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.

CDK4 & 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 ±â€¯0.037, 0.117 ±â€¯0.025, and 0.136 ±â€¯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 transformation. In addition, compound 6g showed the highest in-vitro selectivity towards CDK4/6 inhibition, even compared with Abemaciclib, and it was also proved for favourable in-vivo pharmacokinetic properties in male albino mice. Furthermore, molecule 6g showed promising tumor growth suppression with lower adverse effects in MCF-7 xenograft mice models, which could competently be considered as a novel chemotherapeutic candidate for a further comprehensive preclinical study involving breast cancer therapy.

Synthesis, anti-diabetic evaluation and molecular docking studies of 4-(1-aryl-1H-1, 2, 3-triazol-4-yl)-1,4-dihydropyridine derivatives as novel 11-ß hydroxysteroid dehydrogenase-1 (11ß-HSD1) inhibitors.

11-Beta-Hydroxysteroid dehydrogenase-1(11ß-HSD1) inhibitors are one of the emerging classes of molecules to fight against diabetic complications. A novel series of 4-(1-substituted-1H-1,2,3-triazol-4-yl)-1,4-dihydropyridine derivatives were synthesized and evaluated for their anti-diabetic activity. Two compounds showed anti-diabetic activity very effectively. To clarify the mechanism of action of these compounds, the most potent compounds (5g and 5h) of the synthesized analogs were further studied by testing its 11-Beta Hydroxysteroid dehydrogenase-1 inhibitory activity through in vitro enzymatic experiments. The results showed that the 11ß-HSD1 inhibitory activity of compounds 5g and 5h was stable and efficient. Molecular docking studies revealed compounds 5g (-9.758) and 5h (-8.495) to have a stable binding patterns to the human 11-Beta-Hydroxysteroid dehydrogenase-1.