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

Abstract

A library of new anthranilamide-pyrazolo[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 G(2) /M arrest in HeLa cells and G(1) 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.

Synthesis and biological evaluation of chalcone-linked pyrazolo[1,5-a]pyrimidines as potential anticancer agents

“…30,37,38 Compound SCH727965 (5) 39 with a pyrazoloij1,5a]pyrimidine scaffold in it was found to be a selective CDK inhibitor and is undergoing clinical trials. Also, our previous efforts towards the synthesis of a pyrazoloij1,5-a]pyrimidine scaffold coupled with anthranilamide 40 and aminobenzothiazole 37 led to several compounds with promising anticancer activity, which further substantiates the potential of the pyrazoloij1,5-a]pyrimidine scaffold.…”

Gallic acid-butyramide monohydrate cocrystal: Crystal growth, Structural insights, Theoretical calculations and Molecular docking studies against COVID-19 main protease

“…S4. Weight loss of 5% in the temperature range of 72-100ºC corresponds to a loss of one molecule of water, as the theoretical mass loss for the dehydration of one molecule of water from the crystal lattice of GA-BU is 4.06% 22 . The loss of crystalline water leads to the dissociation of cocrystal.…”

Insights into the medicinal chemistry of heterocycles integrated with a pyrazolo[1,5-a]pyrimidine scaffold

“…Kamal et al 115 have deliberated the synthesis of benzoylpiperazinyl methanones 160a–x by condensation of 2-phenyl-7-(substituted-aryl)pyrazolo[1,5- a ]pyrimidine-5-carboxylic acids with piperazin-1-yl(2-((aryl-methyl)amino)phenyl)methanones in dichloromethane under catalytic conditions of EDCI/HOBt by stirring at 0 °C to room temperature. The respective pyrazolo[1,5- a ]pyrimidinyl amides 160a–x were assessed in vitro as anticancer agents using the MTT assay on human cervical cancer, i.e.…”