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  • In our former work our interest was

    2021-01-14

    In our former work, our interest was in discovery of novel VEGFR-2 inhibitors as anti-angiogenesis agents. Along this line, with natural alkaloid taspine as the lead compound, rounds of structure optimization were performed to develop novel VEGFR-2 inhibitors [[13], [14], [15]]. Among them, BPS-7, biphenyl-aryl urea incorporated with salicylal-doxime, has been developed as potent VEGFR-2 inhibitor. It significantly inhibited the proliferation of human umbilical vein endothelial cells, and also effectively inhibited blood vessel formation in a tissue model for angiogenesis. Further mechanism study revealed that this blue nitro displayed selective inhibition against TIE-2 and EphB4 besides VEGFR-2 [16], making the design of multiple kinase inhibitors feasible. Based on above findings, BPS-7 was used as leading compound in our continued work for developing novel multiple RTKs inhibitors as anti-angiogenesis agents. By doing interaction analysis of BPS-7 with RTKs, we dissected the lead into four regions as shown in Fig. 2 for optimization work. Based on this model, various modification targeting hinge binding group (HBG), crucial for inhibitors' affinity, has been performed to discover original chemotypes. As is known, urea unit, interacting with DFG-motif, is another key part for kinase inhibitors’ binding, thus optimization of DFG-motif interacting group is imperative. Therefore, the work described here is focused on modification of group interacting with DFG-motif. Inspired by bioisosteric paradigm, urea moiety was replaced with 1,2,3-trizole which may bears more hydrogen bond donors and acceptors, providing novel scaffold for multiple RTKs inhibitors. In addition, other three parts were also modified according to our previous work, exploring triple kinase inhibitors with novel scaffold. First, pyridine and 2-methoxy pyridine was incorporated as new HBG of multiple inhibitors, supposing that it might simultaneously form hydrogen bonds with hinge of three RTKs to improve affinity toward three targets. Second, the two methoxyl groups on biphenyl of BSP-7 were removed to reduce the steric hindrance of inhibitors when binding with receptors. Third, various anilines were incorporated as they are beneficial for anti-tumor potency and could enhance the persistence [17]. Encouraged by previous results, we proposed that multiple RTKs-inhibition could afford novel anti-angiogenic agents. Herein, we performed the design, synthesis and biological evaluation of pyridine series compounds. Several pyridine derivatives incorporated with 1,2,3-trizole displayed promising anti-angiogenic potency. The representative compound BD-7 could be considered as a promising lead compound for further structural optimization.
    Results and discussion
    Conclusion Herein, we described the triple inhibitors of VEGFR-2/Tie-2/EphB4 as potential anti-angiogenic agents. Since these RTKs play essential roles in angiogenesis. These multiple inhibitors might be potent to prevent the resistance of single-target drugs. 1,2,3-Trizole was firstly introduced to diaryl urea core as DFG-binding group while various pyridines as hinge-binding group. Finally, a series of pyridine derivatives incorporated with 1,2,3-trizole as multiple inhibitors were designed, synthesized, and evaluated. The biological results indicated that BD7 displayed simultaneous inhibition of VEGFR-2, Tie-2, and EphB4. Meanwhile, it displayed the most potent anti-proliferative activity against human vascular endothelial cell (EA.hy926) comparable to sorafenib. Moreover, Molecular modeling revealed that these compounds could suppress VEGFR-2, Tie-2, and EphB4 kinase activity through preferential binding at the ATP-binding site. In conclusion, our results identified the rationality of design strategies of triple VEGFR-2/Tie-2/EphB4 inhibitors as novel anti-angiogenic agents. Among them, BD7 could be considered as a promising starting point for further optimization of 1,2,3-trizole incorporated derivatives as VEGFR-2/Tie-2/EphB4 inhibitors. Our findings may contribute to the discovery of novel anti-angiogenic agents for the intervention of pathological angiogenesis-related diseases.