First total synthesis and antileishmanial activity of (Z)-16-methyl-11-heptadecenoic acid, a new marine fatty acid from the sponge Dragmaxia undata

Abstract

The first total synthesis for the (Z)-16-methyl-11-heptadecenoic acid, a novel fatty acid from the sponge Dragmaxia undata, was accomplished in seven steps and in a 44% overall yield. The use of (trimethylsilyl)acetylene was key in the synthesis. Based on a previous developed strategy in our laboratory the best synthetic route towards the title compound was first acetylide coupling of (trimethylsilyl)acetylene to the long-chain protected 10-bromo-1-decanol followed by a second acetylide coupling to the short-chain 1-bromo-4-methylpentane, which resulted in higher yields. Complete spectral data is also presented for the first time for this recently discovered fatty acid and the cis double bond stereochemistry of the natural acid was established. The title compound displayed antiprotozoal activity against Leishmania donovani (IC50 = 165.5 ± 23.4 µM) and inhibited the leishmania DNA topoisomerase IB enzyme (LdTopIB) with an IC50 = 62.3 ± 0.7 µM.

Recent Developments in Drug Discovery for Leishmaniasis and Human African Trypanosomiasis

“…264a These findings supported the previous hypothesis that monounsaturated iso-methyl-branched fatty acids impart selectivity over human DNA topoisomerase I. 265 …”

“…All the reported compounds appear to have selectivity over human topoisomerase IB enzyme (hTopIB) . These findings supported the previous hypothesis that monounsaturated iso-methyl-branched fatty acids impart selectivity over human DNA topoisomerase I …”

Synthesis of Marine α-Methoxylated Fatty Acid Analogs that Effectively Inhibit the Topoisomerase IB from Leishmania donovani with a Mechanism Different from that of Camptothecin

“…The experimental procedures employed to assess the toxicity of acids 1 and 2 towards L. infantum and L. donovani are the same as the ones previously described [ 5 , 15 ]. CPT was used as the control drug.…”

Potential therapeutic targets shared between leishmaniasis and cancer

“…Anti-cancer and anti-leishmaniasis effects of herbal compounds such as pentacyclic triterpenoid are well known (Moulisha et al, 2010). Fatty acids from natural sources are inhibitors of therapeutic targets in cancer cells and Leishmania parasites (Carballeira et al, 2011(Carballeira et al, , 2018Carballeira, 2013).…”