Design, synthesis, topoisomerase I & II inhibitory activity, antiproliferative activity, and structure-activity relationship study of pyrazoline derivatives: An ATP-competitive human topoisomerase IIα catalytic inhibitor
- 주제(키워드) Antiproliferative activity , ATP-competitive inhibitor , Pyrazoline derivatives , Topoisomerase
- 등재 SCIE, SCOPUS
- 발행기관 Elsevier Ltd
- 발행년도 2016
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000125543
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.bmc.2016.03.017
- 저작권 이화여자대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
A series of pyrazoline derivatives (5) were synthesized in 92-96% yields from chalcones (3) and hydrazides (4). Subsequently, topo-I and IIα-mediated relaxation and antiproliferative activity assays were evaluated for 5. Among the tested compounds, 5h had a very strong topo-I activity of 97% (Camptothecin, 74%) at concentration of 100μM. Nevertheless, all the compounds 5a-5i showed significant topo II inhibitory activity in the range of 90-94% (Etoposide, 96%) at the same concentration. Cytotoxic potential of these compounds was tested in a panel of three human tumor cell lines, HCT15, BT474 and T47D. All the compounds showed strong activity against HCT15 cell line with IC50 at the range of 1.9-10.4μM (Adriamycin, 23.0; Etoposide, 6.9; and Camptothecin, 7.1μM). Moreover, compounds 5c, 5f and 5i were observed to have strong antiproliferative activity against BT474 cell lines. Since, compound 5d showed antiproliferative activity at a very low IC50 thus 5d was then selected to study on their mode of action with diverse methods of ATP competition assay, ATPase assay and DNA-topo IIα cleavable complex assay and the results revealed that it functioned as a ATP-competitive human topoisomerase IIα catalytic inhibitor. Further evaluation of endogenous topo-mediated DNA relaxation in cells has been conducted to find that, 5d inhibited endogenous topo-mediated pBR322 plasmid relaxation is more efficient (78.0±4.7% at 50μM) than Etoposide (36.0±1.7% at 50μM). © 2016.
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