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Bioorg Med Chem. 2015 Sep 1;23(17):5799-808. doi: 10.1016/j.bmc.2015.07.010. Epub 2015 Jul 11.

Synthesis and apoptotic activity of new pyrazole derivatives in cancer cell lines.

Author information

1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, 'Carol Davila' University of Medicine and Pharmacy, Traian Vuia 6, Bucharest 020956, Romania. Electronic address: nitulescu_mihai@yahoo.com.
2
C.D. Nenitzescu Institute of Organic Chemistry, 202B Spl. Independentei, Bucharest 060023, Romania.
3
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, 'Carol Davila' University of Medicine and Pharmacy, Traian Vuia 6, Bucharest 020956, Romania.
4
Stefan S Nicolau Institute of Virology, 285 Mihai Bravu Avenue, Bucharest 030304, Romania.

Abstract

We designed and synthesized new pyrazole thiourea chimeric derivatives and confirmed their structures by NMR and IR spectra. Apoptotic effects were studied in human cancer cells. The N-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-N'-(3-bromophenyl)-thiourea compound (4b) exhibited the highest apoptosis-inducing effect. Compound 4b and the thiazole derivatives, 5b and 6b, increased the expression of tumor necrosis factor receptors TRAIL-R2 and TRAIL-R1, accompanied by down-modulation of pro-caspase 3 levels, and the augmentation of cleaved caspase 3. They also reduced the levels of apoptosis inhibitory proteins and the expression of the heat-shock proteins Hsp27 and Hsp70. All the tested pyrazole derivatives induced a concentration-dependent increase of cells in G2/M phases. The analysis of the experimental data indicates the reduction of Akt phosphorylation as the most probable cellular mechanism of action for the tested compounds. The in vitro study indicated that compound 4b could be a promising anti-cancer drug, to be further developed in animal models of cancer.

KEYWORDS:

Akt; Apoptosis; Cell cycle; IAP; Pyrazole; TRAIL-R2

PMID:
26193760
DOI:
10.1016/j.bmc.2015.07.010
[Indexed for MEDLINE]

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