title: Development of a novel class of mitochondrial ubiquinol-cytochrome c reductase binding protein (UQCRB) modulators as promising antiangiogenic leads.
abstract: Recently, we identified a novel therapeutic target and a small molecule for regulating angiogenesis. Our study showed that ubiquinol-cytochrome c reductase binding protein (UQCRB) of the mitochondrial complex III plays a crucial role in hypoxia-induced angiogenesis via mitochondrial reactive oxygen species (ROS) mediated signaling. Herein, we developed new synthetic small molecules that specifically bind to UQCRB and regulate its function. To improve the pharmacological properties of 6-((1-hydroxynaphthalen-4-ylamino)dioxysulfone)-2H-naphtho[1,8-bc]thiophen-2-one (HDNT), a small molecule that targets UQCRB, a series of HDNT derivatives were designed and synthesized. Several derivatives showed a significant increase in hypoxia inducible factor 1α (HIF-1α) inhibitory potency compared to HDNT. The compounds bound to UQCRB and suppressed mitochondrial ROS-mediated hypoxic signaling, resulting in potent inhibition of angiogenesis without inducing cytotoxicity. Notably, one of these new derivatives significantly suppressed tumor growth in a mouse xenograft model. Therefore, these mitochondrial UQCRB modulators could be potential leads for the development of novel antiangiogenic agents.
authors.affiliation: Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University , Seoul 120-749, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jung
authors.forename: Misun
authors.initials: M
authors.lastname: Cho
authors.forename: Yonghyo
authors.initials: Y
authors.lastname: Kim
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C557886:6-((1-hydroxynaphthalen-4-ylamino)dioxysulfone)-2H-naphtho(1,8-bc)thiophen-2-one; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D006575:Heterocyclic Compounds, 3-Ring; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C027208:ubiquinone-binding proteins