Synthesis of a 2-aryl-3-aroyl indole salt (OXi8007) resembling combretastatin A-4 with application as a vascular disrupting agent.
Synthesis of a 2-aryl-3-aroyl indole salt (OXi8007) resembling combretastatin A-4 with application as a vascular disrupting agent.
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2-Aryl-3-芳酰吲哚盐（OXI8007）的合成类似于Combretastatin A-4，并用作血管破坏剂。
DOI：
10.1021/np400374w
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发表时间：
2013-09-27
影响因子：
5.1
通讯作者：
Pinney KG
中科院分区：
文献类型：
--
作者：
Hadimani MB;Macdonough MT;Ghatak A;Strecker TE;Lopez R;Sriram M;Nguyen BL;Hall JJ;Kessler RJ;Shirali AR;Liu L;Garner CM;Pettit GR;Hamel E;Chaplin DJ;Mason RP;Trawick ML;Pinney KG
天然产物秋水仙碱和考布他汀A-4（CA 4）是微管蛋白组装的有效抑制剂，并且它们激发了大量小分子潜在抗癌剂的设计和合成。基于吲哚的分子支架在这些SAR修饰中是突出的，导致药物数量迅速增加。通过化学合成制备2-芳基-3-芳酰基吲哚基苯酚8（OXi 8006）的水溶性磷酸酯前药33（OXi 8007），发现其对所选的人癌细胞系具有强细胞毒性（例如，对DU-145细胞的GI 50 = 36 nM）。游离苯酚8（OXi 8006）是微管蛋白组装的强抑制剂（IC 50 = 1.1 µM）。相应的磷酸酯前药33（OXi 8007）在初步体内研究中也显示出对肿瘤脉管系统的显著干扰，所述初步体内研究利用携带原位PC-3（前列腺）肿瘤的SCID小鼠模型，如通过彩色多普勒超声成像的。这些结果的组合提供了基于吲哚的磷酸酯前药33（OXi 8007）作为血管破坏剂（VDA）发挥作用的证据，其可证明可用于治疗癌症。
The natural products colchicine and combretastatin A-4 (CA4) 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 a 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 (VDA) that may prove useful for the treatment of cancer.
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影响因子：
3.2
作者：
Lee, Hsueh-Yun;Chang, Jang-Yang;Liou, Jing-Ping
通讯作者：
Liou, Jing-Ping
DOI：
10.1093/jnci/83.11.757
发表时间：
1991-06-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
MONKS, A;SCUDIERO, D;BOYD, M
通讯作者：
BOYD, M
DOI：
10.1016/0304-4165(81)90231-2
发表时间：
1981-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
HAMEL, E;LIN, CM
通讯作者：
LIN, CM
影响因子：
2.9
作者：
HAMEL, E;LIN, CM
通讯作者：
LIN, CM
影响因子：
5.7
作者：
Kremmidiotis, Gabriel;Leske, Annabell F.;Flynn, Bernard
通讯作者：
Flynn, Bernard