title: Diterpenylquinone hybrids: synthesis and assessment of gastroprotective mechanisms of action in human cells.
abstract: A modern approach in the search for new bioactive molecules is the synthesis of novel chemical entities combining molecules of different biosynthetic origin presenting biological effects as single compounds. Gastroprotective compounds from South American medicinal plants, namely quinones and diterpenes, were used as building blocks to obtain hybrid diterpenylquinones. Starting from the labdane diterpene junicedric acid and two isomers, as well as from three quinones, including lapachol, 18 hybrid molecules were synthesized. Six of them are described for the first time. The potential gastroprotective mechanisms of action of the compounds were assessed in dose-response experiments using human gastric epithelial cells (AGS) and human lung fibroblasts (MRC-5). The following studies were carried out: stimulation of cell proliferation, cytoprotection against sodium taurocholate (NaT)-induced damage, synthesis of PGE2 and total reduced sulfhydryl (GSH) content. The antioxidant capacity of the compounds was determined on the inhibition of the lipoperoxidation in human erythrocyte membranes. Hybrid compounds presented activities different from those shown by the starting compounds, supporting the potential of this approach in the search for new bioactive molecules. The effects might be modulated by selective modification in the terpene or quinone moieties of the new molecules. Structure-activity relationships are discussed.
authors.affiliation: Laboratorio de Cultivo Celular, Facultad de Ciencias de la Salud, Universidad de Talca, Casilla 747, 3460000 Talca, Chile. ctheodul@utalca.cl
authors.forename: Cristina
authors.initials: C
authors.lastname: Theoduloz
authors.forename: Ivanna
authors.initials: I
authors.lastname: Bravo
authors.forename: Mariano Walter
authors.initials: MW
authors.lastname: Pertino
authors.forename: Guillermo
authors.initials: G
authors.lastname: Schmeda-Hirschmann
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection; D015232:Dinoprostone / Q000378:metabolism; D004224:Diterpenes / Q000138:chemical synthesis / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005753:Gastric Mucosa / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D015227:Lipid Peroxidation / Q000187:drug effects; D061251:Primary Cell Culture; D011809:Quinones / Q000138:chemical synthesis / Q000494:pharmacology*; D013270:Stomach / Q000473:pathology; D013276:Stomach Ulcer / Q000188:drug therapy
chemical_list: D004224:Diterpenes; D011809:Quinones; D005978:Glutathione; D015232:Dinoprostone
references.citation: Life Sci. 2005 Sep 9;77(17):2193-205
references.pmid: 15916778
references.citation: J Ethnopharmacol. 2012 Jan 6;139(1):234-43
references.pmid: 22100564
references.citation: J Gastroenterol. 2004;39(2):202-3
references.pmid: 15198093
references.citation: J Ethnopharmacol. 2008 Aug 13;118(3):455-9
references.pmid: 18579323
references.citation: Am J Physiol. 1998 Oct;275(4):G620-8
references.pmid: 9756489
references.citation: Drug Dev Res. 2010 Feb;71(1):20-32
references.pmid: 21399701
references.citation: Z Naturforsch C J Biosci. 2003 Jul-Aug;58(7-8):495-501
references.pmid: 12939034
references.citation: Gastroenterology. 1990 Jun;98(6):1452-9
references.pmid: 2338188
references.citation: Bioorg Med Chem. 2007 Sep 1;15(17):5760-74
references.pmid: 17583515
references.citation: Planta Med. 1999 Aug;65(6):522-6
references.pmid: 10483371
references.citation: J Ethnopharmacol. 2005 Oct 3;101(1-3):271-6
references.pmid: 15985351
references.citation: Bioorg Med Chem. 2006 Jul 15;14(14):5061-71
references.pmid: 16554161
references.citation: Life Sci. 2006 Apr 18;78(21):2503-9
references.pmid: 16309708
references.citation: Molecules. 2011 Oct 13;16(10):8614-28
references.pmid: 21996716
references.citation: Dig Dis Sci. 1990 Apr;35(4):467-76
references.pmid: 2318093
references.citation: Biochem Pharmacol. 2001 Jun 1;61(11):1439-48
references.pmid: 11331080
references.citation: Z Naturforsch C J Biosci. 2005 Jul-Aug;60(7-8):511-22
references.pmid: 16163822
references.citation: Bioorg Med Chem Lett. 2002 Feb 11;12(3):477-82
references.pmid: 11814823
references.citation: J Gastrointest Surg. 1999 May-Jun;3(3):308-18
references.pmid: 10481124
references.citation: Planta Med. 2012 Nov;78(17):1807-12
references.pmid: 23047252
references.citation: Bioorg Med Chem. 2006 Nov 1;14(21):7231-40
references.pmid: 16842998
references.citation: BMC Gastroenterol. 2004 Feb 10;4:4
references.pmid: 15028114
references.citation: Free Radic Res. 2003 Apr;37(4):447-52
references.pmid: 12747739
references.citation: Eur J Med Chem. 2013 Sep;67:19-27
references.pmid: 23831506
references.citation: J Clin Gastroenterol. 1998;27 Suppl 1:S1-11
references.pmid: 9872492