Department of Chemistry and Biochemistry, Baylor University , One Bear Place #97348, Waco, Texas 76798-7348, United States.
J Nat Prod. 2013 Sep 27;76(9):1668-78. doi: 10.1021/np400374w. Epub 2013 Sep 9.
The natural products colchicine and combretastatin A-4 are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI₅₀ = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC₅₀ = 1.1 μM) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent that may prove useful for the treatment of cancer.
天然产物秋水仙碱和康普瑞汀 A-4 是微管组装的有效抑制剂，它们激发了大量小分子潜在抗癌药物的设计和合成。吲哚基分子支架是这些 SAR 修饰中突出的一种，导致越来越多的药物出现。通过化学合成制备了 2-芳基-3-芳酰基吲哚基酚 8（OXi8006）的水溶性磷酸盐前药 33（OXi8007），并发现其对选定的人类癌细胞系具有很强的细胞毒性（例如，对 DU-145 细胞的 GI₅₀=36 nM）。游离酚 8（OXi8006）是微管组装的强抑制剂（IC₅₀=1.1 μM）。相应的磷酸盐前药 33（OXi8007）在初步的体内研究中也表现出对肿瘤血管的明显干扰，该研究利用 SCID 小鼠模型，对原位 PC-3（前列腺）肿瘤进行彩色多普勒超声成像。这些结果表明，吲哚基磷酸盐前药 33（OXi8007）作为一种血管破坏剂发挥作用，可能对癌症治疗有用。
