TY - JOUR
T1 - Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents
AU - Thapa, Pritam
AU - Jun, Kyu Yeon
AU - Kadayat, Tara Man
AU - Park, Chanmi
AU - Zheng, Zhi
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 Basic Science Research Program through the (NRF) funded by Korea government (MEST) ( National Research Foundation of Korea NRF-2013R1A1A2060408 ).
Publisher Copyright:
© 2015 Elsevier Ltd.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - To develop novel selective topoisomerase II inhibitors, we designed and synthesized a series of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines and evaluated their topoisomerase inhibitory activity and cytotoxicity against three human cancer cell lines (DU145, HCT15, and T47D) and a normal cell line (MCF10A). All of the prepared compounds displayed stronger or similar topoisomerase II inhibitory activity as well as cytotoxicity against three human cancer cell lines compared to etoposide. Compounds 10a, 10g, 11a, 11f, 11g, 12a, 12f, and 12g especially showed stronger topoisomerase II inhibitory activity as compared to etoposide at both 100 μM and 20 μM. A structure-activity relationship study revealed that hydroxyphenyl moiety at 4-position of pyridine and ortho-hydroxyphenyl or thienyl moiety at 2-position of pyridine has an important role in displaying selective topoisomerase II inhibition. The compound 12b with para-hydroxyphenyl and meta-hydroxyphenyl at 4- and 2-position of pyridine, respectively, showed the most significant cytotoxicity against all three cancer cell lines, whereas less cytotoxicity to a normal cell line as compared to adriamycin.
AB - To develop novel selective topoisomerase II inhibitors, we designed and synthesized a series of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines and evaluated their topoisomerase inhibitory activity and cytotoxicity against three human cancer cell lines (DU145, HCT15, and T47D) and a normal cell line (MCF10A). All of the prepared compounds displayed stronger or similar topoisomerase II inhibitory activity as well as cytotoxicity against three human cancer cell lines compared to etoposide. Compounds 10a, 10g, 11a, 11f, 11g, 12a, 12f, and 12g especially showed stronger topoisomerase II inhibitory activity as compared to etoposide at both 100 μM and 20 μM. A structure-activity relationship study revealed that hydroxyphenyl moiety at 4-position of pyridine and ortho-hydroxyphenyl or thienyl moiety at 2-position of pyridine has an important role in displaying selective topoisomerase II inhibition. The compound 12b with para-hydroxyphenyl and meta-hydroxyphenyl at 4- and 2-position of pyridine, respectively, showed the most significant cytotoxicity against all three cancer cell lines, whereas less cytotoxicity to a normal cell line as compared to adriamycin.
KW - Antiproliferative agents
KW - Cytotoxicity
KW - Hydroxylated 4-phenyl-2-aryl chromenopyridines
KW - Structure-activity relationships
KW - Topoisomerase II inhibitor
UR - http://www.scopus.com/inward/record.url?scp=84942195912&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2015.08.018
DO - 10.1016/j.bmc.2015.08.018
M3 - Article
C2 - 26361737
AN - SCOPUS:84942195912
SN - 0968-0896
VL - 23
SP - 6454
EP - 6466
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 19
M1 - 12522
ER -
