Total synthesis and antileishmanial activity of the natural occurring acetylenic fatty acids 6-heptadecynoic acid and 6-icosynoic acid.
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 Delta(6) acetylenic fatty acids displayed good antiprotozoal activity towards Leishmania donovani promastigotes (EC(50) = 1-6 microg/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 microg/mL) than the (6Z)-heptadecenoic acid (EC(50) > 25 microg/mL). The saturated fatty acids n-heptadecanoic acid and n-eicosanoic acid were not effective towards L. donovani, indicating that the Delta(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 microM), a possible intracellular target for these compounds. This is the first study assessing fatty acids as inhibitors of the Leishmania DNA topoisomerase IB enzyme.
Department of Chemistry, University of Puerto Rico, P.O. Box 23346, San Juan, PR 00931-3346, USA. nmcarballeira@uprrp.edu
Néstor M
NM
Carballeira
Michelle M
MM
Cartagena
Christopher Fernández
CF
Prada
Celia Fernández
CF
Rubio
Rafael
R
Balaña-Fouce
D000480:Alkynes / Q000138:chemical synthesis*; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis* / Q000502:physiology*; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development*; D051379:Mice
D000480:Alkynes; D000981:Antiprotozoal Agents; D005231:Fatty Acids, Unsaturated; C031203:2-hexadecynoic acid