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

• DOI: 10.1016/j.ejmech.2016.02.050
• Publication Date: 2016-02-22T23:36:40Z
• Authors: Radha Karki; Kyu-Yeon Jun; Tara Man Kadayat; Somin Shin; Til Bahadur Thapa...; Ganesh Bist; Aarajana Shrestha; Younghwa Na; Youngjoo Kwon; Eung-Seok Lee
• Keywords: 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Pyridines; Quantitative Structure-Activity Relationship; Antineoplastic Agents; 3. Good health; 03 medical and health sciences; DNA Topoisomerases, Type II; DNA Topoisomerases, Type I; Cell Line, Tumor; Humans; Topoisomerase II Inhibitors; Drug Screening Assays, Antitumor; Topoisomerase I Inhibitors; Cell Proliferation

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.