(R)-6-[N-(3-(4-chlorophenyl) propyl] derivative of (R)-roscovitine inhibits lung carcinoma progression via cyclin-dependent kinase suppression.

Cyclin-dependent kinases (CDKs) are crucial regulators of cell cycle checkpoints, capable of phosphorylating proteins and thereby governing essential cellular functions such as differentiation, proliferation, and apoptosis. Although various CDK inhibitors (CDKIs), including (R)-roscovitine, also known as seliciclib, have demonstrated promising outcomes in preclinical models, their clinical translation has been limited. This study aimed to design and synthesize (R)-roscovitine derivatives with improved pharmacological profiles. A series of compounds (4a-4q) was synthesized, structurally validated and evaluated against cancerous cells, including lung carcinoma (A549), triple-negative breast cancer (MDA-MB-231), and malignant melanoma (A375) cells and normal human epithelial (BEAS-2B) and embryonic lung fibroblasts (MRC-5) cells. Furthermore, the compound was assessed for its inhibitory potential against a broad panel of CDKs. Among these, the (R)-6-[N-(3-(4-chlorophenyl) propyl)] analogue (4 g) showed the highest inhibition of CDK2 and CDK13, along with potent antiproliferative activity (IC = 0.61 ± 0.06 μM) against A549 cells compared to (R)-roscovitine (13.30 ± 1.05 μM). Similarly, Compound 4 g showed an IC value of 1.437 ± 0.17 μM and 1.280 ± 0.37 μM in BEAS-2B and MRC-5 cells, which is 2 to 2.35 folds of the IC value in A549 cells. Compound 4 g significantly (p < 0.0001) induced S-phase cell cycle arrest and suppressed cellular migration and invasion of A549 cells. In silico docking studies revealed a strong and stable interaction with CDK13, with a binding affinity of -8.0 kcal/mol. Compound 4 g demonstrates promising anticancer potential, likely mediated by CDK inhibition with comparatively lower toxicity toward normal cells, however, it requires further toxicological assessment and preclinical studies.