Natural feruloyl monoglyceride macrocycles as protecting factors against free-radical damage of lipidic membranes Brigida D’Abrosca, Antonio Fiorentino, * Severina Pacifico, Giuseppe Cefarelli, Piera Uzzo, Marianna Letizia and Pietro Monaco Dipartimento di Scienze della Vita – Seconda Universita ` degli Studi di Napoli – via Vivaldi 43, 81100 Caserta, Italy Received 3 April 2007; revised 16 May 2007; accepted 17 May 2007 Available online 21 May 2007 Abstract—Nine novel natural feruloyl monoglyceride (MGs) macrocycles have been isolated from the leaves of Carex distachya, an herbaceous plant growing in the Mediterranean maquis. All the structures have been elucidated on the basis of their spectroscopic features, especially two-dimensional NMR (DQ-COSY, TOCSY, NOESY, ROESY, HSQC, HMBC, HSQC–TOCSY) and ESI- MS. All the compounds have been assayed as protecting factors against the radical damage of the lipids by using different antiox- idant tests. Ó 2007 Elsevier Ltd. All rights reserved. Lipid peroxidation, which can cause extensive damage to subcellular organelles and biomembranes has been demonstrated to occur in isolated mitochondria, lyso- somes and microsomes. 1 The destruction of unsaturated fatty acids which occurs in lipid peroxidation has been linked with altered membrane structure and enzyme inactivation. In addition to lipid hydroperoxides and lipid radicals, lipid peroxidation generates activated oxygen species, such as hydroxyl radicals and radical superoxide anions. Also, oxidative degradation of poly- unsaturated membrane lipids leads to a variety of toxic carbonyl products such as hydroxyalkenals and other products. 2 Malondialdehyde (MDA) is a characteristic product of lipid peroxidation; it not only allows reaction with cellular nucleophiles but leads to self-condensation to form MDA oligomers. MDA is mutagenic and car- cinogenic. 3 Hence, agents with the ability to protect against these reactive species may be therapeutically use- ful. In line with this hypothesis is the widely accepted view that the positive health effects of polyphenols, as cinnamic acids and flavonoids, can be attributed to their antioxidant activity. Ferulic acid is a potent ubiquitous plant antioxidant. Recent studies indicate the synergistic protective effect of ferulic acid and ascorbic acid on lipid peroxidation and antioxidant defense system during induced myocardial infarction and associated oxidative stress in rats. 4 In the search of new secondary metabo- lites from natural sources with antioxidant and radical scavenging activities, we studied Carex distachya, 5 an herbaceous plant belonging to the Cyperaceae family. From organic extract of the plant we recently reported the isolation and the characterization of new antioxi- dant metabolites. 6,7 Continuing the phytochemical study of the plant 8 we isolated nine new feruloyl monoglyceride macrocycles showing a strong antioxidant activity against reactive oxygen species and an inhibition of the MDA synthesis. The extract of the fresh leaves of Carex distachya in ethyl acetate was chromatographed on silica gel and HPLC to effort nine new compounds 1–9. 9 Compound 1 (Fig. 1) showed a molecular formula C 32 H 50 O 7 calculated on the basis of the elemental analysis and the ESI-MS spectrum that showed the pseudomolec- ular peak at m/z 547. This formula indicated the presence of eight unsaturations in the molecule. The 1 H NMR spectrum showed five protons in the ole- finic region. There was a 1,3,4-trisubstituted aromatic ring, as two doublets at d 7.18 (J = 1.8 Hz) and 6.80 (J = 8.4 Hz), a double doublet at d 7.06 (J = 8.4 and 1.8 Hz), and a double bond conjugated with a carbonyl group as two doublets at d 6.35 (J = 15.9 Hz) and 7.59 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.05.047 Keywords: Feruloyl monoglyceride macrocycles; Carex distachya; Li- pidic membranes; Antioxidant activity; Spectroscopic analysis. * Corresponding author. Tel.: +39 0823 274576; fax: +39 0823 274571; e-mail: antonio.fiorentino@unina2.it Bioorganic & Medicinal Chemistry Letters 17 (2007) 4135–4139