Combretastatin A-4磷酸酯盐的合成研究

摘要：CA-4磷酸酯盐(Combretastatin A-4 disodium phosphate ,CA-4P)是抗肿瘤药CA-4的一种前药，与CA-4相比，CA-4P的水溶性更强,易于体内给药。CA-4P不同于传统微管蛋白抑制剂,在小于1/10最大耐受剂量( MTD) 时即可发挥抗肿瘤作用,导致肿瘤血管关闭、坏死。随着人类肿瘤发病率的升高，对抗肿瘤药的需求也与日俱增。目前使用的抗肿瘤药副作用大、选择性差。而CA-4P作为一种天然产物的前药，在很大程度上克服了上述缺陷，随着对其研究的不断深入，可望成为新型抗肿瘤药。58057

本论文的研究内容分为以下两个部分：

1.以CA-4为原料经过与亚磷酸二苄酯成酯以及脱苄基成钠盐一系列反应合成了CA-4磷酸二钠盐。

2.以3,4,5-三甲氧基-3'-羟基-4'-乙氧基二苯乙烷为原料，通过两种不同的方法合成了3,4,5-三甲氧基-4'-乙氧基二苯乙烷3'-O-磷酸二钠盐。

毕业论文关键词： CA-4P；抗肿瘤；前药；合成

Study on the synthesis of Combretastatin A-4 phosphate

Abstract: CA-4 phosphate salt (Combretastatin A-4 disodium phosphate, CA-4P ) is a prodrug of CA-4 as a antitumor drug. Compared with CA-4, CA-4P is better water-soluble and easier to be delivered in vivo. Different from the traditional tubulin inhibitors, CA-4P can exert antitumor effects in less than 1/10 of the maximum tolerated dose (MTD) that cause tumor vasculature shutdown and necrosis. With increase of human tumor incidence, the demand for antitumor drugs is increasing. Current used antitumor drugs are high side effect and poor selectivity. CA-4P, as a prodrug of natural product, overcomes the defects in a large extent and expected to become new antitumor drug by deepening of research.

This dissertation was mainly consisting of the following two parts:

1. Combretastatin A-4 disodium phosphate was prepared from CA-4 as the starting material, through dibenzyl phosphorylation reaction, deprotection and disodium salt formation.

2. The target product 3,4,5-trimethoxy-4'-ethoxydiphenyl ethane-3'-o-disodium phosphate was prepared from 3,4,5-trimethoxy-3'-hydroxy-4'-ethoxydiphenyl ethane as the starting material through two different synthetic methods.

Keywords: Combretastatin A-4 disodium phosphate; antitumor; prodrug; synthesis

1 引言 1

1.1　研究背景 1

1.2　抗肿瘤药物的分类 1

1.2.1 天然抗肿瘤药物 1

1.2.2 细胞毒类抗肿瘤药物 2

1.2.3 肿瘤新生血管生成抑制类药物 2

1.2.4 抗代谢类抗肿瘤药物 3

1.2.5 肿瘤耐药逆转剂 3

1.2.6 以细胞信号转导分子为靶点的抗肿瘤药物 3

1.2.7 分化诱导剂 3

1.2.8 基因调节药物 3

1.2.9 单克隆抗体药物 4

1.3 新型肿瘤生成抑制剂CA-4简介 4

1.4　CA-4P简介 5

1.5 CA-4的药理作用及作用机制 5

1.6 CA-4P的药理作用及作用机制 6

2 Combretastatin A-4磷酸酯盐的设计与合成研究 8

2.1 Combretastatin A-4P的研究 8

2.2 3,4,5,4'-四甲氧基-顺式-二苯乙烯-3'-o-磷酸二钠盐的合成 Combretastatin A-4磷酸酯盐的合成研究:http://www.751com.cn/yixue/lunwen_62988.html