Novel tetrahydroisoquinolines as DHFR and CDK2 inhibitors: synthesis, characterization, anticancer activity and antioxidant properties

In this study, we synthesized new 5,6,7,8-tetrahydroisoquinolines and 6,7,8,9-tetrahydrothieno[2,3-c]isoquinolines based on 4-(N,N-dimethylamino)phenyl moiety as expected anticancer and/or antioxidant agents. The structure of all synthesized compounds were confirmed by spectral date (FT-IR, 1H NMR, 13C NMR) and elemental analysis. We evaluated the anticancer activity of these compounds toward two cell lines: A459 cell line (lung cancer cells) and MCF7 cell line (breast cancer cells). All tested compounds showed moderate to strong anti-cancer activity towards the two cell lines. Compound 7e exhibited the most potent cytotoxic activity against A549 cell line (IC50: 0.155 mu M) while compound 8d showed the most potent one against MCF7 cell line (IC50: 0.170 mu M) in comparison with doxorubicin. In addition, we examined the effect of compounds 7e and 8d regarding the growth of A549 and MCF7 cell lines, employing flow cytometry and Annexin V-FITC apoptotic assay. Our results showed that compound 7e caused cell cycle arrest at the G2/M phase with a 79-fold increase in apoptosis of A459 cell line. Moreover, compound 8d caused cell cycle arrest at the S phase with a 69-fold increase in apoptosis of MCF7 cell line. Furthermore, we studied the activity of these compounds as enzyme inhibitors against several enzymes. Our findings by docking and experimental studies that compound 7e is a potent CDK2 inhibitor with IC50 of 0.149 mu M, compared to the Roscovitine control drug with IC50 of 0.380 mu M. We also found that compound 8d is a significant DHFR inhibitor with an IC50 of 0.199 mu M, compared to Methotrexate control drug with IC50 of 0.131 mu M. Evaluation of the antioxidant properties of ten compounds was also studied in comparison with Vitamin C. Compounds 1, 3, 6, 7c and 8e have higher antioxidant activity than Vitamin C which mean that these compounds can used as potent antioxidant drugs.