TY - JOUR
T1 - Synthesis and biological evaluation of 2-phenol-4-chlorophenyl-6-aryl pyridines as topoisomerase II inhibitors and cytotoxic agents
AU - Thapa, Pritam
AU - Kadayat, Tara Man
AU - Park, Seojeong
AU - Shin, Somin
AU - Thapa Magar, Til Bahadur
AU - Bist, Ganesh
AU - Shrestha, Aarajana
AU - Na, Younghwa
AU - Kwon, Youngjoo
AU - Lee, Eung Seok
N1 - Funding Information:
This research was supported by the 2013 Yeungnam University Research Grant .
Publisher Copyright:
© 2016 Elsevier Inc. All rights reserved.
PY - 2016/6
Y1 - 2016/6
N2 - A new series of 2-phenol-4-chlorophenyl-6-aryl pyridines were designed, synthesized, and evaluated for topoisomerase (topo) I and II inhibitory activities as well as cytotoxic activity against four different human cancer cell lines such as HCT15, T47D, DU145, and Hela. Most of the tested compounds exhibited stronger topo II inhibitory activity at 100 μM as compared to etoposide. All the compounds, except 39, did not show topo I inhibitory activity. Interestingly, compounds that showed better topo II inhibition than etoposide have ortho- or para-chlorophenyl at 4-position of central pyridine, and none of the compounds possess meta-chlorophenyl. SAR study revealed the importance of ortho- or para-chlorophenyl at 4-position of the central pyridine for selective topo II inhibitory activity. Similarly, all compounds possessing meta- or para-hydroxyphenyl moieties showed moderate to significant cytotoxic effects. Particularly, compounds 27-37, and 39 which showed excellent cytotoxicity (IC50 = 0.68-1.25 μM) against T47D breast cancer cells suggest the importance of meta- or para-hydroxyphenyl moiety at 2-position of the central pyridine for the design of anticancer agents with related scaffolds.
AB - A new series of 2-phenol-4-chlorophenyl-6-aryl pyridines were designed, synthesized, and evaluated for topoisomerase (topo) I and II inhibitory activities as well as cytotoxic activity against four different human cancer cell lines such as HCT15, T47D, DU145, and Hela. Most of the tested compounds exhibited stronger topo II inhibitory activity at 100 μM as compared to etoposide. All the compounds, except 39, did not show topo I inhibitory activity. Interestingly, compounds that showed better topo II inhibition than etoposide have ortho- or para-chlorophenyl at 4-position of central pyridine, and none of the compounds possess meta-chlorophenyl. SAR study revealed the importance of ortho- or para-chlorophenyl at 4-position of the central pyridine for selective topo II inhibitory activity. Similarly, all compounds possessing meta- or para-hydroxyphenyl moieties showed moderate to significant cytotoxic effects. Particularly, compounds 27-37, and 39 which showed excellent cytotoxicity (IC50 = 0.68-1.25 μM) against T47D breast cancer cells suggest the importance of meta- or para-hydroxyphenyl moiety at 2-position of the central pyridine for the design of anticancer agents with related scaffolds.
KW - 2-Phenol-4-chlorophenyl-6-aryl pyridines
KW - Cytotoxicity
KW - Synthesis
KW - Topoisomerase I and II inhibition
UR - http://www.scopus.com/inward/record.url?scp=84968765184&partnerID=8YFLogxK
U2 - 10.1016/j.bioorg.2016.04.007
DO - 10.1016/j.bioorg.2016.04.007
M3 - Article
C2 - 27174797
AN - SCOPUS:84968765184
SN - 0045-2068
VL - 66
SP - 145
EP - 159
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
ER -
