title: Synthesis and apoptotic activity of new pyrazole derivatives in cancer cell lines.
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.
authors.affiliation: 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.
authors.forename: George Mihai
authors.initials: GM
authors.lastname: Nitulescu
authors.affiliation: C.D. Nenitzescu Institute of Organic Chemistry, 202B Spl. Independentei, Bucharest 060023, Romania.
authors.forename: Constantin
authors.initials: C
authors.lastname: Draghici
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, 'Carol Davila' University of Medicine and Pharmacy, Traian Vuia 6, Bucharest 020956, Romania.
authors.forename: Octavian Tudorel
authors.initials: OT
authors.lastname: Olaru
authors.affiliation: Stefan S Nicolau Institute of Virology, 285 Mihai Bravu Avenue, Bucharest 030304, Romania.
authors.forename: Lilia
authors.initials: L
authors.lastname: Matei
authors.affiliation: Stefan S Nicolau Institute of Virology, 285 Mihai Bravu Avenue, Bucharest 030304, Romania.
authors.forename: Aldea
authors.initials: A
authors.lastname: Ioana
authors.affiliation: Stefan S Nicolau Institute of Virology, 285 Mihai Bravu Avenue, Bucharest 030304, Romania.
authors.forename: Laura Denisa
authors.initials: LD
authors.lastname: Dragu
authors.affiliation: Stefan S Nicolau Institute of Virology, 285 Mihai Bravu Avenue, Bucharest 030304, Romania.
authors.forename: Coralia
authors.initials: C
authors.lastname: Bleotu
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D011720:Pyrazoles; C031280:pyrazole
keywords: Akt; Apoptosis; Cell cycle; IAP; Pyrazole; TRAIL-R2