Recently, drug therapy using biologics such as bevacizumab, pegaptanib and aflibercept has been successful in treating these diseases. An antibody, aptamer, and fusion protein respectively, these drugs all act by inhibiting vascular endothelial AZ 960 growth factor signaling, a key pro-angiogenic signaling pathway. However these medications face an unfavorable cost to benefit ratio and have the potential for significant acute systemic side effects such as non-ocular hemorrhage and myocardial infarction. There is also a significant population that is refractory to these drugs; up to 45% in one series of AMD patients. In addition, during pathological conditions, levels of inflammatory cytokines such as TNF-a and IL-1 are elevated and these cytokines in turn promote angiogenesis along with VEGF. Hence targeting not only VEGF signaling but multiple proangiogenic signals is required to improve the efficacy of treatment for diseases arising from pathological angiogenesis. At present there is currently no small molecule drug on the market to specifically prevent angiogenesis in the eye, hence there is a pressing need to develop specific novel small molecule drugs to treat these blinding eye diseases. Niltubacin HDAC inhibitor Several small molecules, including natural products, have been identified that inhibit pathological angiogenesis such as artemisinin, curcumin, fumagillin, LLL12, panduratin, decursin, withaferin, and sunitinib. A recent addition to this group is a homoisoflavanone, 5,7-dihydroxy-3–6-methoxychroman-4-one that was isolated from the plant Cremastra appendiculata. The bulb of the orchid C. appendiculata is a traditional medicine in East Asia, used internally to treat several cancers, and externally for skin lesions. This compound has also been isolated from members of the Hyacinthaceae, a rich source of homoisoflavanones, which are a small class of naturally occurring heterocyclic compounds that are structurally similar to isoflavonoids. Compound 1 was shown to possess anti-angiogenic activity both in vitro and in vivo. Shim et al. identified compound 1 as a potent inhibitor of the proliferation of human umbilical vein endothelial cells. Later it was shown that compound 1 inhibited both vascular tube formation and migration of HUVECs induced by basic fibroblast growth factor in vitro. In the chick chorioallantoic membrane model, compound 1 was as effective as retinoic acid in blocking new vessel growth induced by bFGF. The anti-angiogenic property of the compound as isolated from the plant extract was further confirmed in vivo in the laser-induced choroidal neovascularization and oxygen induced retinopathy mouse models, 
used for treatment evaluations in neovascular AMD and in ROP, respectively. Importantly, injection of compound 1 into the vitreous of normal adult mice showed no short-term cytotoxic or inflammatory effects on the retina, nor did it induce apoptosis of retinal cells. These results suggest that proliferative ocular vascular diseases such as ROP, DR, and AMD may be targeted using compound 1 or its derivatives. In order to further explore the potential of homoisoflavanones as treatments for neovascular eye diseases, we synthesized a novel isomer of compound 1, 5,6-dihydroxy-3–7-methoxychroman-4-one, known as SH-11052. In the present study we report this synthesis and show the anti-angiogenic properties of compound 2 in human retinal microvascular endothelial cells. We also demonstrate that compound 2 blocks TNF-a induced NF-kB signaling and the VEGF-induced PI3K/Akt pathway, two major proangiogenic signaling pathways activated during inflammation induced angiogenesis. These results suggest that the compound exerts its anti-angiogenic properties by blocking inflammation-induced angiogenic pathways.