Identification of a novel small molecule targeting UQCRB of mitochondrial complex III and its anti-angiogenic activity

Hye Jin Jung, Ki Hyun Kim, Nam Doo Kim, Gyoonhee Han, Ho Jeong Kwon

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Our recent study has shown that ubiquinol-cytochrome c reductase binding protein (UQCRB), the 13.4-kDa subunit of mitochondrial complex III, plays a crucial role in hypoxia-induced angiogenesis via mitochondrial reactive oxygen species (ROS)-mediated signaling. Here we report a new synthetic small molecule targeting the mitochondrial oxygen sensor UQCRB that was identified by pharmacophore-based virtual screening and in vitro and in vivo competition binding analyses. 6-((1-Hydroxynaphthalen-4-ylamino)dioxysulfone)-2H-naphtho[1, 8-bc]thiophen-2-one (HDNT) binds to the hydrophobic pocket of UQCRB and potently inhibits in vitro angiogenesis of human umbilical vein endothelial cells without cytotoxicity. Furthermore, the binding of HDNT to UQCRB suppressed mitochondrial ROS-mediated hypoxic signal transduction. These results demonstrated that HDNT is a novel synthetic small molecule targeting UQCRB and exhibits anti-angiogenic activity by modulating the oxygen-sensing function of UQCRB.

Original languageEnglish
Pages (from-to)1052-1056
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number3
DOIs
Publication statusPublished - 2011 Feb 1

Fingerprint

Electron Transport Complex III
Carrier Proteins
Molecules
Reactive Oxygen Species
Oxygen
Oxygen sensors
Signal transduction
Endothelial cells
Human Umbilical Vein Endothelial Cells
Cytotoxicity
Signal Transduction
Screening

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

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abstract = "Our recent study has shown that ubiquinol-cytochrome c reductase binding protein (UQCRB), the 13.4-kDa subunit of mitochondrial complex III, plays a crucial role in hypoxia-induced angiogenesis via mitochondrial reactive oxygen species (ROS)-mediated signaling. Here we report a new synthetic small molecule targeting the mitochondrial oxygen sensor UQCRB that was identified by pharmacophore-based virtual screening and in vitro and in vivo competition binding analyses. 6-((1-Hydroxynaphthalen-4-ylamino)dioxysulfone)-2H-naphtho[1, 8-bc]thiophen-2-one (HDNT) binds to the hydrophobic pocket of UQCRB and potently inhibits in vitro angiogenesis of human umbilical vein endothelial cells without cytotoxicity. Furthermore, the binding of HDNT to UQCRB suppressed mitochondrial ROS-mediated hypoxic signal transduction. These results demonstrated that HDNT is a novel synthetic small molecule targeting UQCRB and exhibits anti-angiogenic activity by modulating the oxygen-sensing function of UQCRB.",
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Identification of a novel small molecule targeting UQCRB of mitochondrial complex III and its anti-angiogenic activity. / Jung, Hye Jin; Kim, Ki Hyun; Kim, Nam Doo; Han, Gyoonhee; Kwon, Ho Jeong.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 3, 01.02.2011, p. 1052-1056.

Research output: Contribution to journalArticle

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