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Novel hypoxia-inducible factor 1 alpha (HIF-1α) inhibitors for angiogenesis-related ocular diseases: Discovery of a novel scaffold via ring-truncation strategy : Novel hypoxia-inducible factor 1 alpha (HIF-1 alpha) inhibitors for angiogenesis-related ocular diseases: Discovery of a novel scaffold via ring-truncation strategy

Cited 26 time in Web of Science Cited 31 time in Scopus

An, Hongchan; Lee, Seungbeom; Lee, Jung Mm; Jo, Dong Hyun; Kim, Joohwan; Jeong, Yoo-Seong; Heo, Mi Jeong; Cho, Chang Sik; Choi, Hoon; Seo, Ji Hae; Hwang, Seyeon; Lim, Jihye; Kim, Taewoo; Jun, Hyoung Oh; Sim, Jaehoon; Lim, Changjin; Hur, Joonseong; Ahn, Jungmin; Kim, Hyun Su; Seo, Seung-Yong; Na, Younghwa; Kim, Seok-Ho; Lee, Jeewoo; Lee, Jeeyeon; Chung, Suk-Jae; Kyu, Young-Myeong; Kim, Kyu-Won; Kim, Sang Geon; Kim, Jeong Hun; Suh, Young-Ger

Issue Date
American Chemical Society
Journal of Medicinal Chemistry, Vol.61 No.20, pp.9266-9286
Ocular diseases featuring pathologic neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1 alpha, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1 alpha inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1 alpha inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-la inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1 alpha inhibitors that can be used in lieu of a chromene ring.
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  • College of Medicine
  • Department of Medicine
Research Area Ophthalmology, Retinoblastoma, Translational Medical Research


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