2. Academic Validation
  3. A new series of 2-phenol-4-aryl-6-chlorophenyl pyridine derivatives as dual topoisomerase I/II inhibitors: Synthesis, biological evaluation and 3D-QSAR study

A new series of 2-phenol-4-aryl-6-chlorophenyl pyridine derivatives as dual topoisomerase I/II inhibitors: Synthesis, biological evaluation and 3D-QSAR study

  • Eur J Med Chem. 2016 May 4:113:228-45. doi: 10.1016/j.ejmech.2016.02.050.
Radha Karki 1,  Kyu-Yeon Jun 2,  Tara Man Kadayat 1,  Somin Shin 2,  Til Bahadur Thapa Magar 1,  Ganesh Bist 1,  Aarajana Shrestha 1,  Younghwa Na 3,  Youngjoo Kwon 4,  Eung-Seok Lee 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
  • 2 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program Ewha Womans University, Seoul 120-750, Republic of Korea.
  • 3 College of Pharmacy, Cha University, Pochon 487-010, Republic of Korea.
  • 4 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: ykwon@ewha.ac.kr.
  • 5 College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea. Electronic address: eslee@yu.ac.kr.
PMID: 26945111 DOI: 10.1016/j.ejmech.2016.02.050
Abstract

As a continuous effort to develop novel antitumor agents, a new series of forty-five 2-phenol-4-aryl-6-chlorophenyl pyridine compounds were synthesized and evaluated for cytotoxicity against four different human Cancer cell lines (DU145, HCT15, T47D, and HeLa), and Topoisomerase I and II inhibitory activity. Several compounds (10-15, 20, 22, 24, 28, 42, and 49) displayed strong to moderate dual Topoisomerase I and II inhibitory activity at 100 μM. It was observed that hydroxyl and chlorine moiety at meta or para position of phenyl ring is favorable for dual Topoisomerase inhibitory activity and cytotoxicity. Most of the compounds displayed stronger cytotoxicities than those of all positive controls against the HCT15 and T47D cell lines. For investigation of the structure-activity relationships, a 3D-QSAR analysis using the method of comparative molecular field analysis (CoMFA) was performed. The generated 3D contour maps can be used for further rational design of novel terpyridine derivatives as highly selective and potent cytotoxic agents.

Keywords

2-phenol-4-aryl-6-chlorophenyl pyridine; 3D-QSAR; Antitumor agents; CoMFA; Cytotoxicity; Dual topoisomerase I and II inhibition.

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