The cytotoxicity, antimicrobial and parasiticidal properties of Δ6 alkynoic fatty acids are well established. The activity of these fatty acids is associated with the chain length and the position of the triple bond. It has been recently demonstrated that methoxylated acetylenic fatty acids display antiprotozoal and cytotoxic properties. An example is the (±)-2-methoxy-6-icosynoic acid, which displayed cytotoxicity against the human SH-SY5Y neuroblastoma cell line with a half maximal effective concentration (EC50) of 23 ± 1 μM, and against the human adenocarcinoma cervix cell line (HeLa) with an EC50 = 26 ± 1 μM. Moreover, the C17 methoxylated Δ6 acetylenic and olefinic fatty acids display inhibitory activity against the leishmania DNA topoisomerase IB (LdTopIB) enzyme, a validated target for the treatment of leishmaniasis. In this work we present the synthesis of (±)-2-methoxy-6-hexadecynoic acid (2-OMe-6-HDA) and demonstrate that it displays cytotoxicity against the human A549 lung carcinoma cell line with an EC50= 32 ± 8 μM; while the natural compound 6-hexadecynoic acid (6-HDA) displays an EC50= 65 ± 7 μM against the same cell line. Herein we also demonstrate that the 6-HDA displays inhibitory activity towards LdTopIB (EC50=61 ±3 μM), but previous studies have shown that the 2-methoxylated acetylenic and olefinic counterparts should present better LdTopIB inhibition. The total syntheses of 6-HDA, 2-OMe-6-HDA, and other analogs was achieved in 4 to 10 steps, with overall yields between 26% to 76%. The synthesis and the bioactivity results of these unusual fatty acids will be presented.

Synthesis and biological evaluation of α-methoxylated acetylenic fatty acids

253rd National Meeting (2017)

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