Synthesis of Potent Anticancer Thieno[2,3- d ]Pyrimidine Derivatives

As part of our program to identify novel cytotoxic agents, various series of hexahydrocycloocta[4,5]thieno[2,3-d] pyrimidines and pyrimidin-4-ones substituted by aryl at the C-2 position together with phenylethylamino, substituted amino, hydrazinyl or arylidenhydrazinyl substituents at the C-4 position were synthesised. These compounds were prepared as bioisosteres of gefitinib, an antitumour drug used for the treatment of gastrointestinal stromal tumours. All compounds exhibited antitumour activity against (HCT 116) cell line in vitro. Eight compounds (IC₅₀: 3.89, 4.65, 6.63, 6.94, 7.89, 9.53, 12.00 and 12.30 μg mL⁻¹ respectively) exhibited 4.3 to 1.3 fold more potent antitumour activity than imatinib (IC₅₀: 16.93 μg mL⁻¹). Also, a docking study of the newly synthesised compounds with the active site of CDK2 was described.