatyana; Baykov, Sergey; Kalinin, Stanislav; Nocentini, Alessio; Sharoyko, Vladimir; Poli, Giulio; Tuccinardi, Tiziano; Presnukhina, Sofia; Tennikova, Tatiana B; Supuran, Claudiu T
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1289775
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