期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 19, 页码 7990-7998出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm500863j
关键词
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资金
- National Research Foundation of Korea
- Korean Government [2009-0092964, 2010-0017984, 2012M3A9D1054520]
- Translational Research Center for Protein Function Control, KRF [2009-0083522]
- Next-Generation BioGreen 21 Program [PJ0079772012]
- Rural Development Administration
- National RAMP
- D Program, Ministry of Health Welfare [0620360-1]
Recently we identified a novel therapeutic target and 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 synthesied. Several derivatives showed a significant increase in hypoxia inducible factor 1 alpha (HIF-1 alpha) inhibitory potency. compared to HDNT. The compounds bound to UQCRB and suppressed mitochondrial ROS-mediated hypoxic signaling, resulting in potent inhibitor 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 antiangiogen agents.
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