Pavic Aleksandar, Glišić Biljana Đ, Vojnovic Sandra, Warżajtis Beata, Savić Nada D, Antić Marija, Radenković Slavko, Janjić Goran V, Nikodinovic-Runic Jasmina, Rychlewska Urszula, Djuran Miloš I
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Serbia.
University of Kragujevac, Faculty of Science, Department of Chemistry, R. Domanovića 12, PO Box 60, 34000 Kragujevac, Serbia.
J Inorg Biochem. 2017 Sep;174:156-168. doi: 10.1016/j.jinorgbio.2017.06.009. Epub 2017 Jun 27.
Gold(III) complexes with 1,7- and 4,7-phenanthroline ligands, [AuCl(1,7-phen-κN7)] (1) and [AuCl(4,7-phen-κN4)] (2) were synthesized and structurally characterized by spectroscopic (NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques. In these complexes, 1,7- and 4,7-phenanthrolines are monodentatedly coordinated to the Au(III) ion through the N7 and N4 nitrogen atoms, respectively. In comparison to the clinically relevant anti-angiogenic compounds auranofin and sunitinib, gold(III)-phenanthroline complexes showed from 1.5- to 20-fold higher anti-angiogenic potential, and 13- and 118-fold lower toxicity. Among the tested compounds, complex 1 was the most potent and may be an excellent anti-angiogenic drug candidate, since it showed strong anti-angiogenic activity in zebrafish embryos achieving IC value (concentration resulting in an anti-angiogenic phenotype at 50% of embryos) of 2.89μM, while had low toxicity with LC value (the concentration inducing the lethal effect of 50% embryos) of 128μM. Molecular docking study revealed that both complexes and ligands could suppress angiogenesis targeting the multiple major regulators of angiogenesis, such as the vascular endothelial growth factor receptor (VEGFR-2), the matrix metalloproteases (MMP-2 and MMP-9), and thioredoxin reductase (TrxR1), where the complexes showed higher binding affinity in comparison to ligands, and particularly to auranofin, but comparable to sunitinib, an anti-angiogenic drug of clinical relevance.
合成了含有1,7 - 菲咯啉和4,7 - 菲咯啉配体的金(III)配合物[AuCl(1,7 - phen - κN7)] (1)和[AuCl(4,7 - phen - κN4)] (2)，并通过光谱（核磁共振、红外和紫外可见光谱）和单晶X射线衍射技术对其进行了结构表征。在这些配合物中，1,7 - 菲咯啉和4,7 - 菲咯啉分别通过N7和N4氮原子单齿配位到Au(III)离子上。与临床相关的抗血管生成化合物金诺芬和舒尼替尼相比，金(III)-菲咯啉配合物显示出高1.5至20倍的抗血管生成潜力，以及低13至118倍的毒性。在测试的化合物中，配合物1最为有效，可能是一种优秀的抗血管生成药物候选物，因为它在斑马鱼胚胎中显示出强大的抗血管生成活性，IC值（导致50%胚胎出现抗血管生成表型的浓度）为2.89μM，而毒性较低，LC值（诱导50%胚胎产生致死效应的浓度）为128μM。分子对接研究表明，配合物和配体都可以通过靶向血管生成的多个主要调节因子来抑制血管生成，如血管内皮生长因子受体(VEGFR - 2)、基质金属蛋白酶(MMP - 2和MMP - 9)以及硫氧还蛋白还原酶(TrxR1)，其中配合物与配体相比显示出更高的结合亲和力，特别是与金诺芬相比，但与临床相关的抗血管生成药物舒尼替尼相当。
