Design and Green Synthesis of Thieno[2,3-d]pyrimidine Analogues as Potential Antiproliferative Agents.

Background: Despite of significant progress achieved in the chemotherapy of cancer; it is still among the leading cause of morbidity and mortality worldwide.

Objective: Taking cognizance of the extensive biological potential of reported thieno[2,3-d]pyrimidines and inspired by the clinically available anticancer agents dasatinib and gefitinib, 4-substituted thieno[2,3-d]pyrimidines have been synthesized.

Methods: The compounds were synthesized via microwave-assisted methods and screened for their cytotoxic activity against liver HepG-2, lung NCI-H522, melanoma A-375, pancreatic MIA PaCa-2 and colon CaCo-2 human cancer cell lines using MTT assay.

Results: The antiproliferative potential of most active compounds 20b and 20f (piperidino substituted); and 22d (hybrid analogue of Dasatinib) was further assessed and confirmed by calcein AM and colony formation assay, which revealed the higher potency of hybrid analogue 22d in comparison to piperidino substituted derivative 20f.

Conclusion: Flow cytometer based cell cycle perturbation experiments revealed that antiproliferative effects of the most active compound 22d was associated with increased proportion of cells in the G2/M and subG0/G1 phases of the cell cycle. In silico ADME studies also confer the drug like characteristics of the potent compounds.