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4-Bromo-2-(piperidin-1-yl)thiazol-5-yl-phenyl methanone (12b) inhibits Na(+)/K(+)-ATPase and Ras oncogene activity in cancer cells.

par Lefranc, Florence ;Xu, Zhanjie;Burth, Patricia;Mathieu, Véronique ;Revelant, Germain;Velho de Castro Faria, Mauro;Noyon, Caroline;Garcia, Diogo Gomes;Dufour, Damien ;Bruyère, Céline ;Gonçalves-de-Albuquerque, Cassiano Felippe;Van Antwerpen, Pierre ;Rogister, Bernard;Hesse, Stéphanie;Kirsch, Gilbert;Kiss, Robert
Référence European journal of medicinal chemistry, 63, page (213-223)
Publication Publié, 2013-05

Article révisé par les pairs

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Résumé :

The in vitro growth inhibitory activity of 26 thiazoles (including 4-halogeno-2,5-disubtituted-1,3-thiazoles) and 5 thienothiazoles was assessed on a panel of 6 human cancer cell lines, including glioma cell lines. (4-Chloro-2-(piperidin-1-yl)thiazol-5-yl)(phenyl)methanone (12a) and (4-bromo-2-(piperidin-1-yl)thiazol-5-yl)(phenyl)methanone (12b) displayed ∼10 times greater in vitro growth inhibitory activity than perillyl alcohol (POH), which therapeutically benefits glioma patients through the inhibition of both alpha-1 Na(+)/K(+)-ATPase (NAK) and Ras oncogene activity. The in vitro cytostatic activities (as revealed by quantitative videomicroscopy) displayed by 12a and 12b were independent of the intrinsic resistance to pro-apoptotic stimuli associated with cancer cells. Compounds 12a and 12b displayed relatively similar inhibitory activities on purified guinea pig brain preparations that mainly express NAK alpha-2 and alpha-3 subunits, whereas only compound 12b was efficacious against purified guinea pig kidney preparations that mainly express the NAK alpha-1 subunit, which is also expressed in gliomas, melanomas and non-small-cell lung cancers NSCLCs.