Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor

Kyu Yeon Jun; Eun Young Lee; Mi Ja Jung; Ok Hee Lee; Eung Seok Lee; Hea Young Park Choo; Younghwa Na; Youngjoo Kwon

doi:10.1016/j.ejmech.2011.01.011

Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor

Kyu Yeon Jun, Eun Young Lee, Mi Ja Jung, Ok Hee Lee, Eung Seok Lee, Hea Young Park Choo, Younghwa Na, Youngjoo Kwon

Department of Pharmaceutical Sciences

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

53 Scopus citations

Abstract

Epoxide ring-opened xanthone derivatives were synthesized and tested for their topoisomerase inhibitory activity and cytotoxicity. Most of the compounds showed topo IIα specific inhibitory activity. To clarify the mechanism of action of these compounds, the most potent compound (compound 14) of the synthesized analogues was further studied by testing its ATPase inhibitory activity and through molecular docking experiments. The results showed that the topo IIα inhibitory activity of compound 14 was inversely proportional to ATP concentration. In the ATPase inhibitory test, ATP hydrolysis was reduced less efficiently by compound 14 (28.5 ± 4.6%) than novobiocin (60.4 ± 8.1%). Molecular docking study revealed compound 14 to have a stable binding pattern to the ATP-binding domain of human topo II.

Original language	English
Pages (from-to)	1964-1971
Number of pages	8
Journal	European Journal of Medicinal Chemistry
Volume	46
Issue number	6
DOIs	https://doi.org/10.1016/j.ejmech.2011.01.011
State	Published - Jun 2011

Bibliographical note

Funding Information:
This study was supported by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD) ( KRF-2006-521-E00159 ) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2009-0066925 & 2010-0002646 ). This work was also supported by the National Research Foundation of Korea Grant funded by the Korean Government (Ministry of Education, Science and Technology) [ NRF-2010-355-C00038 ]. K-Y Jun, E Lee, and M-J Jung were partially supported by the Brain Korea 21 project.

Keywords

ATP-competitive topoisomerase IIα inhibitor
Anti-cancer agents
Molecular docking
Xanthones

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10.1016/j.ejmech.2011.01.011

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Jun, K. Y., Lee, E. Y., Jung, M. J., Lee, O. H., Lee, E. S., Park Choo, H. Y., Na, Y., & Kwon, Y. (2011). Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor. European Journal of Medicinal Chemistry, 46(6), 1964-1971. https://doi.org/10.1016/j.ejmech.2011.01.011

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title = "Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor",

abstract = "Epoxide ring-opened xanthone derivatives were synthesized and tested for their topoisomerase inhibitory activity and cytotoxicity. Most of the compounds showed topo IIα specific inhibitory activity. To clarify the mechanism of action of these compounds, the most potent compound (compound 14) of the synthesized analogues was further studied by testing its ATPase inhibitory activity and through molecular docking experiments. The results showed that the topo IIα inhibitory activity of compound 14 was inversely proportional to ATP concentration. In the ATPase inhibitory test, ATP hydrolysis was reduced less efficiently by compound 14 (28.5 ± 4.6%) than novobiocin (60.4 ± 8.1%). Molecular docking study revealed compound 14 to have a stable binding pattern to the ATP-binding domain of human topo II.",

keywords = "ATP-competitive topoisomerase IIα inhibitor, Anti-cancer agents, Molecular docking, Xanthones",

author = "Jun, {Kyu Yeon} and Lee, {Eun Young} and Jung, {Mi Ja} and Lee, {Ok Hee} and Lee, {Eung Seok} and {Park Choo}, {Hea Young} and Younghwa Na and Youngjoo Kwon",

note = "Funding Information: This study was supported by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD) ( KRF-2006-521-E00159 ) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2009-0066925 & 2010-0002646 ). This work was also supported by the National Research Foundation of Korea Grant funded by the Korean Government (Ministry of Education, Science and Technology) [ NRF-2010-355-C00038 ]. K-Y Jun, E Lee, and M-J Jung were partially supported by the Brain Korea 21 project.",

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doi = "10.1016/j.ejmech.2011.01.011",

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Jun, KY, Lee, EY, Jung, MJ, Lee, OH, Lee, ES, Park Choo, HY, Na, Y & Kwon, Y 2011, 'Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor', European Journal of Medicinal Chemistry, vol. 46, no. 6, pp. 1964-1971. https://doi.org/10.1016/j.ejmech.2011.01.011

Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor. / Jun, Kyu Yeon; Lee, Eun Young; Jung, Mi Ja et al.
In: European Journal of Medicinal Chemistry, Vol. 46, No. 6, 06.2011, p. 1964-1971.

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

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T1 - Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor

AU - Jun, Kyu Yeon

AU - Lee, Eun Young

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AU - Lee, Ok Hee

AU - Lee, Eung Seok

AU - Park Choo, Hea Young

AU - Na, Younghwa

AU - Kwon, Youngjoo

N1 - Funding Information: This study was supported by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD) ( KRF-2006-521-E00159 ) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2009-0066925 & 2010-0002646 ). This work was also supported by the National Research Foundation of Korea Grant funded by the Korean Government (Ministry of Education, Science and Technology) [ NRF-2010-355-C00038 ]. K-Y Jun, E Lee, and M-J Jung were partially supported by the Brain Korea 21 project.

PY - 2011/6

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N2 - Epoxide ring-opened xanthone derivatives were synthesized and tested for their topoisomerase inhibitory activity and cytotoxicity. Most of the compounds showed topo IIα specific inhibitory activity. To clarify the mechanism of action of these compounds, the most potent compound (compound 14) of the synthesized analogues was further studied by testing its ATPase inhibitory activity and through molecular docking experiments. The results showed that the topo IIα inhibitory activity of compound 14 was inversely proportional to ATP concentration. In the ATPase inhibitory test, ATP hydrolysis was reduced less efficiently by compound 14 (28.5 ± 4.6%) than novobiocin (60.4 ± 8.1%). Molecular docking study revealed compound 14 to have a stable binding pattern to the ATP-binding domain of human topo II.

AB - Epoxide ring-opened xanthone derivatives were synthesized and tested for their topoisomerase inhibitory activity and cytotoxicity. Most of the compounds showed topo IIα specific inhibitory activity. To clarify the mechanism of action of these compounds, the most potent compound (compound 14) of the synthesized analogues was further studied by testing its ATPase inhibitory activity and through molecular docking experiments. The results showed that the topo IIα inhibitory activity of compound 14 was inversely proportional to ATP concentration. In the ATPase inhibitory test, ATP hydrolysis was reduced less efficiently by compound 14 (28.5 ± 4.6%) than novobiocin (60.4 ± 8.1%). Molecular docking study revealed compound 14 to have a stable binding pattern to the ATP-binding domain of human topo II.

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AN - SCOPUS:79955601050

SN - 0223-5234

VL - 46

SP - 1964

EP - 1971

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

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ER -

Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor

Abstract

Bibliographical note

Keywords

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