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  • SB742457 In our previous research we have focused on


    In our previous research, we have focused on the discovery of novel VEGFR-2 inhibitors as anti-angiogenesis agents. Numbers of biphenyl-aryl urea incorporated with salicylaldoxime including BPS-7 have been developed as potent and selective VEGFR-2 inhibitors (Fig. 3) [12], [13], [14], [15], [16], [17]. Based on conserved active sites of three angiogenic RTKs (VEGFR-2, Tie-2, and EphB4) and similar interaction conformation of inhibitors with them, we propose that the rational design of triple inhibitors of VEGFR-2/Tie-2/EphB4 is a promising strategy for discovery of anti-angiogenesis agents. Extensive structural optimization was conducted to expand structural SB742457 and improve activity using following strategies (Fig. 3): (i) We explored various aromatic-heterocyclics as hinge binding group (HBG) via core-refining approach. Pyridin-2-amine, N-(pyridin-2-yl)acrylamide, quinoxalin-2-amine, and quinazolin-4(3H)-one were introduced as novel HBG. These heterocyclics bearing various hydrogen bond donors or acceptors could retain the essential hydrogen bonds with hinge region of RTKs. We supposed that these groups might simultaneously form hydrogen bonds with hinge region of three RTKs and therefore provide an opportunity to improve affinity with receptors; (ii) The two methoxyl groups on biphenyl were removed to reduce the steric hindrance of ligands binding with receptors. In addition, we investigated the effect of position of urea on their biological activity; (iii) Inspired by the classic bioisosteric paradigm, urea moiety was replaced with cyclopropane-1,1-dicarboxamide which bears more hydrogen bond donors and acceptors; (iv) Aniline bearing halogen substituents is beneficial for antitumor potency and halogen could enhance the persistence and lipid solubility [18]. Therefore, various anilines bearing halogen were incorporated to develop novel anti-angiogenesis agents. In addition, other anilines containing morpholine side chain, tert-butyl, alkynyl, or benzo[d] [1,3]dioxole were also incorporated at terminal as fragments interacting with active site. Herein, we performed the design, synthesis, and biological evaluation of three classes of triple inhibitors of VEGFR-2, Tie-2, and EphB4. Several biphenyl-aryl ureas incorporated with quinazolin-4(3H)-one displayed promising anti-angiogenic and anti-cancer potency. The representative compound VDAU11 could be considered as a promising lead compound for further structural optimization.
    Results and discussion
    Conclusion In summary, we described the triple inhibitors of VEGFR-2/TIE-2/EphB4 as potential anti-angiogenesis and anticancer agents. N-(pyridin-2-yl)acrylamide was firstly introduced to diaryl urea core as hinge-binding group of triple inhibitors. The biological results indicated that VDAU11 displayed stimultaneous inhibition of VEGFR-2, TIE-2 and EphB4 and is marginally better than the positive control (Sorafenib) in two of three inhibitors. Meanwhile, it displayed the most potent antiproliferative activity against human vascular endothelial cell (EA. hy926). In addition, VDAU11 exhibited comparable anticancer activity compared with sorafenib. Several title compounds (CPMA1, CPMA5, CPMA6, CPMA7, VDAU2, VDAU11, QZAU4, and QZAU5) exhibited simultaneous inhibition against VEGFR-2, TIE-2 and EphB4, three angiogenic RTK. They might be considered as novel lead compound for further discovery of triple RTK inhibitors as anti-angiogenesis and anticancer agents. They might not only inhibit the process of angiogenesis, but also prevent drug resistance. Moreover, biological evaluation and molecular docking indicated that N-(pyridin-2-yl)acrylamide was beneficial for potency of these triple inhibitors. It could be considered as a novel hinge-binding group for further discovery of novel anti-angiogenesis agents.
    Experimental section
    Acknowledgments This work was supported by the National Natural Science Foundation of China (NSFC, Grant No. 81573285) and the Fundamental Research Funds for the Central Universities (2015qngz13).