Synthesis, antitumor activity, and structure-activity relationship study of trihydroxylated 2,4,6-triphenyl pyridines as potent and selective topoisomerase II inhibitors

Radha Karki; Chanmi Park; Kyu Yeon Jun; Jun Goo Jee; Jun Ho Lee; Pritam Thapa; Tara Man Kadayat; Youngjoo Kwon; Eung Seok Lee

doi:10.1016/j.ejmech.2014.07.058

Synthesis, antitumor activity, and structure-activity relationship study of trihydroxylated 2,4,6-triphenyl pyridines as potent and selective topoisomerase II inhibitors

Radha Karki, Chanmi Park, Kyu Yeon Jun, Jun Goo Jee, Jun Ho Lee, Pritam Thapa, Tara Man Kadayat, Youngjoo Kwon, Eung Seok Lee

Department of Pharmaceutical Sciences

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

35 Scopus citations

Abstract

A series of eighteen trihydroxylated 2,4,6-triphenyl pyridines were designed and synthesized which contain hydroxyl groups at ortho, meta or para position of each phenyl rings attached to the central pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds exhibited strong and selective topoisomerase II inhibitory activity compared to the positive control, etoposide, and also displayed significant cytotoxicity in low micromolar range. Trihydroxylated 2,4,6-triphenyl pyridines were more potent than mono- and di-hydroxylated 2,4,6-triphenyl pyridines, which have been previously studied in our research group. Positive correlation between topoisomerase II inhibitory activity and cytotoxicity was observed for the most compounds. Molecular docking study shows qualitatively consistent with the results of biological assays.

Original language	English
Pages (from-to)	555-565
Number of pages	11
Journal	European Journal of Medicinal Chemistry
Volume	84
DOIs	https://doi.org/10.1016/j.ejmech.2014.07.058
State	Published - 12 Sep 2014

Bibliographical note

Funding Information:
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( NRF-2012R1A2A2A01046188 ).

Keywords

Anticancer agents
Cytotoxicity
Docking study
Topo II inhibitory activity
Topoisomerase I
Topoisomerase II
Trihydroxylated 2,4,6-triphenyl pyridines

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10.1016/j.ejmech.2014.07.058

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Karki, R., Park, C., Jun, K. Y., Jee, J. G., Lee, J. H., Thapa, P., Kadayat, T. M., Kwon, Y., & Lee, E. S. (2014). Synthesis, antitumor activity, and structure-activity relationship study of trihydroxylated 2,4,6-triphenyl pyridines as potent and selective topoisomerase II inhibitors. European Journal of Medicinal Chemistry, 84, 555-565. https://doi.org/10.1016/j.ejmech.2014.07.058

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title = "Synthesis, antitumor activity, and structure-activity relationship study of trihydroxylated 2,4,6-triphenyl pyridines as potent and selective topoisomerase II inhibitors",

abstract = "A series of eighteen trihydroxylated 2,4,6-triphenyl pyridines were designed and synthesized which contain hydroxyl groups at ortho, meta or para position of each phenyl rings attached to the central pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds exhibited strong and selective topoisomerase II inhibitory activity compared to the positive control, etoposide, and also displayed significant cytotoxicity in low micromolar range. Trihydroxylated 2,4,6-triphenyl pyridines were more potent than mono- and di-hydroxylated 2,4,6-triphenyl pyridines, which have been previously studied in our research group. Positive correlation between topoisomerase II inhibitory activity and cytotoxicity was observed for the most compounds. Molecular docking study shows qualitatively consistent with the results of biological assays.",

keywords = "Anticancer agents, Cytotoxicity, Docking study, Topo II inhibitory activity, Topoisomerase I, Topoisomerase II, Trihydroxylated 2,4,6-triphenyl pyridines",

author = "Radha Karki and Chanmi Park and Jun, {Kyu Yeon} and Jee, {Jun Goo} and Lee, {Jun Ho} and Pritam Thapa and Kadayat, {Tara Man} and Youngjoo Kwon and Lee, {Eung Seok}",

note = "Funding Information: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( NRF-2012R1A2A2A01046188 ). ",

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Karki, R, Park, C, Jun, KY, Jee, JG, Lee, JH, Thapa, P, Kadayat, TM, Kwon, Y & Lee, ES 2014, 'Synthesis, antitumor activity, and structure-activity relationship study of trihydroxylated 2,4,6-triphenyl pyridines as potent and selective topoisomerase II inhibitors', European Journal of Medicinal Chemistry, vol. 84, pp. 555-565. https://doi.org/10.1016/j.ejmech.2014.07.058

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AU - Karki, Radha

AU - Park, Chanmi

AU - Jun, Kyu Yeon

AU - Jee, Jun Goo

AU - Lee, Jun Ho

AU - Thapa, Pritam

AU - Kadayat, Tara Man

AU - Kwon, Youngjoo

AU - Lee, Eung Seok

N1 - Funding Information: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( NRF-2012R1A2A2A01046188 ).

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Y1 - 2014/9/12

N2 - A series of eighteen trihydroxylated 2,4,6-triphenyl pyridines were designed and synthesized which contain hydroxyl groups at ortho, meta or para position of each phenyl rings attached to the central pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds exhibited strong and selective topoisomerase II inhibitory activity compared to the positive control, etoposide, and also displayed significant cytotoxicity in low micromolar range. Trihydroxylated 2,4,6-triphenyl pyridines were more potent than mono- and di-hydroxylated 2,4,6-triphenyl pyridines, which have been previously studied in our research group. Positive correlation between topoisomerase II inhibitory activity and cytotoxicity was observed for the most compounds. Molecular docking study shows qualitatively consistent with the results of biological assays.

AB - A series of eighteen trihydroxylated 2,4,6-triphenyl pyridines were designed and synthesized which contain hydroxyl groups at ortho, meta or para position of each phenyl rings attached to the central pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds exhibited strong and selective topoisomerase II inhibitory activity compared to the positive control, etoposide, and also displayed significant cytotoxicity in low micromolar range. Trihydroxylated 2,4,6-triphenyl pyridines were more potent than mono- and di-hydroxylated 2,4,6-triphenyl pyridines, which have been previously studied in our research group. Positive correlation between topoisomerase II inhibitory activity and cytotoxicity was observed for the most compounds. Molecular docking study shows qualitatively consistent with the results of biological assays.

KW - Anticancer agents

KW - Cytotoxicity

KW - Docking study

KW - Topo II inhibitory activity

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KW - Topoisomerase II

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SN - 0223-5234

VL - 84

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ER -

Synthesis, antitumor activity, and structure-activity relationship study of trihydroxylated 2,4,6-triphenyl pyridines as potent and selective topoisomerase II inhibitors

Abstract

Bibliographical note

Keywords

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