Scaffold-Hopping Design and Synthesis of Thieno[3,2-d]pyrimidines: Anticancer Activity, Apoptosis Induction, and In Silico Inhibition of CDKs

Two series of tricyclic thieno[3,2-<i>d</i>]pyrimidines were synthesized, achieving yields of up to 97%. The tricyclic thieno[3,2-<i>d</i>]pyrimidines examined in this study are synthetic analogs of the deoxyvasicinone alkaloids, where the thiophene ring substitutes for the benzene ring. A systematic investigation was conducted on the scaffold-hopping strategy of these alkaloids, emphasizing the selective synthesis and anticancer properties of thieno[3,2-<i>d</i>]pyrimidines. The anticancer evaluation was performed on human cancer cell lines, specifically cervical HeLa and colon HT-29 carcinoma cells. Additional bioassays included cell migration analyses, cell cycle progression, apoptosis, and molecular docking analyses. Furthermore, molecular docking studies showed that the most active small molecule <b>6e</b> is likely to disrupt the cell cycle process through targeting CDKs (Cyclin-dependent kinases), leading to the inhibition of tumor cell proliferation.