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Total Synthesis and Antileishmanial Activity of the Natural Occurring Acetylenic Fatty Acids 6‐Heptadecynoic Acid and 6‐Icosynoic Acid
Author(s) -
Carballeira Néstor M.,
Cartagena Michelle M.,
Prada Christopher Fernández,
Rubio Celia Fernández,
BalañaFouce Rafael
Publication year - 2009
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/s11745-009-3345-z
Subject(s) - antiprotozoal , fatty acid , leishmania donovani , chemistry , biochemistry , myristic acid , enzyme , stereochemistry , biology , palmitic acid , in vitro , visceral leishmaniasis , leishmaniasis , immunology
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 (6 Z )‐heptadecenoic acid (46% overall yield) and (6 Z )‐icosenoic acid (27% overall yield) were also synthesized. The Δ 6 acetylenic fatty acids displayed good antiprotozoal activity towards Leishmania donovani promastigotes (EC 50 = 1–6 µg/mL), but the 6‐icosynoic acid was the most effective in the series. In addition, the (6 Z )‐icosenoic acid was a much better antiprotozoal compound (EC 50 = 5–6 µg/mL) than the (6 Z )‐heptadecenoic acid (EC 50 > 25 µg/mL). The saturated fatty acids n ‐heptadecanoic acid and n ‐eicosanoic acid were not effective towards L. donovani , indicating that the Δ 6 unsaturation in these fatty acids is necessary for leishmanicidal activity. In addition, both the 6‐icosynoic acid and the (6 Z )‐icosenoic acid were inhibitors of the Leishmania DNA topoisomerase IB enzyme (EC 50's = 36–49 µM), a possible intracellular target for these compounds. This is the first study assessing fatty acids as inhibitors of the Leishmania DNA topoisomerase IB enzyme.