Carballeira Néstor M, Cartagena Michelle M, Prada Christopher Fernández, Rubio Celia Fernández, Balaña-Fouce Rafael
Department of Chemistry, University of Puerto Rico, P.O. Box 23346, San Juan, PR 00931-3346, USA.
Lipids. 2009 Oct;44(10):953-61. doi: 10.1007/s11745-009-3345-z. Epub 2009 Sep 30.
The first total syntheses of the naturally occurring acetylenic fatty acids-6-heptadecynoic acid (59% overall yield) and 6-icosynoic acid (34% overall yield)-was accomplished in four steps. Using the same synthetic sequence the naturally occurring fatty acids (6Z)-heptadecenoic acid (46% overall yield) and (6Z)-icosenoic acid (27% overall yield) were also synthesized. The Delta(6) acetylenic fatty acids displayed good antiprotozoal activity towards Leishmania donovani promastigotes (EC(50) = 1-6 microg/mL), but the 6-icosynoic acid was the most effective in the series. In addition, the (6Z)-icosenoic acid was a much better antiprotozoal compound (EC(50) = 5-6 microg/mL) than the (6Z)-heptadecenoic acid (EC(50) > 25 microg/mL). The saturated fatty acids n-heptadecanoic acid and n-eicosanoic acid were not effective towards L. donovani, indicating that the Delta(6) unsaturation in these fatty acids is necessary for leishmanicidal activity. In addition, both the 6-icosynoic acid and the (6Z)-icosenoic acid were inhibitors of the Leishmania DNA topoisomerase IB enzyme (EC(50's) = 36-49 microM), a possible intracellular target for these compounds. This is the first study assessing fatty acids as inhibitors of the Leishmania DNA topoisomerase IB enzyme.
天然存在的炔脂肪酸——6-十七碳炔酸（总产率59%）和6-二十碳炔酸（总产率34%）的首次全合成通过四步完成。使用相同的合成序列，还合成了天然存在的脂肪酸（6Z）-十七碳烯酸（总产率46%）和（6Z）-二十碳烯酸（总产率27%）。δ（6）炔脂肪酸对杜氏利什曼原虫前鞭毛体显示出良好的抗原虫活性（半数有效浓度EC(50)=1-6微克/毫升），但6-二十碳炔酸是该系列中最有效的。此外，（6Z）-二十碳烯酸是比（6Z）-十七碳烯酸（半数有效浓度EC(50)>25微克/毫升）更好的抗原虫化合物（半数有效浓度EC(50)=5-6微克/毫升）。饱和脂肪酸正十七烷酸和正二十烷酸对杜氏利什曼原虫无效，表明这些脂肪酸中的δ（6）不饱和对于杀利什曼原虫活性是必要的。此外，6-二十碳炔酸和（6Z）-二十碳烯酸都是利什曼原虫DNA拓扑异构酶IB酶的抑制剂（半数有效浓度EC(50)=36-49微摩尔），这可能是这些化合物的细胞内靶点。这是第一项评估脂肪酸作为利什曼原虫DNA拓扑异构酶IB酶抑制剂的研究。
