Benzothiazole derivatives as human DNA topoisomerase IIα inhibitors

Abstract

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 IIa 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 IIa inhibitor with the lowest IC 50 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 groovebinding agent. BM3 initially bound to the DNA topoisomerase IIa enzyme, then to DNA. As a result, the tested benzothiazole derivatives were obtained as strong topoisomerase IIa inhibitors. The benzothiazole tosylated salt form BM3 was found as the most effective topoisomerase IIa 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.

Evaluation of inhibitory effects of benzothiazole and 3-amino-benzothiazolium derivatives on DNA topoisomerase II by molecular modeling studies

“…In this study, we used fast flexible docking to study the binding orientations and predict binding affinities of benzothiazole and benzothiazolium derivatives. Such studies have been carried out to understand the forms of interaction of 12 compounds, examined by Kaplan-Ozen and colleagues for human DNA topoisomerases [21]. The results obtained from this study will be useful in understanding the inhibitory mode of benzothiazole and benzothiazolium derivatives, as well as in rapidly and accurately predicting the activities of newly designed inhibitors on the basis of docking scores.…”

“…A set of previously synthesized benzothiazole and 3-amino-benzothiazolium derivatives [16] tested for DNA topoisomerase II inhibitory activity were chosen from our previous study [21] as shown in Table 1. The DNA topoisomerase II inhibitory activities of these compounds are represented as IC 50 values in the millimolar, micromolar or nanomolar range [21].…”

“…Our group has been working for many years on the synthesis of some new heterocyclic compounds that were potentially DNA topoisomerase I and II inhibitors, and molecular modelling studies of these compounds [15][16][17][18][19][20][21]. So far some of the compounds exhibited significant topoisomerase II inhibitory activity with IC 50 values differing from 11.4 and 46.8 μM compared with the standard drug etoposide [15,18].…”

Possible Mechanism of Action of Neurokinin-1 Receptors (NK1R) Antagonists

“…Some of the benzoxazole and benzamide compounds, which were previously synthesized in our laboratory, showed strong inhibitory activity for human DNA Topoisomerases and Glutathione S-Transferases and also anticancer effects observed on various cell cultures [12][13][14][15][16][17][18][19][20]. These findings encouraged us to search for the new anticancer target NK1R by comparing their activities with the well-known NK1R antagonist aprepitant.…”

“…Over the last decade our group have been working on the drug design studies on the new anticancer active compounds by using both computational techniques and experimental work such as synthesis and activity studies [12][13][14][15][16][17][18][19][20]. Some of the benzoxazole and benzamide compounds, which were previously synthesized in our laboratory, showed strong inhibitory activity for human DNA Topoisomerases and Glutathione S-Transferases and also anticancer effects observed on various cell cultures [12][13][14][15][16][17][18][19][20].…”