Capitosti Scott M, Hansen Todd P, Brown Milton L
Department of Chemistry, University of Virginia, McCormick Road, PO Box 400319, Charlottesville, VA 22904, USA.
Bioorg Med Chem. 2004 Jan 15;12(2):327-36. doi: 10.1016/j.bmc.2003.11.007.
The identification of agents with antiproliferative activity against endothelial cells has significant value for the treatment of many angiogenesis-dependent pathologies. Herein, we describe the discovery of a series of thalidomide analogues possessing inhibitory effects against both endothelial and prostate cancer cells. More specifically, several analogues exhibited low micromolar to mid-nanomolar potency in the inhibition of human microvascular endothelial cell (HMEC) proliferation, both in the presence and absence of vascular endothelial growth factor (VEGF), with the tetrafluorophthalimido class of compounds demonstrating the greatest potency. Additionally, all the compounds were screened against two different androgen independent prostate cancer cell lines (PC-3 and DU-145). Again, the tetrafluorophthalimido analogues exhibited the greatest effect with GI(50) values in the low micromolar range. Thalidomide was found to demonstrate selective inhibition of androgen receptor positive LNCaP prostate cancer cells. Furthermore, we showed that, as an example, tetrafluorophthalimido analogue 19 was able to completely inhibit the prostate specific antigen (PSA) secretion by the LNCaP cell line, while thalidomide demonstrated a 70% inhibition. We have also demonstrated that a correlation exists between HMEC and prostate cancer cell proliferation for this structural class. Altogether, our study suggests that these analogues may serve as promising leads for the development of agents that target both androgen dependent and independent prostate cancer and blood vessel growth.
鉴定对内皮细胞具有抗增殖活性的药物对于治疗许多依赖血管生成的疾病具有重要价值。在此，我们描述了一系列对内皮细胞和前列腺癌细胞均具有抑制作用的沙利度胺类似物的发现。更具体地说，几种类似物在有和没有血管内皮生长因子（VEGF）的情况下，对人微血管内皮细胞（HMEC）增殖的抑制作用表现出低微摩尔至中纳摩尔的效力，其中四氟邻苯二甲酰亚胺类化合物显示出最大的效力。此外，所有化合物都针对两种不同的雄激素非依赖性前列腺癌细胞系（PC-3和DU-145）进行了筛选。同样，四氟邻苯二甲酰亚胺类似物表现出最大的效果，其GI(50)值在低微摩尔范围内。发现沙利度胺对雄激素受体阳性的LNCaP前列腺癌细胞具有选择性抑制作用。此外，我们表明，例如，四氟邻苯二甲酰亚胺类似物19能够完全抑制LNCaP细胞系分泌前列腺特异性抗原（PSA），而沙利度胺显示出70%的抑制率。我们还证明了对于这一结构类别，HMEC和前列腺癌细胞增殖之间存在相关性。总之，我们的研究表明，这些类似物可能成为开发针对雄激素依赖性和非依赖性前列腺癌以及血管生长的药物的有前景的先导物。
