Selective CDK4/6 inhibition of novel 1,2,3-triazole tethered acridinedione derivatives induces G1/S cell cycle transition arrest via Rb phosphorylation blockade in breast cancer models

Bioorg Chem. 2021 Nov;116:105377. doi: 10.1016/j.bioorg.2021.105377. Epub 2021 Sep 17.ABSTRACTCDK4 & CDK6 are essential regulators of initial cell cycle phases and are always considered an exciting choice for anti-cancer therapy. In the present study, we presented the structure-based rational design & synthesis of a new class of 1,2,3-triazole tethered acridinedione derivatives (6a-l) as selective CDK4/6 inhibitors. Title molecules were prepared as a result of the rate-determining reaction between substituted derivatives of 1-Phenyl-1H-1,2,3-triazole-4-carbaldehydes and substituted dimedones, and the molecules were structurally characterized by IR, 1H,13C NMR, and MS spectral data. All molecules were screened for in-vitro cytotoxic potential against a group of human breast tumor cell lines of distinct origin with differential Rb expression status. Out of entire series of conjugated hexahydro acridinediones, 6g showed potent cytotoxic effect against MCF-7, BT-474, and SK-BR3 cell lines with IC50values 0.173 ± 0.037, 0.117 ± 0.025, and 0.136 ± 0.027 μM, respectively. Further, CDK inhibition assays revealed that the compounds 6g and 6h selectively inhibit CDK4/6 over other CDK-parter complexes of the family against the selected cell line group except for MDA-MB468 cells. Furthermore, apoptotic evaluation and cell cycle analysis determined that compound 6g successfully triggered apoptosis in all examined cell lines except MDA-MB468 through blocking G1/S cell cycle tra...
Source: Bioorganic Chemistry - Category: Chemistry Authors: Source Type: research