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The fatty acids (±)-2-methoxy-6 Z -heptadecenoic acid, (±)-2-methoxy-6-hepta-decynoic acid, and (±)-2-methoxyheptadecanoic acid were synthesized and their inhibitory activity against the  Leishmania  DNA topoisomerase IB enzyme ( Ld TopIB) determined. Both 2-OMe-17:1 fatty acids were synthesized from 4-bromo-1-pentanol, the olefinic fatty acid in 10 steps and in 7 % overall yield, while the acetylenic fatty acid in 7 steps and in 14 % overall yield. The 2-OMe-17:0 acid was prepared in 6 steps and in 42 % yield from 1-hexa-decanol. The 2-OMe-17:1 acids inhibited  Ld TopIB, with the acetylenic acid displaying an EC 50  = 16.6 ± 1.1 μM, but the 2-OMe-17:0 acid did not inhibit  Ld TopIB. The (±)-2-methoxy-6 Z -heptadecenoic acid preferentially inhibited  Ld TopIB over the human TopIB enzyme. Unsaturation seems to be a prerequisite for effective inhibition, rationalized in terms of weak intermolecular interactions between the active site of  Ld TopIB and either the double or triple bonds of the fatty acids. Toxicity toward  Leishmania donovani  promastigotes was also investigated, resulting in the order acetylenic &amp;gt; olefinic &amp;gt; saturated with the (±)-2-methoxy-6-heptadecynoic acid displaying an EC 50  = 74.0 ± 17.1 μM. Our results indicate that α-methoxylation decreases the toxicity of C 17:1  fatty acids toward  L. donovani  promastigotes, but improves their selectivity index.

pure and applied chemistry

First total synthesis of the (±)-2-methoxy-6-heptadecynoic acid and related 2-methoxylated analogs as effective inhibitors of the Leishmania topoisomerase IB enzyme