Identification of a promising hit from a new series of pyrazolo[1,5-a]pyrimidine based compounds as a potential anticancer agent with potent CDK1 inhibitory and pro-apoptotic properties through a multistep in vitro assessment
Elgiushy, Hossam R; Mohamed, Sameh H; Sawaf, Hussein; Hassan, Zeinab; Abou-Taleb, Nageh A; El-Labbad, Eman M; Hassan, Ashraf S; Abouzid, Khaled A M; Abouzid, Khaled; Ali Taha, Heba;
Abstract
A new series of sixteen new 2-arylamino-5,7-disubstituted-N-aryl-pyrazolo[1,5-a]pyrimidine-3-carboxamide derivatives was designed and synthesized. The antitumor activities of the new compounds were initially screened through the developmental therapeutics program at NCI-USA 60 cell line panel. 2-((2,4-dimethoxyphenyl)amino)-5,7-diphenylpyrazolo[1,5-a]pyrimidine-3-carboxamide (7a) was identified as a potential hit with a mean percentage of growth inhibition of 48.5% over the 60-NCI cancer cell lines whereas the other fifteen compounds ranged from 0.5 to 10.72%. In MTT assay, compound 7a exhibited IC50 of 6.28 ± 0.26 µM and 17.7 ± 0.92 µM against HCT-116 colorectal cancer and WI-38 human lung fibroblast normal cell lines, respectively. In cell cycle analysis, compound 7a arrested cell cycle at G2/M phase. It was able to inhibit CDK1 (Cyclin-Dependent Kinase 1)/Cyc B (Cyclin B) complex at IC50 161.2 ± 2.7 nM. The apoptosis-inducing ability of compound 7a was assessed through apoptosis detection flow-cytometry and gene expression analysis of apoptosis markers and caspase cascade which revealed that compound 7a exerts pro-apoptotic effect and increased expression of p53, Bax, cytochrome c, caspases (-3,-8, and-9), and decreased expression of Bcl-2. This suggests that the pro-apoptotic effect is exerted through the intrinsic pathway. The molecular docking study revealed a unique binding mode at the ATP binding pocket of CDK1/Cyc B/Cks2 through its 2,4-dimethoxyphenyl-amino. These results suggest that compound 7a could be a promising hit as a targeted protein kinase inhibitor which exerts its antitumor effect through CDK1 inhibition and pro-apoptotic action.
Other data
Title | Identification of a promising hit from a new series of pyrazolo[1,5-a]pyrimidine based compounds as a potential anticancer agent with potent CDK1 inhibitory and pro-apoptotic properties through a multistep in vitro assessment | Authors | Elgiushy, Hossam R; Mohamed, Sameh H; Sawaf, Hussein; Hassan, Zeinab; Abou-Taleb, Nageh A; El-Labbad, Eman M; Hassan, Ashraf S; Abouzid, Khaled A M; Abouzid, Khaled ; Ali Taha, Heba | Keywords | Antitumor;Cyclin dependant kinase CDK1;Pyrazolo[1,5-a]pyrimidine;Pro-apoptotic;Kinase inhibitor;Apoptosis | Issue Date | Mar-2022 | Publisher | ACADEMIC PRESS INC ELSEVIER SCIENCE | Journal | Bioorganic chemistry | Volume | 120 | ISSN | 0045-2068 | DOI | 10.1016/j.bioorg.2022.105646 | PubMed ID | 35134645 | Scopus ID | 2-s2.0-85124008256 | Web of science ID | WOS:000820618400003 |
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