Design and synthesis of novel quinone inhibitors targeted to the redox function of apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (Ape1/Ref-1)

Rodney L. Nyland, Meihua Luo, Mark Kelley, Richard F. Borch

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

The multifunctional enzyme apurinic endonuclease 1/redox enhancing factor 1 (Ape1/ref-1) maintains genetic fidelity through the repair of apurinic sites and regulates transcription through redox-dependent activation of transcription factors. Ape1 can therefore serve as a therapeutic target in either a DNA repair or transcriptional context. Inhibitors of the redox function can be used as either therapeutics or novel tools for separating the two functions for in vitro study. Presently there exist only a few compounds that have been reported to inhibit Ape1 redox activity; here we describe a series of quinones that exhibit micromolar inhibition of the redox function of Ape1. Benzoquinone and naphthoquinone analogues of the Ape1-inhibitor E3330 were designed and synthesized to explore structural effects on redox function and inhibition of cell growth. Most of the naphthoquinones were low micromolar inhibitors of Ape1 redox activity, and the most potent analogues inhibited tumor cell growth with IC50 values in the 10-20 μM range.

Original languageEnglish
Pages (from-to)1200-1210
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number3
DOIs
StatePublished - 2010

Fingerprint

DNA-(Apurinic or Apyrimidinic Site) Lyase
Oxidation-Reduction
Naphthoquinones
Multifunctional Enzymes
Quinones
Growth
benzoquinone
DNA Repair
Inhibitory Concentration 50
Transcription Factors
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Design and synthesis of novel quinone inhibitors targeted to the redox function of apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (Ape1/Ref-1). / Nyland, Rodney L.; Luo, Meihua; Kelley, Mark; Borch, Richard F.

In: Journal of Medicinal Chemistry, Vol. 53, No. 3, 2010, p. 1200-1210.

Research output: Contribution to journalArticle

@article{76fce392e401493d9314fe4ad74528d5,
title = "Design and synthesis of novel quinone inhibitors targeted to the redox function of apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (Ape1/Ref-1)",
abstract = "The multifunctional enzyme apurinic endonuclease 1/redox enhancing factor 1 (Ape1/ref-1) maintains genetic fidelity through the repair of apurinic sites and regulates transcription through redox-dependent activation of transcription factors. Ape1 can therefore serve as a therapeutic target in either a DNA repair or transcriptional context. Inhibitors of the redox function can be used as either therapeutics or novel tools for separating the two functions for in vitro study. Presently there exist only a few compounds that have been reported to inhibit Ape1 redox activity; here we describe a series of quinones that exhibit micromolar inhibition of the redox function of Ape1. Benzoquinone and naphthoquinone analogues of the Ape1-inhibitor E3330 were designed and synthesized to explore structural effects on redox function and inhibition of cell growth. Most of the naphthoquinones were low micromolar inhibitors of Ape1 redox activity, and the most potent analogues inhibited tumor cell growth with IC50 values in the 10-20 μM range.",
author = "Nyland, {Rodney L.} and Meihua Luo and Mark Kelley and Borch, {Richard F.}",
year = "2010",
doi = "10.1021/jm9014857",
language = "English",
volume = "53",
pages = "1200--1210",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "3",

}

TY - JOUR

T1 - Design and synthesis of novel quinone inhibitors targeted to the redox function of apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (Ape1/Ref-1)

AU - Nyland, Rodney L.

AU - Luo, Meihua

AU - Kelley, Mark

AU - Borch, Richard F.

PY - 2010

Y1 - 2010

N2 - The multifunctional enzyme apurinic endonuclease 1/redox enhancing factor 1 (Ape1/ref-1) maintains genetic fidelity through the repair of apurinic sites and regulates transcription through redox-dependent activation of transcription factors. Ape1 can therefore serve as a therapeutic target in either a DNA repair or transcriptional context. Inhibitors of the redox function can be used as either therapeutics or novel tools for separating the two functions for in vitro study. Presently there exist only a few compounds that have been reported to inhibit Ape1 redox activity; here we describe a series of quinones that exhibit micromolar inhibition of the redox function of Ape1. Benzoquinone and naphthoquinone analogues of the Ape1-inhibitor E3330 were designed and synthesized to explore structural effects on redox function and inhibition of cell growth. Most of the naphthoquinones were low micromolar inhibitors of Ape1 redox activity, and the most potent analogues inhibited tumor cell growth with IC50 values in the 10-20 μM range.

AB - The multifunctional enzyme apurinic endonuclease 1/redox enhancing factor 1 (Ape1/ref-1) maintains genetic fidelity through the repair of apurinic sites and regulates transcription through redox-dependent activation of transcription factors. Ape1 can therefore serve as a therapeutic target in either a DNA repair or transcriptional context. Inhibitors of the redox function can be used as either therapeutics or novel tools for separating the two functions for in vitro study. Presently there exist only a few compounds that have been reported to inhibit Ape1 redox activity; here we describe a series of quinones that exhibit micromolar inhibition of the redox function of Ape1. Benzoquinone and naphthoquinone analogues of the Ape1-inhibitor E3330 were designed and synthesized to explore structural effects on redox function and inhibition of cell growth. Most of the naphthoquinones were low micromolar inhibitors of Ape1 redox activity, and the most potent analogues inhibited tumor cell growth with IC50 values in the 10-20 μM range.

UR - http://www.scopus.com/inward/record.url?scp=77249176627&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77249176627&partnerID=8YFLogxK

U2 - 10.1021/jm9014857

DO - 10.1021/jm9014857

M3 - Article

VL - 53

SP - 1200

EP - 1210

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -