Dihydroxylated 2,6-diphenyl-4-chlorophenylpyridines: Topoisomerase I and IIα dual inhibitors with DNA non-intercalative catalytic activity.

Abstract

With the aim to develop novel antiproliferative agents, a new series of eighteen dihydroxylated 2,6-diphenyl-4-chlorophenylpyridines were systematically designed, prepared, and investigated for their topoisomerase (topo) I and IIα inhibitory properties and antiproliferative effect in three different human cancer cell lines (HCT15, T47D, and HeLa). Compounds 22-30 which possess a meta- or para-phenol on 2-, or 6-position of central pyridine ring showed significant dual topo I and topo IIα inhibitory activities with strong antiproliferative activities against all the tested human cancer cell lines. However, compounds 13-21 which possess an ortho-phenol on 2-, or 6-position of central pyridine ring did not show significant topo I and topo IIα inhibitory activities but displayed moderate antiproliferative activities against all the tested human cancer cell lines. Compound 23 exhibited the highest antiproliferative potency as much as 348.5 and 105 times compared to etoposide and camptothecin, respectively, in T47D cancer cell line. The structure-activity relationship study revealed that the para position of a hydroxyl group at 2-and 6-phenyl ring and chlorine atom at the para position of 4-phenyl ring of the central pyridine exhibited the most significant topo I and topo IIα inhibition, which might indicate introduction of the chlorine atom at the phenyl ring of 4-pyridine have an important role as dual inhibitors of topo I and topo IIα. Compound 30 which showed the most potent dual topo I and topo IIα inhibition with strong antiproliferative activity in T47D cell line was selected to perform further study on the mechanism of action, which revealed that compound 30 functions as a potent DNA non-intercalative catalytic topo I and IIα dual inhibitor.

• Authors: Ganesh Bist, Seojeong Park, Chanju Song, Til Bahadur Thapa Magar, Aarajana Shrestha, Youngjoo Kwon, Eung-Seok Lee
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 133 Pg. 69-84 (Jun 16 2017) ISSN: 1768-3254 [Electronic] France
• PMID: 28384547 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Biphenyl Compounds
• Pyridines
• Topoisomerase II Inhibitors
• diphenyl
• DNA Topoisomerases, Type I

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Biphenyl Compounds (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Topoisomerases, Type I (chemical synthesis, chemistry, pharmacology)
• Halogenation
• Humans
• Neoplasms (drug therapy, metabolism)
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Topoisomerase II Inhibitors (chemical synthesis, chemistry, pharmacology)