Department of Pharmaceutical Biochemistry, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
Bioorg Med Chem Lett. 2013 Apr 1;23(7):2083-8. doi: 10.1016/j.bmcl.2013.01.125. Epub 2013 Feb 10.
Previously, we have found that BRN-103, a nicotinamide derivative, inhibits vascular endothelial growth factor (VEGF)-mediated angiogenesis signaling in human endothelial cells. During our continuous efforts to identify more potent anti-angiogenic agents, we synthesized various nicotinamide derivatives and evaluated their anti-angiogenic effects. We found that 2-{1-[1-(6-chloro-5-fluoropyrimidin-4-yl)ethyl]piperidin-4-ylamino}-N-(3-chlorophenyl) pyridine-3-carboxamide (BRN-250) significantly inhibited human umbilical vascular endothelial cells (HUVECs) proliferation, migration, tube formation, and microvessel growth in a concentration range of 10-100 nM. Furthermore, BRN-250 inhibited the VEGF-induced phosphorylation and intracellular tyrosine kinase activity of VEGF receptor 2 (VEGFR2) and the activation of its downstream AKT pathway. Taken together, these findings suggest that BRN-250 be considered a potential lead compound for cancer therapy.
先前，我们发现烟酰胺衍生物 BRN-103 能够抑制人血管内皮细胞中血管内皮生长因子 (VEGF) 介导的血管生成信号。在我们不断努力寻找更有效的抗血管生成剂的过程中，我们合成了各种烟酰胺衍生物，并评估了它们的抗血管生成作用。我们发现 2-{1-[1-(6-氯-5-氟嘧啶-4-基)乙基]哌啶-4-基氨基}-N-(3-氯苯基)吡啶-3-甲酰胺 (BRN-250) 在 10-100 nM 的浓度范围内显著抑制人脐静脉内皮细胞 (HUVEC) 的增殖、迁移、管形成和微血管生长。此外，BRN-250 抑制了 VEGF 诱导的 VEGFR2 磷酸化和细胞内酪氨酸激酶活性及其下游 AKT 途径的激活。综上所述，这些发现表明 BRN-250 可被视为癌症治疗的潜在先导化合物。
