Benzothiazole derivatives as human DNA topoisomerase II alpha inhibitors


Kaplan-Ozen C., Tekiner-Gulbas B., Foto E., YILDIZ İ., DİRİL N. , Aki E., ...Daha Fazla

MEDICINAL CHEMISTRY RESEARCH, cilt.22, ss.5798-5808, 2013 (SCI İndekslerine Giren Dergi) identifier identifier

  • Cilt numarası: 22 Konu: 12
  • Basım Tarihi: 2013
  • Doi Numarası: 10.1007/s00044-013-0577-5
  • Dergi Adı: MEDICINAL CHEMISTRY RESEARCH
  • Sayfa Sayıları: ss.5798-5808

Özet

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 II alpha 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 II alpha 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 II alpha enzyme, then to DNA. As a result, the tested benzothiazole derivatives were obtained as strong topoisomerase II alpha inhibitors. The benzothiazole tosylated salt form BM3 was found as the most effective topoisomerase II alpha 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.