New Gastroprotective Labdeneamides from (4S,9R,10R) Methyl 18-carboxy-labda-8,13(E)-diene-15-oate

Abstract

Starting from the diterpene (4S,9R,10R) methyl 18-carboxy-labda-8,13(E)-dien-15-oate (PMD) and its 8(9)-en isomer [PMD 8(9)-en], 11 amides were prepared and assessed for a gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice. Basal cytotoxicity of the compounds was determined on the following human cell lines: normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), and hepatocellular carcinoma (Hep G2). All compounds are described for the first time. At the single oral dose of 0.1 mg/kg, compounds 1, 10, and 11 presented a strong gastroprotective effect, at least comparable with that of the reference compound lansoprazole at 1 mg/kg, reducing gastric lesions by 76.7, 67.7, and 77.2 %, respectively. The leucyl amide methyl ester 3, tryptophanyl amide methyl ester 5, and benzyl amide 6 of PMD presented a selective basal cytotoxicity on Hep G2 cells with IC₅₀ values of 136.8, 105.3, and 94.2 µM, respectively, while the IC₅₀ values towards AGS cells were 439.5, 928.0, and 937.3 µM, respectively. The three compounds did not affect fibroblast viability with IC₅₀ values > 1000 µM. Compounds 7, 8, 10, and 11 showed no toxic effect against the three selected cell lines.

Key words

(4S,9R,10R) methyl 18-carboxy-labda-8,13(E)-diene-15-oate amide derivatives - labdane diterpenes - gastroprotective effect - basal cytotoxicity - Polyalthia macropoda - Annonaceae

References

• 1 Rodríguez J A, Bustamante C, Astudillo L, Schmeda-Hirschmann G. Gastroprotective activity of solidagenone on experimentally induced gastric lesions in rats.  J Pharm Pharmacol. 2002;  54 399-404
• 2 Rodríguez J A, Astudillo L, Schmeda-Hirschmann G. Oleanolic acid promotes healing of acetic acid-induced chronic gastric ulcers in rats.  Pharmacol Res. 2003;  48 291-294
• 3 Rodríguez J A, Theoduloz C, Sánchez M, Razmilic I, Schmeda-Hirschmann G. Gastroprotective and ulcer-healing effect of new solidagenone derivatives in human cell cultures.  Life Sci. 2005;  77 2193-2205
• 4 Rodríguez J A, Theoduloz C, Sánchez M, Yáñez T, Razmilic I, Schmeda-Hirschmann G. Gastroprotective activity of a new semi-synthetic solidagenone derivative in mice.  J Pharm Pharmacol. 2005;  57 265-271
• 5 Schmeda-Hirschmann G, Rodríguez J A, Astudillo L. Gastroprotective activity of the diterpene solidagenone and its derivatives on experimentally induced gastric lesions in mice.  J Ethnopharmacol. 2002;  81 111-115
• 6 Schmeda-Hirschmann G, Astudillo L, Rodríguez J A, Theoduloz C, Yáñez T. Gastroprotective effect of the Mapuche crude drug Araucaria araucana resin and its main constituents.  J Ethnopharmacol. 2005;  101 271-276
• 7 Theoduloz C, Rodríguez J A, Pertino M, Schmeda-Hirschmann G. Antitumor activity of jatrophone and jatropholone derivatives.  Planta Med. 2009;  75 1520-1522
• 8 Wada H, Kodato S, Kawamori M, Morikawa T, Nakai H, Takeda M, Saito S, Onoda Y, Tamaki H. Antiulcer activity of dehydroabietic acid derivatives.  Chem Pharm Bull. 1985;  33 1472-1487
• 9 Onoda Y, Magaribuchi T, Tamaki H. Effects of the new anti-ulcer agent 12-sulfodehydroabietic acid monosodium salt on duodenal alkaline secretion in rats.  Arzneimittelforschung. 1990;  40 576-578
• 10 Onoda Y, Takido M, Magaribuchi T, Tamaki H. Effects of 12-sulfodehydroabietic acid monosodium salt (TA-2711), a new anti-ulcer agent, on gastric mucosal lesions induced by necrotizing agents and gastric mucosal defensive factors in rats.  Jpn J Pharmacol. 1990;  52 631-638
• 11 Farina C, Pinza M, Pifferi G. Synthesis and anti-ulcer activity of new derivatives of glycyrrhetic, oleanolic and ursolic acids.  Il Farmaco. 1998;  53 22-32
• 12 Pearson J P, Roberts N B. Mucosal protective effects of ecabet sodium: pepsin inhibition and interaction with mucus.  Clin Sci. 2001;  100 411-417
• 13 Izquierdo R, Astudillo L, Rodríguez J A, Theoduloz C, Palenzuela J A, Schmeda-Hirschmann G. Gastroprotective effect and cytotoxicity of labdeneamides.  Planta Med. 2007;  73 310-317
• 14 Schmeda-Hirschmann G, Astudillo L, Sepúlveda B, Rodríguez J A, Theoduloz C, Yáñez T, Palenzuela J A. Gastroprotective effect and cytotoxicity of natural and semisynthetic labdane diterpenes from Araucaria araucana.  Z Naturforsch. 2005;  60 (C) 511-522
• 15 Schmeda-Hirschmann G, Pertino M W, Rodriguez J A, Monsalve F, Droguett D, Theoduloz C. Synthesis, gastroprotective effect and cytotoxicity of new amino acid diterpene monoamides and diamides.  Molecules. 2010;  15 7378-7394
• 16 Schmeda-Hirschmann G, Rodriguez J A, Theoduloz C, Valderrama J. Gastroprotective effect and cytotoxicity of labdeneamides with amino acids.  Planta Med. 2011;  77 340-345
• 17 Sepúlveda B, Astudillo L, Rodríguez J A, Yáñez T, Theoduloz C, Schmeda-Hirschmann G. Gastroprotective and cytotoxic effect of dehydroabietic acid derivatives.  Pharmacol Res. 2005;  2 429-437
• 18 Richomme P, Godet M C, Foussard F, Toupet L, Sévenet T, Bruneton J. A novel leishmanicidal labdane from Polyalthia macropoda.  Planta Med. 1991;  57 552-554
• 19 Halle W, Spielmann H. Two procedures for the prediction of acute toxicity (LD₅₀) from cytotoxicity data.  ATLA. 1992;  20 40-49
• 20 Szelenyi I, Thiemer K. Distention ulcer as a model for testing of drugs for ulcerogenic side effects.  Arch Toxicol. 1978;  13 99-105
• 21 Areche C, Rodríguez J A, Razmilic I, Yañez T, Theoduloz C, Schmeda-Hirschmann G. Gastroprotective and cytotoxic effect of semisynthetic ferruginol derivatives.  J Pharm Pharmacol. 2007;  59 289-300
• 22 Rodríguez J A, Haun M. Cytotoxicity of trans-dehydrocrotonin from Croton cajucara (Euphorbiaceae) on V79 cells and hepatocytes.  Planta Med. 1999;  65 522-526
• 23 Silva Melo P, Durán N, Hiruma-Lima C A, Souza-Brito A R M, Haun M. Comparison of the gastroprotective effect of a diterpene lactone isolated from Croton cajucara with its synthetic derivatives.  J Ethnopharmacol. 2003;  87 169-174
• 24 Parra A, Rivas F, Lopez P E, Garcia-Granados A, Martinez A, Albericio F, Marquez N, Muñoz E. Solution- and solid-phase synthesis and anti-HIV activity of maslinic acid derivatives containing amino acids and peptides.  Bioorg Med Chem. 2009;  17 1139-1145
• 25 Wu F, Yi Y, Sun P, Zhang D. Synthesis, in vitro inhibitory activity towards COX-2 and haemolytic activity of derivatives of esculentoside A.  Bioorg Med Chem Lett. 2007;  17 6430-6433
• 26 Wei Y, Ma C-M, Hattori M. Synthesis and evaluation of a-seco type triterpenoids for anti-HIV-1 protease activity.  Eur J Med Chem. 2009;  44 4112-4120
• 27 de Carvalho P B, Ferreira E I. Leishmaniasis phytotherapy. Nature's leadership against an ancient disease.  Fitoterapia. 2001;  72 599-618
• 28 Tincusi B M, Jiménez I A, Bazzocchi I L, Moujir L M, Mamani Z A, Barroso J P, Ravelo A G, Hernández B V. Antimicrobial terpenoids from the oleoresin of the Peruvian medicinal plant Copaifera paupera.  Planta Med. 2002;  68 808-812