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Targeting Transcriptional CDKs 7, 8, and 9 with Anilinopyrimidine Derivatives as Anticancer Agents: Design, Synthesis, Biological Evaluation and In Silico Studies

Cyclin-dependent kinases (CDKs) are promising targets in chemotherapy. In this study, we report a series of 2-anilinopyrimidine derivatives with CDK inhibitory activity. Twenty-one compounds were synthesized and their CDK inhibitory and cytotoxic activities were evaluated. The representative compoun...

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Detalles Bibliográficos
Autores principales: Eskandrani, Razan, Al-Rasheed, Lamees S., Ansari, Siddique Akber, Bakheit, Ahmed H., Almehizia, Abdulrahman A., Almutairi, Maha, Alkahtani, Hamad M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10254914/
https://www.ncbi.nlm.nih.gov/pubmed/37298748
http://dx.doi.org/10.3390/molecules28114271
Descripción
Sumario:Cyclin-dependent kinases (CDKs) are promising targets in chemotherapy. In this study, we report a series of 2-anilinopyrimidine derivatives with CDK inhibitory activity. Twenty-one compounds were synthesized and their CDK inhibitory and cytotoxic activities were evaluated. The representative compounds demonstrate potent antiproliferative activities toward different solid cancer cell lines and provide a promising strategy for the treatment of malignant tumors. Compound 5f was the most potent CDK7 inhibitor (IC(50) = 0.479 µM), compound 5d was the most potent CDK8 inhibitor (IC(50) = 0.716 µM), and compound 5b was the most potent CDK9 inhibitor (IC(50) = 0.059 µM). All the compounds satisfied the Lipinski’s rule of five (molecular weight < 500 Da, number of hydrogen bond acceptors <10, and octanol–water partition coefficient and hydrogen bond donor values below 5). Compound 5j is a good candidate for lead optimization because it has a non-hydrogen atom (N) of 23, an acceptable ligand efficiency value of 0.38673, and an acceptable ligand lipophilic efficiency value of 5.5526. The synthesized anilinopyrimidine derivatives have potential as anticancer agents.