Phenotypic Discovery of Thiocarbohydrazone with Anticancer Properties and Catalytic Inhibition of Human DNA Topoisomerase IIα

Phenotypic screening of a-substituted thiocarbohydrazones revealed promising activity of 1,5-bis(salicylidene)thiocarbohydrazide against leukemia and breast cancer cells. Supplementary cell-based studies indicated an impairment of DNA replication via the ROS-independent pathway. The structural similarity of a-substituted thiocarbohydrazone to previously published thiosemicarbazone catalytic inhibitors targeting the ATP-binding site of human DNA topoisomerase IIa prompted us to investigate the inhibition activity on this target. Thiocarbohydrazone acted as a catalytic inhibitor and did not intercalate the DNA molecule, which validated their engagement with this cancer target. A comprehensive computational assessment of molecular recognition for a selected thiosemicarbazone and thiocarbohydrazone provided useful information for further optimization of this discovered lead compound for chemotherapeutic anticancer drug discovery.

Automated summary

Phenotypic screening identified 1,5-bis(salicylidene)thiocarbohydrazide as a promising compound against leukemia and breast cancer cells, inhibiting DNA replication through a ROS-independent pathway. The similarity of thiocarbohydrazone to known thiosemicarbazone inhibitors targeting DNA topoisomerase IIa prompted investigation of their inhibition activity. Computational assessment provided insights for further optimization of this lead compound for anticancer drug development.