Multi-target design of fused cyclic pyrimidine-2-thione candidates as DNA intercalators and topoisomerase I/II inhibitors.

AIM: We aimed to design and synthesize novel pyrimidine-2-thione derivatives (1-13) as Topoisomerase I/II (Topo I/II) inhibitors with DNA intercalation potential for cancer treatment.

MATERIALS &

METHODS

Inhibitory concentration 50 (IC50) against mammary gland breast cancer, hepatocellular carcinoma, and colorectal carcinoma was determined for all compounds. The frontier candidates (2, 6, 9, 10, and 11) were evaluated for their DNA-binding ability, Topo I, and Topo II inhibiting potential. Moreover, cell cycle and apoptosis analysis were carried out.

RESULTS

Compound 2 displayed the best DNA-binding affinity with an IC50 value of 37.24 µM in comparison to doxorubicin (Dox). Both compounds 2 and 9 showed superior nanomolar Topo I inhibitory potential, compared to Dox. Similarly, compounds 2 and 9 achieved better Topo II inhibition, exceeding that of Dox. It was revealed that compound 9 halted the cell cycle at both the P1 and G2 phases. In addition, compound 9 was able to boost the apoptosis at both the early and late apoptotic phases.

CONCLUSION

Consequently, the compounds afforded can be regarded as prominent lead anticancer compounds for further optimization and investigation.