Development of imidazolone based angiotensin II receptor type I inhibitor small molecule as a chemotherapeutic agent for cell cycle inhibition

Cell cycle inhibitors are considered as hallmark strategy for cancer treatment due to their relatively higher selectivity and efficacy on various cancer types in comparison to cytotoxic agents. Small molecules target dividing cells in G1/S, G2 or M phases of cells to arrest and eventually trigger cancer cells to enter apoptosis and/or inhibit tumor growth. Cell cycle arrest at G2/M phase is a widely used approach to inhibit proliferating cancer cells. We report a novel angiotensin II receptor type I (AT1R) antagonist that also targets CDC2 (CDK1) kinase thereby showing a putative anti-cancer activity. The molecule named 19D was tested in various cancer cell lines at different concentrations. Molecular mechanisms of action triggered by the treatment of 19D were investigated for anti-cancer activity at cellular and molecular level. 19D molecule showed a potent cell cycle arrest with anti-proliferation activity. Cells treated with 19D showed nuclear deteriorations and apoptotic induction on cancer cells. Moreover, the mechanism of cell cycle inhibition was revealed as G2/M arrest via suppressing the CDC2 kinase cell cycle check point inhibitor. In conclusion, 19D (an AT1R antagonist) is a novel small molecule/imidazolone derivative which has been demonstrated as a fairly potent anti-cancer molecule. Abbreviations: AT1R: angiotensin II receptor type 1; BSA: bovine serum albumine; CDC2: cyclin-dependent kinase 1; CDK: cyclin-dependent kinase; DMEM: Dulbecco’s modified eagle medium; DMSO: dimethylsulfoxide; EDTA: ethylenediaminetetraacetic acid; FBS: fetal bovine serum; HBSS: Hank’s balanced salt solution; IC50: half maximal inhibitory concentration; PBS-T: phosphate buffered saline–TritonX; PBS: phosphate buffered saline; PDB: protein data bank; SDS: sodium dodecyl sulfate; TBS-T: Tris buffered saline–TritonX.