Design, synthesis and biological evaluation of photoaffinity probes of antiangiogenic homoisoflavonoids

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Lee, Bit¹  Sun, Wei¹  Lee, Hyungjun¹  Basavarajappa, Halesha^2,3  Sulaiman, Rania S.^2,4,5  Sishtla, Kamakshi²  Fei, Xiang¹  Corson, Timothy W.^2,3,4  Seo, Seung-Yong¹ 

[1] Gachon Univ, Coll Pharm, Inchon 21936, South Korea

[2] Indiana Univ Sch Med, Eugene & Marilyn Glick Eye Inst, Dept Ophthalmol, Indianapolis, IN 46202 USA

[3] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[4] Indiana Univ Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA

[5] Cairo Univ, Dept Biochem, Fac Pharm, Cairo, Egypt

关键词: Homoisoflavonoids;    Photoaffinity probes;    Antiangiogenic agents;    Human retinal microvascular endothelial cells;    Wet age-related macular degeneration;   

DOI  :  10.1016/j.bmcl.2016.07.043

来源: Elsevier

【 摘 要 】

A naturally occurring homoisoflavonoid, cremastranone (1) inhibited angiogenesis in vitro and in vivo. We developed an analogue SH-11037 (2) which is more potent than cremastranone in human retinal microvascular endothelial cells (HRECs) and blocks neovascularization in animal models. Despite their efficacy, the mechanism of these compounds is not yet fully known. In the course of building on a strong foundation of SAR and creating a novel chemical tool for target identification of homoisoflavonoid-binding proteins, various types of photoaffinity probes were designed and synthesized in which benzophenone and biotin were attached to homoisoflavanonoids using PEG linkers on either the C-3' or C-7 position. Notably, the photoaffinity probes linking on the phenol group of the C-3' position retain excellent activity of inhibiting retinal endothelial cell proliferation with up to 72 nM of GI(50). (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

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