Regioselective synthesis of water-soluble monophosphate derivatives of combretastatin A-1.
Regioselective synthesis of water-soluble monophosphate derivatives of combretastatin A-1.
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DOI：
10.1021/np200104t
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发表时间：
2011-07-22
影响因子：
5.1
通讯作者：
Pinney KG
中科院分区：
文献类型：
--
作者：
Tanpure RP;Nguyen BL;Strecker TE;Aguirre S;Sharma S;Chaplin DJ;Siim BG;Hamel E;Lippert JW;Pettit GR;Trawick ML;Pinney KG
天然产物combretastatin A-4 （CA4）和combretastatin A-1 （CA1）是有效的肿瘤血管破坏剂（VDAs）和微管蛋白组装抑制剂（IC50 = 1 ~ 2 μM）。磷酸化的前药CA4P和CA1P正在进行抗癌的人体临床试验。CA1是独特的，因为它的邻酚的掺入，这提供了机会，以制备二磷酸和区域异构体的单磷酸衍生物。在这里，我们描述了第一个适合于区域特异性制备ca1 -单磷酸盐，CA1MPA （8a/b）和CA1MPB （4a/b）的合成路线。必要的区域化学，以区分两个邻近的酚群是完成与托基保护组策略。四种单磷酸类似物（包括Z和E异构体）在体外对选定的人类癌细胞系的细胞毒性与相应的二磷酸同系物相当。此外，Z-CA1MPA （8a）和Z-CA1MPB （4a）作为微管蛋白组装抑制剂（IC50 bb0 40 μM）是无活性的，正如在纯蛋白实验中预期的那样。
The natural products combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent cancer vascular disrupting agents (VDAs) and inhibitors of tubulin assembly (IC50 = 1–2 μM). The phosphorylated prodrugs CA4P and CA1P are undergoing human clinical trials against cancer. CA1 is unique due to its incorporation of a vicinal phenol, which has afforded the opportunity to prepare both diphosphate and regioisomeric monophosphate derivatives. Here, we describe the first synthetic routes suitable for the regiospecific preparation of the CA1-monophosphates, CA1MPA (8a/b) and CA1MPB (4a/b). The essential regiochemistry necessary to distinguish between the two vicinal phenolic groups was accomplished with a tosyl protecting group strategy. Each of the four monophosphate analogues (including Z and E isomers) demonstrated in vitro cytotoxicity against selected human cancer cell lines comparable to their corresponding diphosphate congeners. Furthermore, Z-CA1MPA (8a) and Z-CA1MPB (4a) were inactive as inhibitors of tubulin assembly (IC50 > 40 μM), as anticipated in this pure protein assay.
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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
影响因子：
3.5
作者：
Monk, KA;Siles, R;Pinney, KG
通讯作者：
Pinney, KG
影响因子：
6.6
作者：
Mooney, Colin J.;Nagaiah, Govardhanan;Remick, Scot C.
通讯作者：
Remick, Scot C.
影响因子：
5.1
作者：
Pettit, George R.;Thornhill, Andrew J.;Moser, Bryan R.;Hogan, Fiona
通讯作者：
Hogan, Fiona
影响因子：
7.3
作者：
Pettit, GR;Toki, B;Pettit, RK
通讯作者：
Pettit, RK