ABSTRACT
The first total synthesis for the novel fatty acid (±)-2-methoxy-6-icosynoic acid was accomplished in seven steps and in a 14% overall yield starting from 2-(4-bromobutoxy)-tetrahydro-2H-pyran. The title compound displayed an EC50=23±1 µM against the human SH-SY5Y neuroblastoma cell line and an EC50=26±1 µM against the human adenocarcinoma cervix cell line (HeLa) after 48 h of exposure. The corresponding non-methoxylated analog 6-icosynoic acid did not display cytotoxicity (EC50>500 µM) toward the studied cell lines as well as the 2-methoxyicosanoic acid (EC50>300 µM). The critical micelle concentration (CMC=20-30 µM) for the (±)-2-methoxy-6-icosynoic acid was also determined. It was found that α-methoxylation decreases the CMC of a fatty acid.
Subject(s)
Fatty Acids, Unsaturated/chemical synthesis , Fatty Acids/chemical synthesis , Apoptosis/drug effects , Cell Line, Tumor , Fatty Acids/chemistry , Fatty Acids/toxicity , Fatty Acids, Unsaturated/chemistry , Fatty Acids, Unsaturated/toxicity , HeLa Cells , Humans , Micelles , Neuroblastoma/metabolism , Neuroblastoma/pathology , StereoisomerismABSTRACT
An activity guided isolation of the H(2)O subextract of the crude extract of Melampyrum arvense L. afforded iridoid glucosides: aucubin (1), melampyroside (2), mussaenoside (3), mussaenosidic acid (4), 8-epi-loganin (5); flavonoids: apigenin (6), luteolin (7), luteolin 7-O-ß-glucopyranoside (8); a lignan glycoside dehydrodiconiferyl alcohol 9-O-ß-glucopyranoside (9); and benzoic acid (10). ß-Sitosterol (11) and a fatty acid mixture (12) were identified as the active principles of the CHCl(3) subextract. The structures of the isolates were elucidated by spectroscopic methods, while the composition of 12 was identified by GC-MS after methylation. Luteolin (7) appeared as the most active compound against Trypanosoma brucei rhodesiense and Leishmania donovani (IC(50) values 3.8 and 3.0 µg/mL). Luteolin 7-O-ß-glucopyranoside (8) displayed the best antiplasmodial activity against Plasmodium falciparum (IC(50) value 2.9 µg/mL). This is the first detailed phytochemical study on Turkish M. arvense and the first report of the antiprotozoal effect of Melampyrum species and its constituents.
Subject(s)
Antiprotozoal Agents/pharmacology , Orobanchaceae/chemistry , Plant Extracts/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/isolation & purification , Gas Chromatography-Mass Spectrometry , Inhibitory Concentration 50 , Leishmania donovani/drug effects , Luteolin/chemistry , Luteolin/isolation & purification , Luteolin/pharmacology , Nuclear Magnetic Resonance, Biomolecular , Orobanchaceae/metabolism , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plasmodium gallinaceum/drug effects , Trypanosoma brucei brucei/drug effectsABSTRACT
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.
