Structure-activity relationship in the gastric cytoprotective effect of several sesquiterpene lactones

Abstract

The structural requirements for the gastric cytoprotective activity of several sesquiterpene lactones are reported. A theoretical-experimental study on the potentially active centers is carried out. The biological evaluation of reduced analogues and the simulation of the molecular interactions between these compounds and an endogenous cysteine residue suggest that the presence of a non sterically hindered Michael acceptor seems to be an essential structural requirement for the cytoprotective activity in this family of compounds. This observation suggests that cytoprotection is mediated through a Michael reaction between the sulfhydryl-containing peptides of the mucosa and Michael acceptors present in the molecules under study. This mechanism of action is in addition to and distinct from the one proposed in our previous paper, namely, that these sesquiterpenes stimulate endogenous synthesis of prostaglandins.

Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties

“…The structural activity relationship of the antiulcerogenic activity and the mechanism of action were investigated. It has been ascertained that a sterically unhindered Michael acceptor is an essential requirement for the activity, interacting with the thiol containing compounds of the gastric mucosa (Giordano et al, 1992).…”

Antioxidant properties of natural compounds used in popular medicine for gastric ulcers

“…DhL increases gastric glycoprotein synthesis (1), as confirmed by histological studies of the gastric and duodenal mucosa (10). The A. douglasiana extract and DhL prevent lesions of the gastric mucosa induced by ethanol and other necrotizing compounds (10) and the absolute ethanol-induced gastric injury (4).…”

“…DhL increases gastric glycoprotein synthesis (1), as demonstrated by histological studies of the gastric and duodenal mucosa (2), and prevents lesions of the gastric mucosa induced by ethanol and other necrotizing agents (3). The A. douglasiana Besser extract and DhL prevent the absolute ethanol-induced gastric injury (4). The mechanism of the protective action of DhL is unknown although it seems to be related to endogenous prostaglandin.…”

Uma revisão das atividades biológicas da trans-desidrocrotonina, um produto natural obtido de Croton cajucara

“…A atividade citotóxica da DCTN foi estudada em diversas células tumorais das seguintes linhagens: células fi broblásticas pulmonares de hamsters chineses (Souza-Brito et al, 1998;Grynberg et al, 1999;Melo et al, 2001;Rodriguez;Haun, 1999;Freire et al, 2003), células promielocíticas leucêmicas (HL60) (Anazetti et al, 2003;Anazetti et al, 2004;Corrêa et al, 2005), hepatócitos de ratos (Rodriguez; Haun, 1999; Corrêa et al, 2005) (Maciel et al, 2002a;Grynberg et al, 1999;Melo et al, 2004).…”

“…Certos grupos funcionais são essenciais para a atividade biológica de terpenóides, como os aceptores de Michael (cetona α,β-insaturada e α-metileno-γ-lactona) que são reconhecidos como grupamentos químicos responsáveis pelas atividades antiulcerogênica (Giordano et al, 1992) e antitumoral (Nakayachi et al, 2004;Ahn;Sok, 1996) de compostos orgânicos em geral. Como exemplo específi co podemos citar os resultados citotóxicos observados na relação estrutura/ atividade de lactonas sesquiterpênicas, onde três grupos químicos presentes nas moléculas desses compostos contribuem para a atividade biológica (Mullins et al, 1997;Wattenberg, 1995), dentre eles, destaca-se o grupo α-metileno-γ-lactona, que participa de reações do tipo Michael com moléculas biológicas e inativa enzimaschaves (Kupchan et al, 1971 Figura 2.…”