Anthranilamide-Pyrazolo[1,5-a]pyrimidine Conjugates as p53 Activators in Cervical Cancer Cells

作者：Kamal Ahmed^*; Tamboli Jaki R; Ramaiah M Janaki; Adil S F; Rao G Koteswara; Viswanath A; Mallareddy Adla; Pushpavalli S N C V L; Pal Bhadra Manika

来源：ChemMedChem, 2012, 7(8): 1453-1464.

DOI：10.1002/cmdc.201200205

• antitumor agents
• apoptosis
• caspase-3
• cell cycle
• roscovitine

A library of new anthranilamidepyrazolo[1,5-a]pyrimidine conjugates were designed, synthesized, and evaluated for their anticancer activity in cervical cancer cells such as HeLa and SiHa that possess low levels of p53. All 24 conjugates showed antiproliferative activity, while some of them exhibit significant cytotoxicity. In assays related to cell-cycle distribution, these conjugates induced G2/M arrest in HeLa cells and G1 cell-cycle arrest in SiHa cells. Immunocytochemistry assays revealed that these compounds cause nuclear translocation of p53, thereby indicating the activation of p53. In cervical cancer cells, the p53 protein is degraded by E6 oncoprotein. Immunoblot and RT-PCR analyses proved the presence of mitochondria-mediated apoptosis with involvement p53 target genes such as BAX, Bcl2, and p21 (CDKI). Moreover, these compounds increased the phosphorylated forms of p53 and provide signals for apoptosis induction. Interestingly, one of the conjugates, (2-phenyl-7-(3,4,5-trimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl)(4-(2-(thiophen-2-ylmethylamino)benzoyl)piperazin-1-yl)methanone, is the most promising candidate in this series and has the potential to be taken up for further detailed studies.

• 出版日期2012-8