title: Design, synthesis and biological evaluation of photoaffinity probes of antiangiogenic homoisoflavonoids.
abstract: 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 72nM of GI50.
authors.affiliation: College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, South Korea.
authors.forename: Bit
authors.initials: B
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, South Korea.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, South Korea.
authors.forename: Hyungjun
authors.initials: H
authors.lastname: Lee
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Halesha
authors.initials: H
authors.lastname: Basavarajappa
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Rania S
authors.initials: RS
authors.lastname: Sulaiman
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Kamakshi
authors.initials: K
authors.lastname: Sishtla
authors.affiliation: College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, South Korea.
authors.forename: Xiang
authors.initials: X
authors.lastname: Fei
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Corson
authors.affiliation: College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, South Korea. Electronic address: syseo@gachon.ac.kr.
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Seo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007529:Isoflavones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019920:Photoaffinity Labels / Q000737:chemistry
chemical_list: C524883:5,7-dihydroxy-3-(3-hydroxy-4-methoxybenzyl)-6-methoxychroman-4-one; D020533:Angiogenesis Inhibitors; D002867:Chromones; D007529:Isoflavones; D019920:Photoaffinity Labels; C000622107:SH-11037; D010649:Phenylalanine
keywords: Antiangiogenic agents; Homoisoflavonoids; Human retinal microvascular endothelial cells; Photoaffinity probes; Wet age-related macular degeneration