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

Abstract

Abstract 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 structures of all synthesized compounds were confirmed by spectroscopic data and elemental analyses. We evaluated the anticancer activity of these compounds towards two cell lines: A459 (lung cancer cell line) and MCF7 (breast cancer cell line). All tested compounds showed moderate to strong anti-cancer activity towards the two cell lines. Compound 7e exhibited the strongest cytotoxic activity against A549 cell line (IC50: 0.155 µM) while compound 8d showed the strongest one against MCF7 cell line (IC50: 0.170 µM) compared with doxorubicin. In addition, we examined the impact of compounds 7e and 8d on the growth of A549 and MCF7 cell lines, employing flow cytometery and an Annexin V-FITC apoptotic assay. Compound 7e caused cell cycle arrest at the G2/M phase with a 79-fold increase in apoptosis of A459 cell line. In contrast, 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 showed that compound 7e is a potent CDK2 inhibitor with IC50 of 0.149 µM, compared to the Roscovitine control drug which showed an IC50 of 0.380 µM. We also found that compound 8d is a significant DHFR inhibitor with an IC50 of 0.199 µM, compared to Methotrexate control drug which showed IC50 of 0.131 µM. Evaluation the antioxidant properties of ten compounds was also included and promising results obtained.