Asymmetric synthesis and biological evaluation of Danshensu derivatives as anti-myocardial ischemia drug candidates
Asymmetric synthesis and biological evaluation of Danshensu derivatives as anti-myocardial ischemia drug candidates
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抗心肌缺血候选药物丹参素衍生物的不对称合成及生物学评价
DOI：
10.1016/j.bmc.2009.02.065
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发表时间：
2009-05-01
影响因子：
3.5
通讯作者：
Zhu, Yi Zhun
中科院分区：
文献类型：
--
作者：
Dong, Cunnan;Wang, Yang;Zhu, Yi Zhun
本文报道了丹参素衍生物（R）-2-乙酰氧基-3-（3，4-二乙酰氧基苯基）丙酸甲酯（1a）、（R）-2-乙酰氧基-3-（3，4-亚甲二氧基苯基）丙酸甲酯（1b）及其外消旋体7和10的合成及生物活性。这些衍生物的设计，以提高其化学稳定性和脂溶性，通过保护丹参素的酚羟基与乙酰基或亚甲基，可以很容易地水解，以释放生物活性丹参素。以（Z）-2-乙酰氧基-3-（3，4-二乙酰氧基苯基）-2-丙烯酸甲酯（6a）和（Z）-2-乙酰氧基-3-（3，4-亚甲二氧基苯基）-2-丙烯酸甲酯（6 b）为原料，催化氢化合成了1a和1b，对映体过量分别为92%ee和98%ee，产率>89%。通过将反应温度保持在60 ℃，以高化学选择性以86%的产率获得了意想不到的中间产物（Z）-2-乙酰氧基-3-（3，4-二羟基苯基）丙烯酸（4c），并通过X射线单晶衍射分析鉴定了其结构。1a、1b及其外消旋体7、10和4c对缺氧诱导的细胞损伤具有较强的保护活性。体外实验表明，这些化合物均能提高细胞活力，抑制脂质过氧化。1a和4c通过在基因和蛋白水平上调节凋亡相关分子的表达，上调bcl-2的表达，下调bax和caspase-3的表达，从而抑制细胞凋亡。体内实验表明，4c具有抗心肌缺血作用，其特征在于减少梗死面积和增加血清中可检测到的细胞内酶水平。因此，这些丹参素衍生物可能是抗心肌缺血治疗的良好候选药物，值得进一步研究。(C)2009爱思唯尔有限公司保留所有权利。
The synthesis and bioactivities of Danshensu derivatives (R)-methyl 2-acetoxy-3-(3,4-diacetoxyphenyl) propanoate (1a), (R)-methyl 2-acetoxy-3-(3,4-methylenedioxyphenyl) propanoate (1b) and their racemates 7 and 10 were reported in this paper. These derivatives were designed to improve their chemical stability and liposolubility by protecting Danshensu's phenolic hydroxyl groups with acetyl or methylene which could be readily hydrolyzed to release bioactive Danshensu. The asymmetric synthesis of 1a and 1b were achieved by catalytic hydrogenation of (Z)-methyl 2-acetoxy-3-(3,4-diacetoxyphenyl)-2-propenoate (6a) and (Z)-methyl 2-acetoxy-3-(3,4-methylenedioxyphenyl)-2-propenoate (6b) in excellent enantiomeric excesses (92% ee and 98% ee, respectively) and good yields (>89%). An unexpected intermediate product, (Z)-2-acetoxy-3-(3,4-dihydroxyphenyl) acrylic acid (4c) was obtained with high chemoselectivity in 86% yield by keeping the reaction temperature at 60 degrees C and its structure was identified by Xray single crystal diffraction analysis. 1a, 1b and their racemates 7, 10 as well as 4c exhibited potent protective activities against hypoxia-induced cellular damage. The in vitro test showed that all these compounds could increase cell viability, and inhibit lipid hyperoxidation. Furthermore, 1a and 4c could inhibit apoptosis by regulating the expression of apoptosis-related molecule in gene and protein levels, up-regulating the expression of bcl-2 and down-regulating bax and caspase-3. The in vivo test indicated that 4c exhibited anti-myocardial ischemic effects featured by reducing infarction size and increasing the level of the intracellular enzymes detectable in serum. Therefore, these Danshensu derivatives may be good drug candidates for anti-myocardial ischemia therapy and merit further investigation. (C) 2009 Elsevier Ltd. All rights reserved.