Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents

Pritam Thapa; Kyu Yeon Jun; Tara Man Kadayat; Chanmi Park; Zhi Zheng; Til Bahadur Thapa Magar; Ganesh Bist; Aarajana Shrestha; Younghwa Na; Youngjoo Kwon; Eung Seok Lee

doi:10.1016/j.bmc.2015.08.018

Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents

Pritam Thapa, Kyu Yeon Jun, Tara Man Kadayat, Chanmi Park, Zhi Zheng, Til Bahadur Thapa Magar, Ganesh Bist, Aarajana Shrestha, Younghwa Na, Youngjoo Kwon, Eung Seok Lee

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

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.

Original language	English
Article number	12522
Pages (from-to)	6454-6466
Number of pages	13
Journal	Bioorganic and Medicinal Chemistry
Volume	23
Issue number	19
DOIs	https://doi.org/10.1016/j.bmc.2015.08.018
State	Published - 1 Oct 2015

Bibliographical note

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.

Keywords

Antiproliferative agents
Cytotoxicity
Hydroxylated 4-phenyl-2-aryl chromenopyridines
Structure-activity relationships
Topoisomerase II inhibitor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2015.08.018

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Thapa, P., Jun, K. Y., Kadayat, T. M., Park, C., Zheng, Z., Thapa Magar, T. B., Bist, G., Shrestha, A., Na, Y., Kwon, Y., & Lee, E. S. (2015). Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents. Bioorganic and Medicinal Chemistry, 23(19), 6454-6466. Article 12522. https://doi.org/10.1016/j.bmc.2015.08.018

@article{6e19264b78b04690bd9ba7989402e234,

title = "Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents",

abstract = "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.",

keywords = "Antiproliferative agents, Cytotoxicity, Hydroxylated 4-phenyl-2-aryl chromenopyridines, Structure-activity relationships, Topoisomerase II inhibitor",

author = "Pritam Thapa and Jun, {Kyu Yeon} and Kadayat, {Tara Man} and Chanmi Park and Zhi Zheng and {Thapa Magar}, {Til Bahadur} and Ganesh Bist and Aarajana Shrestha and Younghwa Na and Youngjoo Kwon and Lee, {Eung Seok}",

note = "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: {\textcopyright} 2015 Elsevier Ltd.",

year = "2015",

month = oct,

day = "1",

doi = "10.1016/j.bmc.2015.08.018",

language = "English",

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Thapa, P, Jun, KY, Kadayat, TM, Park, C, Zheng, Z, Thapa Magar, TB, Bist, G, Shrestha, A, Na, Y, Kwon, Y & Lee, ES 2015, 'Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents', Bioorganic and Medicinal Chemistry, vol. 23, no. 19, 12522, pp. 6454-6466. https://doi.org/10.1016/j.bmc.2015.08.018

Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents. / Thapa, Pritam; Jun, Kyu Yeon; Kadayat, Tara Man et al.
In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 19, 12522, 01.10.2015, p. 6454-6466.

Research output: Contribution to journal › Article › peer-review

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

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SN - 0968-0896

VL - 23

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JO - Bioorganic and Medicinal Chemistry

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ER -

Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents

Abstract

Bibliographical note

Keywords

UN SDGs

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