Rational design, synthesis, and evaluation of novel 2,4-Chloro- and Hydroxy-Substituted diphenyl Benzofuro[3,2-b]Pyridines: Non-intercalative catalytic topoisomerase I and II dual inhibitor
- 주제(키워드) 2 , 4-chloro- and hydroxy-substituted diphenyl benzofuro[3 , 2-b]pyridines , Anticancer agent , Antiproliferative activity , Dual topoisomerase I and II inhibition , Non-intercalative catalytic inhibiton
- 등재 SCIE, SCOPUS
- 발행기관 Elsevier Masson SAS
- 발행년도 2017
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000141683
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.ejmech.2017.01.003
- 저작권 이화여자대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Novel series of conformationally constrained 2,4-chloro- and hydroxy-substituted diphenyl benzofuro[3,2-b]pyridines were rationally designed and synthesized. Their biological activities were evaluated for topoisomerase I and II inhibitory activity, and antiproliferative activity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds with phenol moiety at 4-position of central pyridine exhibited significant dual topoisomerase I and II inhibitory activities, and strong antiproliferative activity in low micromolar range. Structure activity relationship study suggested that phenol moiety at 4-position of the central pyridine regardless of chlorophenyl moiety at 2-position of the central pyridine has an important role in dual topoisomerase inhibitory activity as well as antiproliferative activity. For investigation of mode of action for compound 14 which displayed the most strong dual topoisomerase I and II inhibitory activity and antiproliferative activity against HCT15 cell, we performed cleavable complex assay, band depletion assay, comet assay, and competitive EtBr displacement assay. Compound 14 functioned as non-intercalative catalytic topo I and II dual inhibitor. In addition, compound 14 induced apoptosis in HCT15 cells through increase of Bax, decrease of Bcl-2 and increase of PARP cleavage. © 2017 Elsevier Masson SAS
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