Surles J R, Morris-Natschke S, Marx M H, Piantadosi C
University of North Carolina-Chapel Hill, School of Pharmacy, Chapel Hill 27599-7360.
Lipids. 1993 Jan;28(1):55-7. doi: 10.1007/BF02536361.
Phospholipids containing a 1-alkylamido linkage have shown promising in vitro neoplastic cell growth inhibitory properties and anti-human immunodeficiency viral activity. We have synthesized a series of alkylamido ether lipid analogues on a milligram scale for initial evaluation, but for further in vivo testing of these bioactive phospholipids, synthesis on a larger scale is required. The multigram synthesis of 1-alkylamido ether phospholipids was accomplished by modifying reaction conditions in the amidation step and changing reagents and solvent systems in both the detritylation and phosphorylation steps. This was most crucial in the phosphorylation step, where in the multigram synthesis 2-bromoethyl dichlorophosphate in diethyl ether/tetrahydrofuran (7:3, vol/vol) gave much improved yields as compared to the 2-chloro-2-oxo-1,3,2-dioxaphospholane reagent. The modifications also resulted in a product that could be more easily purified in sufficient quantities for use in in vivo inhibition studies.
含有1-烷基酰胺键的磷脂已显示出有前景的体外肿瘤细胞生长抑制特性和抗人类免疫缺陷病毒活性。我们已经以毫克规模合成了一系列烷基酰胺醚脂质类似物用于初步评估，但为了对这些生物活性磷脂进行进一步的体内测试，需要更大规模的合成。通过在酰胺化步骤中修改反应条件以及在脱三苯甲基化和磷酸化步骤中改变试剂和溶剂体系，完成了1-烷基酰胺醚磷脂的多克规模合成。这在磷酸化步骤中最为关键，在多克规模合成中，与2-氯-2-氧代-1,3,2-二氧磷杂环戊烷试剂相比，在乙醚/四氢呋喃（7:3，体积/体积）中的2-溴乙基二氯磷酸酯产生了更高的产率。这些修改还得到了一种可以更容易地大量纯化以用于体内抑制研究的产物。
