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: Praveenkumar E; Department of Chemistry, University College of Science, Osmania University, Hyderabad, Telangana 500 007, India., Gurrapu N; Department of Chemistry, University College of Science, Osmania University, Hyderabad, Telangana 500 007, India., Kolluri PK; Department of Chemistry, University College of Science, Osmania University, Hyderabad, Telangana 500 007, India., Shivaraj; Department of Chemistry, University College of Science, Osmania University, Hyderabad, Telangana 500 007, India., Subhashini NJP; Department of Chemistry, University College of Science, Osmania University, Hyderabad, Telangana 500 007, India. Electronic address: njsubhashini@osmania.ac.in., Dokala A; Dept. of Medicinal Chemistry, Center for Molecular Cancer Research (CMCR), Vishnu Institute of Pharmaceutical Education & Research (VIPER), Narsapur, Medak, Telangana, India; Molecular Signaling Group, Center for Cellular and Molecular Biology (CCMB), Tarnaka, Hyderabad, India.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2021 Nov; Vol. 116, pp. 105377. Date of Electronic Publication: 2021 Sep 17.
DOI: 10.1016/j.bioorg.2021.105377
Abstrakt: 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, 1 H, 13 C 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 IC 50 values 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.
(Copyright © 2021. Published by Elsevier Inc.)
Databáze: MEDLINE
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