Design, synthesis, biological evaluation, structure-activity relationship study, and mode of action of 2-phenol-4,6-dichlorophenyl-pyridines
- 주제(키워드) 2-Phenol-4 , 6-dichlorophenyl-pyridines , Anti-proliferative activity , Topoisomerase inhibitor , Structure-activity relationship
- 주제(기타) Biochemistry & Molecular Biology; Chemistry, Organic
- 설명문(일반) [Shrestha, Aarajana; Kadayat, Tara Man; Bist, Ganesh; Katila, Pramila; Lee, Eung-Seok] Yeungnam Univ, Coll Pharm, Gyongsan 712749, South Korea; [Park, Seojeong; Shin, Somin; Kwon, Youngjoo] Ewha Womans Univ, Ewha Global Top Program 5, Grad Sch Pharmaceut Sci, Coll Pharm, Seoul 120750, South Korea; [Kadayat, Tara Man] Daegu Gyeongbuk Med Innovat Fdn, New Drug Dev Ctr, Daegu 41061, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 ACADEMIC PRESS INC ELSEVIER SCIENCE
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000151598
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.bioorg.2018.03.033
초록/요약
Human DNA topoisomerases (Topos) are essential nuclear enzyme whose level of expression is potential indicator for prediction of responsive result of chemotherapy. Topos has become a key cellular target for most of the anticancer agents that regulates topological problems of DNA during cellular metabolic processes such as replication, transcription, and recombination. Inspired by previous studies of 2,4,6-trisubstituted pyridines to find out safer and effective topoisomerase targeted anticancer agent, twenty-seven 2-phenol-4,6-dichlorophenyl-pyridines were designed, synthesized, and tested for their topo I and II alpha inhibitory and anti-proliferative activity. Most of the dichlorinated meta- and para-phenolic series compounds (1-18) exhibited potent and selective topo II alpha inhibition along with significant anti-proliferative activity in the HCT-15 and T47D cell lines compared to the positive control, etoposide. Interestingly, dichlorinated ortho-phenolic series compounds (19-27) exhibited potent and dual topo inhibition but very weak anti-proliferative activity in the tested cancer cell lines. Structure-activity relationship with previously synthesized compounds revealed the importance of chlorine moiety to improve the potency of topo inhibitory activity. Further mechanistic study confirmed that compounds 2 and 12 acted as non-intercalative specific topo II alpha catalytic inhibitor with less DNA damage, and induced G1 arrest and apoptosis in HCT-15 and T47D cell lines, respectively. (C) 2018 Published by Elsevier Inc.
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