Benzothiazole derivatives as human DNA topoisomerase IIα inhibitors

作者：Kaplan Ozen C^*; Tekiner Gulbas B; Foto E; Yildiz I; Diril N; Aki E; Yalcin I

来源：Medicinal Chemistry Research, 2013, 1-11.

DOI：10.1007/s00044-013-0577-5

• Anticancer drugs
• Benzothiazole derivatives
• Catalytic inhibitor
• DNA binding
• Human topoisomerase II&alpha
• Intercalation

Benzothiazole derivatives resembling the structure of DNA purine bases were tested to determine their topoisomerase inhibition activities. Based on DNA topoisomerase I and II relaxation assay results, all 12 derivatives acted as human topoisomerase IIα inhibitors, whereas only two compounds inhibited Calf thymus topoisomerase I. 3-amino-2-(2-bromobenzyl)-1,3-benzothiazol-3-ium 4-methylbenzensulfonate (BM3) was observed to be the most effective human topoisomerase IIα inhibitor with the lowest IC50 value of 39 nM. The mechanistic studies suggested that BM3 was neither a DNA intercalator nor a topoisomerase poison, it was only a DNA minor groove-binding agent. BM3 initially bound to the DNA topoisomerase IIα enzyme, then to DNA. As a result, the tested benzothiazole derivatives were obtained as strong topoisomerase IIα inhibitors. The benzothiazole tosylated salt form BM3 was found as the most effective topoisomerase IIα inhibitor. BM3';s mechanisms of action might be its direct interaction with the enzyme. BM3';s minor groove-binding property might also contribute to this action. Hence, BM3 could be a good candidate as a new anticancer agent.