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.
Carballeira
Néstor M
NM
Department of Chemistry, University of Puerto Rico, P.O. Box 23346, San Juan, PR 00931-3346, USA. nmcarballeira@uprrp.edu
Cartagena
Michelle M
MM
Prada
Christopher Fernández
CF
Rubio
Celia Fernández
CF
Balaña-Fouce
Rafael
R
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