Eldehna Wagdy M, Abou-Seri Sahar M, El Kerdawy Ahmed M, Ayyad Rezk R, Hamdy Abdallah M, Ghabbour Hazem A, Ali Mamdouh M, Abou El Ella Dalal A
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Molecular Modeling Unit, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
Eur J Med Chem. 2016 May 4;113:50-62. doi: 10.1016/j.ejmech.2016.02.029. Epub 2016 Feb 15.
A series of anilinophthalazine derivatives 4a-j was initially synthesized and tested for its VEGFR-2 inhibitory activity where it showed promising activity (IC50 = 0.636-5.76 μM). Molecular docking studies guidance was used to improve the binding affinity for series 4a-j towards VEGFR-2 active site. This improvement was achieved by increasing the hydrophobic interaction with the hydrophobic back pocket of the VEGFR-2 active site lined with the hydrophobic side chains of Ile888, Leu889, Ile892, Val898, Val899, Leu1019 and Ile1044. Increasing the hydrophobic interaction was accomplished by extending the anilinophthalazine scaffold with a substituted phenyl moiety through an uriedo linker which should give this extension the flexibility required to accommodate itself deeply into the hydrophobic back pocket. As planned, the designed uriedo-anilinophthalazines 7a-i showed superior binding affinity than their anilinophthalazine parents (IC50 = 0.083-0.473 μM). In particular, compounds 7g-i showed IC50 of 0.086, 0.083 and 0.086 μM, respectively, which are better than that of the reference drug sorafenib (IC50 = 0.09 μM).
最初合成了一系列苯胺基酞嗪衍生物4a-j，并对其VEGFR-2抑制活性进行了测试，结果显示出有前景的活性（IC50 = 0.636 - 5.76 μM）。利用分子对接研究指导来提高4a-j系列对VEGFR-2活性位点的结合亲和力。这种提高是通过增加与VEGFR-2活性位点疏水后口袋的疏水相互作用来实现的，该口袋由Ile888、Leu889、Ile892、Val898、Val899、Leu1019和Ile1044的疏水侧链排列而成。通过用取代苯基部分通过脲基连接子扩展苯胺基酞嗪支架来增加疏水相互作用，这应该赋予这种扩展深入疏水后口袋所需的灵活性。按计划，设计的脲基-苯胺基酞嗪7a-i显示出比其苯胺基酞嗪母体更高的结合亲和力（IC50 = 0.083 - 0.473 μM）。特别是，化合物7g-i的IC50分别为0.086、0.083和0.086 μM，优于参考药物索拉非尼（IC50 = 0.09 μM）。
