Synthesis and Biological Evaluation of Novel Homoisoflavonoids for Retinal Neovascularization

Abstract

Eye diseases characterized by excessive angiogenesis such as wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity are major causes of blindness. Cremastranone is an anti-angiogenic, naturally occurring homoisoflavanone with efficacy in retinal and choroidal neovascularization models and antiproliferative selectivity for endothelial cells over other cell types. We undertook a cell-based structure-activity relationship study to develop more potent cremastranone analogs, with improved antiproliferative selectivity for retinal endothelial cells. Phenylalanyl-incorporated homoisoflavonoids showed improved activity and remarkable selectivity for retinal microvascular endothelial cells. A lead compound inhibited angiogenesis in vitro without inducing apoptosis, and had efficacy in the oxygen-induced retinopathy model in vivo.

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

“… a the GI 50 values reported in ref 27. b 95% confidence interval shown in parentheses. c ND, not determined. …”

“…25, 31, 32 Seeking more potent and selective compounds than cremastranone, we identified SH-11037 which is observed to have novel antiangiogenic activity against human retinal microvascular endothelial cells (HRECs) and blocks neovascularization in the OIR and L-CNV models. 27, 33 Although the studies of mechanisms and medicinal chemistry could contribute to many therapeutic facets of the antiangiogenic homoisoflavonoids, their exact mechanisms of action and cellular targets remain unknown, so the search for direct interacting proteins is valuable. 34, 35 Herein we report design and synthesis of homoisoflavonoid-biotin conjugates for inhibiting proliferation of endothelial cells and identifying targets, adapting a synthetic strategy we previously employed to generate homoisoflavanones.…”

“…25–27 The phenolic OH on the C-3′ position was alkylated with tert -butyl bromoacetate under basic conditions, followed by the acidic treatment of the ester 12 to afford the carboxylic acid 13 . Finally, the carboxylic acid 13 was coupled with the intermediate 10 by HBTU-mediated amidation to provide the desired photoaffinity probe 3 in moderate yield.…”

“…This amide compound 4b was synthesized from homoisoflavanone 17 27 having an amino group on the C3′ position to which Boc-Tyr(Bn)-OH was added by EDCI-mediated amidation (Scheme 4). The resulting amide 18 was treated with H 2 and Pd/C to generate phenol 19 .…”

“…Thus benzophenone-linked biotin could be attached at the C-7 position of 2 using our synthetic approach to cremastranone (Scheme 5). According to the procedures reported previously, 27 the known acetophenone 21 as a starting material was converted to 7-hydroxy-5,6-dimethoxy-4-chromanone 22 via 2 steps in good yield. The C-7 alkylation of the compound 22 with benzyl 4-bromobutyrate provided the compound 23 .…”