Discovery of novel purine analogues against breast cancer selectively targeting CDK2: optimization, synthesis, biological evaluation and docking study.

CDK2 inhibition is a promising breast cancer treatment. Purines target CDK2 and are effective against breast cancer, proving a therapeutic scaffold. New purine-based compounds, 5a-5j were synthesized using chloro-amine coupling and phenacylation in a two-step procedure, characterized, and tested for anticancer activity. The highest yield (82%), without column purification or a costly catalyst like Pd/Cu, was achieved with concentrated HCl. The synthesis and site-selective substitution at the purine ring's C-2 position were confirmed by H NMR, C NMR, IR, MS, and HMBC spectroscopy. In the NCI-60 study, compounds 5e and 5f inhibited growth of MDA-MB-231 cells by 93% and 91%, respectively. In addition, compound 5f exhibited higher cytotoxicity against MDA-MB-231 and MDA-MB-468, with IC of 0.19 and 0.72 µM, respectively (triple-negative breast cancer). Furthermore, 5f demonstrated higher selective cytotoxicity against MDA-MB-231 and MDA-MB-468 than the Vero (non-cancerous) cell line, with selectivity indexes of 460.63 and 121.55, respectively. Compared to the reference (IC = 0.79 µM), 5f demonstrated a greater affinity against CDK2 with a lower IC of 0.47 µM, confirming its anticancer potential. Moreover, higher docking score of 5f than standard shows that the purine derivative acted via inhibition of CDK2.