Erlotinib br Small molecule homoisoflavonoid in combination

Small molecule homoisoflavonoid in combination with anti-VEGF therapy Basavarajappa et al. [11] reported a new synthetic homoisoflavonoid compound, SH-11037 by modifying the structure of naturally occurring homoisoflavonoid cremastranone. SH-11037 exhibited promising inhibition of human retinal microvascular endothelial cell (HREC) as well as migration along with inhibition of matrigel tube formation and thus, proved to be a promising Erlotinib against angiogenesis [11]. In ex vivo mouse choroidal sprouting assay, SH-11037 was found to inhibit sprout formation in choroidal tissue in a dose-dependent manner [39]. At 10μM dose, it also reduced a 40% decrease in the hyaloid vessel and hyaloid vessel branch development as evidenced in a zebrafish larvae model that is also an indication of good ocular angiogenic activity [39]. Moreover, it did not produce any ocular toxicity without affecting retinal function and pre-existing vessels and was found to reduce choroidal neovascularization (CNV) lesion volume as evidenced in a laser-induced CNV (L-CNV) mouse model [39]. Again, intravitreal administration of SH-11037 reduced 55% CNV lesion volume in a CB7BL/6J mouse model that was comparable to the anti-VEGF164 antibody treatment [39]. In combination with standard anti-VEGF drug aflibercept in different concentrations, 0.5μM of SH-11037 significantly reduced HREC proliferation and the combination therapy was found to be better effective than the single drug therapy. Moreover, a significant synergistic anti-neovascularization effect was noticed in combination of SH-11037 and anti-VEGF164 when tested in L-CNV mouse model [39]. Therefore, the structural modification of SH-11037 may increase the chance of obtaining a better lead molecule that should be utilized further to treat ocular neovascularization in combination with anti-VEGF drugs. In this connection, molecular modeling strategies may contribute to the identification of better effective homoisoflavonoid lead molecules compared to the existing ones.
Comparative chemometric modelling on some homoisoflavonoids Currently, computational methodologies have become a crucial component of drug discovery programs, from hit identification to lead optimization and beyond [40], [41], [42]. Consequently, various approaches have been developed to shorten the research cycle and reduce the expense and risk of failure for drug discovery [43]. Based on the flavonol compound cremastranone (cpd 2) having potential antiangiogenic activity in retinal neovascularization, Basavarajappa et al. [11] designed a series of homoisoflavonoids (cpd 15–53) (Table 1). The best compound 15 (SH-11037) was found to exhibit the potential antimigratory activity of HRECs at a lower micromolar concentration in the matrigel tube formation assay. It was also found to arrest the G2/M phase cellular growth in a dose-dependent manner [11]. In this context, we performed chemometric computational approaches on these homoisoflavonoid compounds (cpd 15–53) (Table 1) to refine the structures of these compounds for achieving potential antiangiogenic agents targeted to ocular neovascularization. Therefore, statistically robust 2D-QSAR equations were constructed by using stepwise multiple linear regression (S-MLR), factor analysis-multiple linear regression (FA-MLR) and principal component regression analysis (PCRA) methods and the effectiveness of 2D-QSAR results were validated with external parameters. Additionally, support vector machine (SVM), artificial neural network (ANN) and classification-based QSAR methodologies were also carried out. The findings enlightened some of the molecular features of homoisoflavonoids necessary to inhibit the growth of the human retinal microvascular endothelial cell (HREC).
Future perspective As far as the ocular neovascularization is concerned, a number of people have been suffering from this disease worldwide. Apart from the photodynamic therapy and laser photocoagulation, a number of drugs may be used for the treatment of ocular neovascularization though possess adverse effects. Therefore, small antiangiogenic molecules with higher potency and lower toxic effects are still in demand. However, a number of small molecules from natural origin express their antiangiogenic effects used in the treatment of ocular neovascularization. In this article, homoisoflavonoids being the potential antiangiogenic agents in the treatment of ocular neovascularization have been highlighted in details. Moreover, these homoisoflavonoids are quantitatively judged in terms of statistical validation through multi-chemometric modeling approaches for the betterment and refinement of their structures required for higher antiangiogenic activity targeted to ocular neovascularization. The molecular modeling study of these homoisoflavoinoids has been taken into consideration as this may provide important structural information for obtaining potential lead molecules that may be utilized further in combination with anti-VEGF therapy against ocular neovascularization. However, further modifications of these structures were also done to enhance the antiangiogenic activity. Benzophenone photoaffinity probe was tagged with the homoisoflavonoid structure along with biotin reporter and a polyethylene glycol (PEG) linker function to enhance the antiangiogenic activity profile [62]. Depending on the position of the photoaffinity probe attachment, the inhibitory activity may vary. Attachment of the photoaffinity probes linking at the C-3′ position of the phenolic group was found to be highly potent antiangiogenic agent whereas C-7 probe compounds reduced the activity drastically. Cpd 54 (Fig. 5) showed the best HREC inhibitory potency (IC50=72nM). About 3-fold decrease in HREC inhibition was noticed for cpd 55 (IC50=210nM). Cpd 56 and 57 drastically reduced the inhibition (IC50=42 and 44μM).