Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoisomerase II-specific catalytic inhibitor

Kyu Yeon Jun; Hanbyeol Kwon; So Eun Park; Eunyoung Lee; Radha Karki; Pritam Thapa; Jun Ho Lee; Eung Seok Lee; Youngjoo Kwon

doi:10.1016/j.ejmech.2014.04.066

Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoisomerase II-specific catalytic inhibitor

Kyu Yeon Jun, Hanbyeol Kwon, So Eun Park, Eunyoung Lee, Radha Karki, Pritam Thapa, Jun Ho Lee, Eung Seok Lee, Youngjoo Kwon

Department of Pharmaceutical Sciences

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

34 Scopus citations

Abstract

We describe our rationale for designing specific catalytic inhibitors of topoisomerase II (topo II) over topoisomerase I (topo I). Based on 3D-QSAR studies of previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives, 9 novel dihydroxylated 2,4-diphenyl-6-thiophen-2-yl pyridine compounds were designed, synthesized, and their biological activities were evaluated. These compounds have 2-thienyl ring substituted on the R³ group on the pyridine ring and they all showed excellent specificity toward topo II compared to topo I. In vitro experiments were performed for compound 13 to determine the mechanism of action for this series of compounds. Compound 13 inhibited topoisomerase II specifically by non-intercalative binding to DNA and did not stabilize enzyme-cleavable DNA complex. Compound 13 efficiently inhibited cell viability, cell migration, and induced G1 arrest. Also from 3D-QSAR studies, the results were compared with other previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives to explain the structure-activity relationships.

Original language	English
Pages (from-to)	428-438
Number of pages	11
Journal	European Journal of Medicinal Chemistry
Volume	80
DOIs	https://doi.org/10.1016/j.ejmech.2014.04.066
State	Published - 10 Jun 2014

Bibliographical note

Funding Information:
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2011–0011007 ). K.-Y. Jun was supported by RP-Grant 2012 of Ewha Womans University .

Keywords

3D-QSAR
Anticancer agents
Cytotoxicity
Dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridines
Topoisomerase I
Topoisomerase II

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10.1016/j.ejmech.2014.04.066

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title = "Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoisomerase II-specific catalytic inhibitor",

abstract = "We describe our rationale for designing specific catalytic inhibitors of topoisomerase II (topo II) over topoisomerase I (topo I). Based on 3D-QSAR studies of previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives, 9 novel dihydroxylated 2,4-diphenyl-6-thiophen-2-yl pyridine compounds were designed, synthesized, and their biological activities were evaluated. These compounds have 2-thienyl ring substituted on the R3 group on the pyridine ring and they all showed excellent specificity toward topo II compared to topo I. In vitro experiments were performed for compound 13 to determine the mechanism of action for this series of compounds. Compound 13 inhibited topoisomerase II specifically by non-intercalative binding to DNA and did not stabilize enzyme-cleavable DNA complex. Compound 13 efficiently inhibited cell viability, cell migration, and induced G1 arrest. Also from 3D-QSAR studies, the results were compared with other previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives to explain the structure-activity relationships.",

keywords = "3D-QSAR, Anticancer agents, Cytotoxicity, Dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridines, Topoisomerase I, Topoisomerase II",

author = "Jun, {Kyu Yeon} and Hanbyeol Kwon and Park, {So Eun} and Eunyoung Lee and Radha Karki and Pritam Thapa and Lee, {Jun Ho} and Lee, {Eung Seok} and Youngjoo Kwon",

note = "Funding Information: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2011–0011007 ). K.-Y. Jun was supported by RP-Grant 2012 of Ewha Womans University . ",

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doi = "10.1016/j.ejmech.2014.04.066",

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T1 - Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoisomerase II-specific catalytic inhibitor

AU - Jun, Kyu Yeon

AU - Kwon, Hanbyeol

AU - Park, So Eun

AU - Lee, Eunyoung

AU - Karki, Radha

AU - Thapa, Pritam

AU - Lee, Jun Ho

AU - Lee, Eung Seok

AU - Kwon, Youngjoo

N1 - Funding Information: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2011–0011007 ). K.-Y. Jun was supported by RP-Grant 2012 of Ewha Womans University .

PY - 2014/6/10

Y1 - 2014/6/10

N2 - We describe our rationale for designing specific catalytic inhibitors of topoisomerase II (topo II) over topoisomerase I (topo I). Based on 3D-QSAR studies of previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives, 9 novel dihydroxylated 2,4-diphenyl-6-thiophen-2-yl pyridine compounds were designed, synthesized, and their biological activities were evaluated. These compounds have 2-thienyl ring substituted on the R3 group on the pyridine ring and they all showed excellent specificity toward topo II compared to topo I. In vitro experiments were performed for compound 13 to determine the mechanism of action for this series of compounds. Compound 13 inhibited topoisomerase II specifically by non-intercalative binding to DNA and did not stabilize enzyme-cleavable DNA complex. Compound 13 efficiently inhibited cell viability, cell migration, and induced G1 arrest. Also from 3D-QSAR studies, the results were compared with other previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives to explain the structure-activity relationships.

AB - We describe our rationale for designing specific catalytic inhibitors of topoisomerase II (topo II) over topoisomerase I (topo I). Based on 3D-QSAR studies of previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives, 9 novel dihydroxylated 2,4-diphenyl-6-thiophen-2-yl pyridine compounds were designed, synthesized, and their biological activities were evaluated. These compounds have 2-thienyl ring substituted on the R3 group on the pyridine ring and they all showed excellent specificity toward topo II compared to topo I. In vitro experiments were performed for compound 13 to determine the mechanism of action for this series of compounds. Compound 13 inhibited topoisomerase II specifically by non-intercalative binding to DNA and did not stabilize enzyme-cleavable DNA complex. Compound 13 efficiently inhibited cell viability, cell migration, and induced G1 arrest. Also from 3D-QSAR studies, the results were compared with other previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives to explain the structure-activity relationships.

KW - 3D-QSAR

KW - Anticancer agents

KW - Cytotoxicity

KW - Dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridines

KW - Topoisomerase I

KW - Topoisomerase II

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SN - 0223-5234

VL - 80

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JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoisomerase II-specific catalytic inhibitor

Abstract

Bibliographical note

Keywords

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