ABSTRACT
In an effort to identify new anti-inflammatory and antibacterial agents with potential application in wound healing, five new dibenzofurans, 1,3,7,9-tetrahydroxy-2,8-dimethyl-4,6-di(2-methylbutanoyl)dibenzofuran (1), 1,3,7,9-tetrahydroxy-2,8-dimethyl-4-(2-methylbutanoyl)-6-(2-methylpropionyl)dibenzofuran (2), 1,3,7,9-tetrahydroxy-2,8-dimethyl-4,6-di(2-methylpropionyl)dibenzofuran (3), 1,3,7,9-tetrahydroxy-4,6-dimethyl-2-(2-methylbutanoyl)-8-(2-methylpropionyl)dibenzofuran (4), and 1,3,7,9-tetrahydroxy-4,6-dimethyl-2,8-di(2-methylpropionyl)dibenzofuran (5), were isolated from the leaves of Pilidiostigma glabrum together with one previously described dibenzofuran. Structure elucidation was achieved by way of spectroscopic measurements including 2D-NMR spectroscopy. Compounds with 2,8-acyl substitutions had potent antibacterial activity against several Gram-positive strains (MIC in the low micromolar range), while compounds with 4,6-acyl substitutions were less active. All compounds except 3 inhibited the synthesis of nitric oxide in RAW264 macrophages with IC(50) values in the low micromolar range. Compounds with 2,8-acyl substitutions also inhibited the synthesis of PGE(2) in 3T3 cells, whereas 4,6-acyl-substituted compounds were inactive. None of the compounds inhibited the synthesis of TNF-α in RAW264 cells. The compounds showed variable but modest antioxidant activity in the oxygen radical absorbance capacity assay. These findings highlight that much of the Australian flora remains unexplored and may yet yield many new compounds of interest. Initial clues are provided on structure/activity relationships for this class of bioactives, which may enable the design and synthesis of compounds with higher activity and/or selectivity.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Benzofurans/isolation & purification , Benzofurans/pharmacology , Macrophages/drug effects , Myrtaceae/chemistry , Animals , Anti-Bacterial Agents/chemistry , Anti-Inflammatory Agents/chemistry , Australia , Benzofurans/chemistry , Mice , Molecular Structure , Nitric Oxide/analysis , Nitric Oxide/antagonists & inhibitors , Nuclear Magnetic Resonance, Biomolecular , Plant Leaves/chemistry , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
Bioactivity-guided fractionation of an ethanolic extract of the rhizome of Pleuranthodium racemigerum, a tropical Zingiberaceae species from Northeastern Australia, resulted in the isolation and structural elucidation of 1-(4''-methoxyphenyl)-7-(4'-hydroxyphenyl)-(E)-hept-2-ene (1), a new diarylheptanoid related to curcumin. Compound 1 was a fairly potent inhibitor of prostaglandin E(2) production in 3T3 murine fibroblasts (IC(50) approximately 34 microM) and also displayed moderate cytotoxicity against this cell line (IC(50) = 52.8 microM). The compound also demonstrated cytotoxic activity against the P388D1 murine lymphoblast cell line (IC(50) = 117.0 microM) and four human cell lines: Caco-2 colonic adenocarcinoma (IC(50) = 44.8 microM), PC3 prostate adenocarcinoma (IC(50) = 23.6 microM), HepG2 hepatocyte carcinoma (IC(50) = 40.6 microM), and MCF7 mammary adenocarcinoma (IC(50) = 56.9 microM). The cytotoxicity of compound 1 closely resembled that of curcumin, in terms of both IC(50) values and dose-response curves.
