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
| Autor: | N.J.P. Subhashini, Appaji Dokala, E. Praveenkumar, Nirmala Gurrapu, Prashanth Kumar Kolluri, Shivaraj |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Antineoplastic Agents Breast Neoplasms Biochemistry Structure-Activity Relationship Cyclin-dependent kinase Cell Line Tumor Drug Discovery Cytotoxic T cell Humans Phosphorylation Molecular Biology Protein Kinase Inhibitors Cell Proliferation biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Rational design Retinoblastoma Cyclin-Dependent Kinase 4 Cell Cycle Checkpoints Cyclin-Dependent Kinase 6 Triazoles S cell Apoptosis Cell culture Cancer research biology.protein Acridines Female Cyclin-dependent kinase 6 CDK4/6 Inhibition |
| Zdroj: | Bioorganic chemistry. 116 |
| ISSN: | 1090-2120 |
| Popis: | 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 ± 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 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. |
| Databáze: | OpenAIRE |
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