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Abstract
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.

Author information

An H1, Lee S1, Lee JM1, Jo DH2, Kim J3, Jeong YS1, Heo MJ1, Cho CS2, Choi H1, Seo JH1, Hwang S1, Lim J1, Kim T1, Jun HO2, Sim J1,4, Lim C1,4, Hur J1, Ahn J1, Kim HS1,4, Seo SY5, Na Y4, Kim SH4, Lee J1, Lee J1, Chung SJ1, Kim YM3, Kim KW1, Kim SG1, Kim JH2,6, Suh YG1,4.
1
College of Pharmacy , Seoul National University , Seoul 08826 , Republic of Korea.
2
Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute , Seoul National University Hospital , Seoul 03080 , Republic of Korea.
3
Department of Molecular and Cellular Biochemistry, School of Medicine , Kangwon National University , Gangwon-do 24341 , Republic of Korea.
4
College of Pharmacy , CHA University , Gyeonggi-do 11160 , Republic of Korea.
5
College of Pharmacy , Gachon University , Incheon 21936 , Republic of Korea.
6
Department of Ophthalmology, College of Medicine , Seoul National University , Seoul 03080 , Republic of Korea.