Design, synthesis and apoptosis inducing effect of novel (Z)-3-(3'-methoxy-4'-(2-amino-2-oxoethoxy)-benzylidene)indolin-2-ones as potential antitumour agents.

Autor: Senwar KR; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India., Reddy TS; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India., Thummuri D; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India., Sharma P; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India., Naidu VG; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India., Srinivasulu G; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India., Shankaraiah N; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: shankar.niperhyd@gov.in.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2016 Aug 08; Vol. 118, pp. 34-46. Date of Electronic Publication: 2016 Apr 11.
DOI: 10.1016/j.ejmech.2016.04.025
Abstrakt: A series of new (Z)-3-(3'-methoxy-4'-(2-amino-2-oxoethoxy)benzylidene)indolin-2-one derivatives has been synthesized and evaluated for their cytotoxic activity against selected human cancer cell lines of prostate (PC-3 and DU-145), breast (BT-549 and MDA-MB-231) and non-tumorigenic prostate epithelial cells (RWPE-1). Among the tested, one of the compounds 4p exhibited potent cytotoxicity selectively on prostate cancer cell lines (PC-3 and DU-145; IC50: 1.89 ± 0.6 and 1.94 ± 0.2 μM, respectively). Further experiments were conducted with 4p on PC-3 cancer cells to study the mechanisms of growth inhibition and apoptosis inducing effect. Treatment of PC-3 cells with test compound 4p resulted in inhibition of cell migration through disorganization of F-actin protein. The flow-cytometry analysis results showed that the compound arrested PC-3 cancer cells in the G2/M phase of cell cycle in a dose dependent manner. Hoechst staining and annexin-V binding assay revealed that the compound 4p inhibited tumor cell proliferation through induction of apoptosis. Western blot studies demonstrated that the compound 4p treatment led to activation of caspase-3, increased expression of pro-apoptotic Bax and significantly decreased expression of anti-apoptotic Bcl-2 in human prostate cancer PC-3 cells. In addition, the mitochondrial membrane potential (ΔΨm) was also affected and the levels of intracellular Ca(2+) were raised.
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Databáze: MEDLINE
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