br Acknowledgements br Introduction The angiogenic ocular co

Acknowledgements
Introduction The angiogenic ocular conditions represent the most common cause of blindness in developed countries [1]. It can affect all ages, for example, retinopathy of prematurity (ROP) in infants [2], [3], diabetic retinopathy (DR) [4] in working age adults and age-related macular degeneration (AMD) in elderly [5]. Due to ROP, huge numbers of premature infants lose their vision [6]. A report suggests that the DR causes 8% of the legal blindness among young adults in the United States [4]. Worldwide, a large number of elderly people are also affected by AMD. In the United States alone, more than 2 million elderly people are suffered from AMD [7]. Therefore, the angiogenesis of the eye may claim to be a significant public health problem globally. Several modern therapies like cryotherapy, laser therapy, and surgical interventions are important options to combat neovascular eye diseases. But these treatment options loss popularity due to the unwanted vision-damaging side effects [8]. Blocking the pathological angiogenesis in the eyes by anti-VEGF (anti-vascular endothelial growth factor) compounds including bevacizumab, ranibizumab, pegaptanib and aflibercept is the alternate treatment strategy. However, VEGF helps in the proliferation, migration and tube formation during angiogenic growth of normal blood vessels [9]. Therefore, targeting VEGF is detrimental for normal endothelial SynaptoRedTM C2 leading to adverse effects [10]. Till now, there is no FDA approved small molecules targeted to the treatment of ocular angiogenesis available in the market [11] though aflibercept and ranibizumab are FDA approved anti-VEGF drugs. These drugs exhibit their efficacy for the treatment of ocular neovascularization [12], [13]. However, small molecules such as pazopanib, squalamine, and vatalanib are in clinical investigations [11]. So, there is an earnest requirement of some novel safe small molecules targeting ocular neovascularization. Small molecules from natural origin like sunitinib, curcumin, withaferin, artemisinin, decursin, fumagillin, panduratin, homoisoflavanone etc. may be a promising option to treat neovascularization [14], [15]. In this article, homoisoflavonoids targeted to ocular neovascularization have been highlighted along with the betterment and refinement of their structures so that these can provide some fruitful information for better lead candidates in future.
Angiogenesis related to ocular diseases Angiogenesis is a balance between angiogenic and anti-angiogenic factors. It is related to vessel remodeling and maturation, endothelial cell migration as well as extracellular matrix degradation. As far as the ocular angiogenesis is concerned, the fragile vasculature is developed leading to fluid accumulation and inflammation in the ocular cavity along with hemorrhage which, in turn, results in corneal transparency as well as structural and functional alteration in retinal neurons leading to a loss of vision. This may further trigger fibrous scarring and retinal damage irreversibly and may lead to blindness [16], [17]. Photodynamic therapy, as well as laser photocoagulation, may be effective therapeutic strategies to treat retinal and choroidal neovascularization [18]. As vascular endothelial growth factor (VEGF) is the major angiogenic factor during neovascularization [19], a number of VEGF inhibitors namely aflibercept, bevacizumab, ranibizumab and pegaptanib are used to treat the disease [17]. All these drugs act through targeting the VEGF signaling pathway (Fig. 1). Though these are successfully used for age-related macular degeneration (AMD) patients, these may lead to a number of adverse effects such as stroke, myocardial infarction, non-ocular hemorrhage as well as delayed healing of wound [17], [20]. Intravitreous injection of these drugs may also lead to ocular hemorrhage, inflammation and retinal detachment [21].