Hardwickiic acid

Biological activities and cytotoxicity of diterpenes from Copaifera spp. Oleoresins.[Pubmed:25859778]

Molecules. 2015 Apr 9;20(4):6194-210.

Copaifera spp. are Amazonian species widely studied and whose oleoresins are used by local people for various medicinal purposes. However, a detailed study of the activity of the main phytochemical components of these oleoresins remains to be done. Here, we studied the cytotoxicity and in vitro anti-inflammatory effects of six diterpene acids: copalic, 3-hydroxy-copalic, 3-acetoxy-copalic, hardwickiic, kolavic-15-metyl ester, and kaurenoic, isolated from the oleoresins of Copaifera spp. The diterpenes did not show cytotoxicity in normal cell lines, nor did they show significant changes in viability of tumoral line cells. The 3-hydroxy-copalic was able to inhibit the enzyme tyrosinase (64% +/- 1.5%) at 250 microM. The kolavic-15-metyl ester at 200 microM showed high inhibitory effect on lipoxygenase (89.5% +/- 1.2%). Among the diterpenes tested, only kaurenoic and copalic acids showed significant hemolytic activities with 61.7% and 38.4% at 100 microM, respectively. In addition, it was observed that only the copalic acid (98.5% +/- 1.3%) and Hardwickiic acid (92.7% +/- 4.9%) at 100 mM inhibited nitric oxide production in macrophages activated by lipopolysaccharide. In this assay, the diterpenes did not inhibit tumor necrosis factor-alpha production. The acids inhibited the production of IL-6, 3-acetoxy-copalic (23.8% +/- 8.2%), kaurenoic (11.2% +/- 5.7%), kolavic-15-methyl ester (17.3% +/- 4.2%), and copalic (4.2% +/- 1.8%), respectively, at 25 microM. The kaurenoic, 3-acetoxy-copalic and copalic acids increased IL-10 production. This study may provide a basis for future studies on the therapeutic role of diterpenic acids in treating acute injuries such as inflammation or skin disorders.

Antimicrobial activity of the methanolic extract, fractions and compounds from the stem bark of Irvingia gabonensis (Ixonanthaceae).[Pubmed:17766070]

J Ethnopharmacol. 2007 Oct 8;114(1):54-60.

The antimicrobial activity of the methanolic extract from the stem bark of Irvingia gabonensis (IGM), fractions and compounds isolated from IGM [3-friedelanone (1), betulinic acid (2), oleanolic acid (3), 3,3',4'-tri-O-methylellagic acid (4), 3,4-di-O-methylellagic acid (5) and Hardwickiic acid (6)] was evaluated against Gram-positive bacteria (6 species), Gram-negative bacteria (13 species) and three Candida species using dilution methods for the determination of the minimal inhibition concentration (MIC) and the minimal microbicidal concentration (MMC). From the obtained results, IGM prevented the growth of all the species of microorganisms tested at a concentration limit of 312.50 microg/ml. Compounds 4-6 also inhibited the growth of all the tested microbial species while compounds 1-3 showed selective activities. The lowest MIC values (78.12 microg/ml) were obtained with IGM on 13 of the 22 microorganisms tested. The corresponding value of 1.22 microg/ml (4.26 microM) for compounds was recorded with compound 6 on Neisseria gonorrhoeae. The obtained results confirmed the use of Irvingia gabonensis in the treatment of bacterial and fungal infections.

Effects of the neoclerodane Hardwickiic acid on the presynaptic opioid receptors which modulate noradrenaline and dopamine release in mouse central nervous system.[Pubmed:23357481]

Neurochem Int. 2013 Mar;62(4):354-9.

We have comparatively investigated the effects of Hardwickiic acid and Salvinorin A on the K(+)-evoked overflow of [(3)H]noradrenaline ([(3)H]NA) and [(3)H]dopamine ([(3)H]DA) from mouse hippocampal and striatal nerve terminals, respectively. The K(+)-evoked overflow of [(3)H]DA was inhibited in presence of Salvinorin A (100 nM) but not in presence of Hardwickiic acid (100 nM). Hardwickiic acid (100 nM) mimicked Salvinorin A (100 nM) in facilitating K(+)-evoked hippocampal [(3)H]NA overflow and the two compounds were almost equipotent. Facilitation of [(3)H]NA overflow caused by 100 nM Hardwickiic acid was prevented by the kappa-opioid receptor (KOR) antagonist norbinaltorphimine (norBNI, 100 nM) and by the selective delta-opioid receptor (DOR) antagonist naltrindole (100 nM), but was not altered by 100 nM D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), a selective mu-opioid receptor (MOR) antagonist. We conclude that Hardwickiic acid modulates hippocampal [(3)H]NA overflow evoked by a mild depolarizing stimulus by acting at presynaptic opioid receptor subtypes.

A chemical proteomics approach reveals Hsp27 as a target for proapoptotic clerodane diterpenes.[Pubmed:22802135]

Mol Biosyst. 2012 Oct;8(10):2637-44.

Clerodane diterpenoids are a class of naturally occurring molecules widely distributed in the Lamiaceae family. Neo-clerodane diterpenoids from Salvia ssp were recently described as compounds inhibiting the proliferation of human cancer cell lines. To gain new insights into molecular mechanism(s) underlying the antitumor potential of this class of compounds, we used a chemical proteomics approach to analyse the cellular interactome of Hardwickiic acid (HAA) selected as a representative molecule. HAA was linked to an opportune 1,1'-carbonyldiimidazole modified by 1,12-dodecanediamine and then immobilized on a matrix support. The modified beads were then used as bait for fishing the potential partners of HAA in a U937 cell lysate. We identified heat shock protein 27 (Hsp27), an ATP-independent antiapoptotic chaperone characterized for its tumorigenic and metastatic properties and now referenced as a major therapeutic target in many types of cancer, as a major HAA partner. Here, we also report the study of HAA-Hsp27 interaction by means of a panel of chemical and biological approaches, including surface plasmon resonance measurements limited proteolysis, and biochemical assays. Our data suggest that HAA could provide a potential tool to develop strategies for the discovery of Hsp27 chemical inhibitors.