Journal of Medicinal Chemistry p. 9266 - 9286 (2018)
Update date:2022-08-15
Topics:
An, Hongchan
Lee, Seungbeom
Lee, Jung Min
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
Kim, Young-Myeong
Kim, Kyu-Won
Kim, Sang Geon
Kim, Jeong Hun
Suh, Young-Ger
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-1α, 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-1α inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1α inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1α 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-1α inhibitors that can be used in lieu of a chromene ring.
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