Synthesis of acid-labile diplasmenyl lipids for drug and gene delivery applications
Synthesis of acid-labile diplasmenyl lipids for drug and gene delivery applications
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DOI：
10.1016/s0009-3084(99)00033-x
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发表时间：
1999-06-01
影响因子：
3.4
通讯作者：
Thompson, DH
中科院分区：
文献类型：
--
作者：
Boomer, JA;Thompson, DH
内体区室和缺血组织所特有的低pH环境为从适当设计的递送载体触发位点特异性内容物释放提供了一种内在途径。因此，该研究小组专注于新型酸敏感脂质的设计、合成及应用，这些脂质在这些酸性位点内会容易地从层状（L -α）相转变为六方（H - II）相。先前已经证明，缩醛磷脂酰胆碱型脂质具有出色的酸水解和内容物释放动力学（杰拉西莫夫等人，《生物化学与生物物理学报》1324卷（1997年）200 - 214页；芮等人，《美国化学会志》120卷（1998年）11213 - 11218页）。本文描述了基于手性1,2 - 二 - O -（1Z',9Z' - 十八碳二烯基）- sn - 甘油（6）平台合成的三种新的酸敏感脂质，它们分别具有磷酸胆碱（7）、聚（环氧乙烷）（8）和O - 氨甲酰基 - N - 二亚乙基三胺（10）头部基团。中间体6通过从（S）-（+）- 2,2 - 二甲基 - 1,2 - 二氧戊环 - 4 - 甲醇经过六步合成，总产率为28%。随后转化为最终产物的产率从中等（7和10）到优异（8）不等。（C）1999年爱思唯尔科学爱尔兰有限公司。保留所有权利。
The low pH environments characteristic of endosomal compartments and ischemic tissues provide an intrinsic pathway for triggering site-specific contents release from appropriately designed delivery vehicles. Accordingly, research in this group has focused on the design, synthesis and application of novel acid-sensitive lipids that will undergo facile lamellar (L-alpha) to hexagonal (H-II) phase transitions within these acidic sites. Previously, it has been demonstrated that plasmenylcholine-type lipids have: excellent acid hydrolysis and contents release kinetics (Gerasimov et al., Biochim. Biophys. Acta. 1324 (1997) 200-214; Rui et al., J. Am. Chem. Sec. 120 (1998) 11213-11218). This paper describes the synthesis of three new acid sensitive lipids, based on a chiral 1,2-di-O-(1Z',9Z'-octadecadienyl)-sn-glycerol (6) platform, displaying phosphocholine (7), poly(ethyleneoxide) (8), and O-carbamoyl-N-diethylenetriamine (10) headgroups. Intermediate 6 was obtained in 28% overall yield via a six step synthesis from (S)-(+)-2,2-dimethyl-1,2-dioxolane-4-methanol. Subsequent conversion to the final products was acheived in moderate (7 and 10) to excellent yields (8). (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.