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

Abstract

Cremastranone (1), a naturally occurring homoisoflavonoid, 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 its efficacy, the mechanism of this compound 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 GI50.

Synthesis of Either C2- or C4′-Alkylated Derivatives of Honokiol and Their Biological Evaluation for Anti-inflammatory Activity

“…11) Compared with other synthesized analogs, 11a showed the most promising anti-inflammatory activity; thus, it was exploited as an intermediate to obtain C4′-labeled photoaffinity probe of honokiol. 25) By the treatment with trifluoroacetic acid in dichloromethane, the tertbutyl ester group of 11a was removed to afford carboxylic acid 12, as shown in Chart 2. Acid 12 was coupled with the bifunctional molecule 13, which consists of benzophenone 26) and biotin, under PyAOP/HOAt-mediated reaction condition to finally afford the desired photoaffinity probe 14 in good yield.…”

“…25) By the treatment with trifluoroacetic acid in dichloromethane, the tertbutyl ester group of 11a was removed to afford carboxylic acid 12, as shown in Chart 2. Acid 12 was coupled with the bifunctional molecule 13, which consists of benzophenone 26) and biotin, under PyAOP/HOAt-mediated reaction condition to finally afford the desired photoaffinity probe 14 in good yield.…”

A Critical Analysis of the AvailableIn VitroandEx VivoMethods to Study Retinal Angiogenesis

“…However, we also found several studies using nonretinal specific ECs with the aim of studying retinal angiogenesis. In this group, the most used cells are human umbilical vein endothelial cells (HUVECs) [ 26 , 53 , 70 , 76 , 78 , 96 – 130 ]. Human microvascular endothelial cells (HMVECs) [ 131 , 132 ] and human dermal microvascular endothelial cells (HMVEC-D) [ 133 ] constitute other examples.…”

“…RPE secretes essential factors for the structural integrity of the retina, and it is well established that RPE has a crucial role in the development of many retinopathies through the production of many proangiogenic factors [ 12 ]. The authors used these cells either in coculture with ECs [ 88 , 129 ] or independently [ 45 , 59 , 70 , 81 , 96 , 109 , 116 , 119 , 124 , 125 , 155 , 156 ]. When in coculture, it is possible to assess direct cell-cell interactions.…”

A short synthesis of 7-amino alkoxy homoisoflavonoides

“…3 To date, a wide range of biological behaviors of homoiso-avonoids, their synthesis and biosynthesis have been studied and reported in the literature. 1,4 These types of compounds have shown many biological activities such as antiangiogenic, 5 antifungal, 6 hypocholesterolemic, 7 antimutagenic, 8 anti-inammatory, 9 and antiviral activities. 10,11 Among natural products containing homoisoavonoid scaffold, Bonducellin (isolated from Caesalpinia bonducella and Caesalpinia pulcherrima) 12 acts as inhibitor of multidrug resistance efflux pump.…”