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

• Published in: European journal of medicinal chemistry Vol. 63; pp. 213 - 223
• Main Authors: 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
• Format: Journal Article Web Resource
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.05.2013; Elsevier
• Subjects: Animals; Apoptosis resistance; Brain - drug effects; Brain - enzymology; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Guinea Pigs; Humans; In vitro; Kidney - drug effects; Kidney - enzymology; Kinetics; Life Sciences & Biomedicine; MCF-7 Cells; Microscopy, Phase-Contrast; Microscopy, Video; Models, Chemical; Molecular Structure; Na+/K+-ATPase; Neurosciences & behavior; Neurosciences & comportement; Perillyl alcohol; Pharmacology & Pharmacy; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Protein Subunits - antagonists & inhibitors; Protein Subunits - metabolism; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - metabolism; Ras oncogene; Science & Technology; Sciences sociales & comportementales, psychologie; Social & behavioral sciences, psychology; Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors; Sodium-Potassium-Exchanging ATPase - metabolism; Thiazoles; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Thienothiazoles; NSCLC; Na+/K+-ATPase; ECACC; POH; QVM; AECs; MTT; Thienothiazoles; Apoptosis resistance; ATCC; K+-pnppase; Perillyl alcohol; GBM; GGR; Thiazoles; In vitro; NAK; Ras oncogene; MDR; FGF-10; DSMZ; DRUG; PATHWAYS; APOPTOSIS; ACTIVATION; PROTEIN; In vitro; SPECIAL EMPHASIS; SODIUM-PUMP; RESISTANCE; GLIOBLASTOMA CELLS
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2013.01.046

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. [Display omitted] The hit compound (12b) of the current series inhibits in vitro the growth of various cancer cell lines through the targeting of the Na+/K+-ATPase and Ras oncogene signaling. ► Cancers associated with dismal prognoses display intrinsic resistance to apoptosis. ► Thus to conventional chemotherapy and radiotherapy.► 12a and 12b inhibit growth in apoptosis-resistant cancer cell lines. ► 12a and 12b revealed cytostatic, not cytotoxic, effects in cancer cells. ► 12b inhibits sodium/potassium pump and Ras oncogene activity.