Total Synthesis and Antileishmanial Activity of the Natural Occurring Acetylenic Fatty Acids 6‐Heptadecynoic Acid and 6‐Icosynoic Acid

Abstract

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 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 (6Z)-icosenoic acid was a much better antiprotozoal compound (EC 50 = 5-6 μg/mL) than the (6Z)-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 (6Z)-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.

The (5Z)‐5‐Pentacosenoic and 5‐Pentacosynoic Acids Inhibit the HIV‐1 Reverse Transcriptase

“…When the position of the triple bond in the C 25 acyl chain was changed from Δ5 to Δ2, a decrease in the inhibitory activity towards HIV-1 RT was observed, as exemplified by an IC 50 of 566 ± 1 μM displayed by the 2-pentacosynoic acid. Moreover, when a shorter chain (C 17 or C 20 ) acetylenic fatty acid was tested, as exemplified by the natural fatty acids 6-heptadecynoic and 6-icosynoic acids, no inhibition of the HIV-1 RT enzyme was observed [58]. Therefore, we can say that both fatty acid chain length and the triple bond position are directly related to the effectiveness of inhibition against the HIV-1 RT.…”

Interaction between natural compounds and human topoisomerase I

“…Fatty acids have been also shown to target Top1 from L. donovani and both a long chain and unsaturation are important factors for efficient leishmanicidal activity (Carballeira et al , 2009 ). In line cEPA has an anti-L. donovani promastigotes effect, confirming the importance of unsaturation for the antileishmanial activity of fatty acid compounds .…”

Conjugated Eicosapentaenoic Acid (cEPA) Inhibits L. donovani Topoisomerase I and has an Antiproliferative Activity Against L. donovani Promastigotes

“…(2). L. donovani promastigotes has been shown to be inhibited by fatty acids having long chain with unsaturated bonds [37], confirming that both the length and the unsaturation are important elements for antileishmanial activity of fatty acids compounds. Our experiments also indicate that the conjugation is an important element in antileishmanial activity.…”

“…In line amphotericin B, that has seven conjugated double bonds, has an effect in both acute and chronic treatment stronger than mitelfosine that doesn't have any conjugate bond Table 1 [3]. It must be noted that the therapeutic index value of cEPA is pretty high, its value being at least 10 times larger than any other fatty acid, or than compounds already in clinical use like mitelfosine, that has a therapeutic index of 2.5 [37], indicating that cEPA can be considered a good candidate for antileishmanial therapy. In this context, it must to be noted that cEPA synthesis is simple and that its chemical precursor EPA (from omega 3 fatty acid series) has a large natural abundance, being found in red and green algae and in fish oil [39][40][41].…”

“…Natural compounds, such as some acetylenic fatty acids, have been shown to have a direct effect both on purified topoisomerase and in L. donovani promastigotes [37]. Recently we have shown that another fatty acid, namely conjugated eicosapentaenoic acid (cEPA) has an inhibitory effect on human topoisomerase [38] and this is likely the molecular reason it inhibits the cell growth of human tumor cell lines, while it has not effect on human fibroblast cell lines [39][40][41].…”