Human Topoisomerase IIα (htopoIIα) is an approved and validated target for designing anticancer agents. Among the various methods to block the functions of htopoIIα, targeting ATP site for its competitive inhibition has been relatively less investigated. Therefore, to identify some novel htopoIIα inhibitors to target the ATP-binding site, we designed and synthesized a small library of 5-aryl-1,3,4-thiadiazole coupled phthalimide derivatives structurally related to thalidomide. Initially, 2-amino-5-aryl-1,3,4-thiadiazole derivatives (TDZ 1-8) were synthesized by ferric chloride catalysed oxidative cyclization of thiosemicarbazone derivatives (THZ 1-8) which were obtained by the reaction of substituted aryl aldehydes with thiosemicarbazide. TDZ 1-8 on reaction with 4-bromophthalic anhydride in presence of 4Å molecular sieves and glacial acetic acid gave 5-bromo-2-(5-aryl-1,3,4-thiadiazol-2-yl)isoindoline-1,3-dione derivatives (PTD 1-8). All the synthesized compounds were characterized by IR, 1H-NMR and LCMS. The final compounds, PTD 1- 8 were docked at the ATP-binding site of chain B of htopoIIα. The compounds with best in silico results were further screened by dye exclusion test for short term cytotoxicity study on Dalton’s lymphoma Ascites (DLA) cells using Trypan blue dye. One of the synthesized compound PTD-2 exhibited prominent in silico and in vitro anticancer activity.
Keywords: Docking, Dye exclusion test, Isoindoline-1, 3-dione, Phthalimide, Thiadiazole, Topoisomerase, thiosemicarbazone , cyclization, aldehydes, PTD 1-8, anticancer activity, DNA backbone, ATP site, etoposide