Structure-cytoprotective activity relationship of simple molecules containing an alpha,beta-unsaturated carbonyl system.

In previous reports we attributed the cytoprotective activity of several sesquiterpene lactones to the presence of a nonhindered electrophilic acceptor in their structure. We suggested that the mechanism of protection would be, at least in part, mediated through a reaction between the electrophilic acceptor and the sulfhydryl-containing groups of the mucosa. We report here the gastric cytoprotective effect of simple molecules containing an alpha, beta-unsaturated carbonyl group. In the present paper, we undertake the study of molecular accessibility and molecular shape, in addition to conformational, electronic, and steric factors. Our results helped to establish two important facts connecting chemical structure with cytoprotective effect. Firstly, an adequate molecular accessibility appears to be necessary to produce the biological response, and secondly, the alpha,beta-unsaturated carbonyl system has to be included in a cyclic structure or, at least, in the proximity of a cyclic system.

Gastric cytoprotective activity of 2-cyclopenten-1-one and related compounds.

The cytoprotective activity of the isolated functional groups of several sesquiterpene lactones is reported. Among them the highest activity is shown by alpha-methylen-gamma-butyrolactone and 2-cyclopenten-1-one. The activity shown by those Michael acceptors with a beta carbon hindered by an alkyl substituent was always lower or almost null. A three-way mechanism of action is proposed: a) reduced glutathione synthesis, b) prostaglandin synthesis and c) mucosal glycoprotein synthesis.

Mucus synthesis and sulfhydryl groups in cytoprotection mediated by dehydroleucodine, a sesquiterpene lactone.

The aerial parts of Artemisia douglasiana have been used in folk medicine as a cytoprotective agent against the development of peptic ulcer. Dehydroleucodine [1], its active principle, significantly prevents the formation of gastric lesions induced by the exposure of the rats to absolute ErOH. It was found in this study that (a) pretreatment of rats with 1 (40 mg/kg, po) caused a significant increase in glycoprotein synthetic activity, approximately sevenfold as large as that of the control; and (b) pretreatment of the rats with the thiol reagent N-methylmaleimide (NEM) significantly diminished the cytoprotection provided by 1. However, the protective effect of 1 was not totally abolished by pretreatment with a combination of indomethacin and NEM, indicating additional mechanisms are involved in the cytoprotective action of 1.

Structure-activity relationship in the cytoprotective effect of helenalin and related compounds.

Our previous reports indicate that the cytoprotective effect of helenalin and several sesquiterpene lactones is mediated through a Michael reaction between the sulfhydryl containing peptides of the gastric mucosa and Michael acceptors present in the sesquiterpene lactone molecules. In the present work the different alternative active sites in molecules containing up to three places which could act as viable Michael acceptors are evaluated. To do this, an extensive conformational and electronic study of helenalin and its derivatives was carried out. The experimental and theoretical results obtained show the gamma-lactone and cyclopentenone groups to be the biologically active places of the molecules under study, whereas tiglic and angelic substituents in these compounds show different behavior as Michael acceptors.

Dehydroleucodine prevents ethanol-induced necrosis in the rat gastric mucosa. A histological study.

The aerial part of Artemisia douglasiana Besser (6) has been used in folk medicine as a cytoprotective agent against the development of peptic ulcer. The dehydroleucodine (DhL), its active principle, significantly prevents the formation of gastric lesions induced by the exposure of the rats to absolute ethanol orally administered. The stomachs of control and experimental rats (after ethanol and pretreated with DhL) were removed, opened along the greater curvature and studied under stereo microscope and with light and scanning electron microscope. Absolute ethanol produced focal visible hemorrhagic lesions, extensive hyperemia, vascular stasis, cell disruption, and necrosis of the mucosa. Abundant mass of mucus was observed with scanning. The stomachs of rats pretreated with DhL showed a reduction of lesions. No hemorrhage and hyperemia were observed. The epithelia of the mucosa had a cobblestone appearance, similar to control rats and was covered by a fine layer of mucus. The mechanism of the protective action of DhL is unknown although it seems to be related to endogenous prostaglandins (PG).

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

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.

Dehydroleucodine prevents ethanol-induced necrosis in the rat gastric mucosa. A histological study.

The aerial part of Artemisia douglasiana Besser (6) has been used in folk medicine as a cytoprotective agent against the development of peptic ulcer. The dehydroleucodine (DhL), its active principle, significantly prevents the formation of gastric lesions induced by the exposure of the rats to absolute ethanol orally administered. The stomachs of control and experimental rats (after ethanol and pretreated with DhL) were removed, opened along the greater curvature and studied under stereo microscope and with light and scanning electron microscope. Absolute ethanol produced focal visible hemorrhagic lesions, extensive hyperemia, vascular stasis, cell disruption, and necrosis of the mucosa. Abundant mass of mucus was observed with scanning. The stomachs of rats pretreated with DhL showed a reduction of lesions. No hemorrhage and hyperemia were observed. The epithelia of the mucosa had a cobblestone appearance, similar to control rats and was covered by a fine layer of mucus. The mechanism of the protective action of DhL is unknown although it seems to be related to endogenous prostaglandins (PG).

Dehydroleucodine prevents ethanol-induced necrosis in the rat gastric mucosa. A histological study

The aerial part of Artemisia douglasiana Besser (6) has been used in folk medicine as a cytoprotective agent against the development of peptic ulcer. The dehydroleucodine (DhL), its active principle, significantly prevents the formation of gastric lesions induced by the exposure of the rats to absolute ethanol orally administered. The stomachs of control and experimental rats (after ethanol and pretreated with DhL) were removed, opened along the greater curvature and studied under stereo microscope and with light and scanning electron microscope. Absolute ethanol produced focal visible hemorrhagic lesions, extensive hyperemia, vascular stasis, cell disruption, and necrosis of the mucosa. Abundant mass of mucus was observed with scanning. The stomachs of rats pretreated with DhL showed a reduction of lesions. No hemorrhage and hyperemia were observed. The epithelia of the mucosa had a cobblestone appearance, similar to control rats and was covered by a fine layer of mucus. The mechanism of the protective action of DhL is unknown although it seems to be related to endogenous prostaglandins (PG).

Dehydroleucodine prevents ethanol-induced necrosis in the rat gastric mucosa. A histological study

The aerial part of Artemisia douglasiana Besser (6) has been used in folk medicine as a cytoprotective agent against the development of peptic ulcer. The dehydroleucodine (DhL), its active principle, significantly prevents the formation of gastric lesions induced by the exposure of the rats to absolute ethanol orally administered. The stomachs of control and experimental rats (after ethanol and pretreated with DhL) were removed, opened along the greater curvature and studied under stereo microscope and with light and scanning electron microscope. Absolute ethanol produced focal visible hemorrhagic lesions, extensive hyperemia, vascular stasis, cell disruption, and necrosis of the mucosa. Abundant mass of mucus was observed with scanning. The stomachs of rats pretreated with DhL showed a reduction of lesions. No hemorrhage and hyperemia were observed. The epithelia of the mucosa had a cobblestone appearance, similar to control rats and was covered by a fine layer of mucus. The mechanism of the protective action of DhL is unknown although it seems to be related to endogenous prostaglandins (PG).

Dehydroleucodine prevents ethanol-induced necrosis in the rat gastric mucosa. A histological study.

The aerial part of Artemisia douglasiana Besser (6) has been used in folk medicine as a cytoprotective agent against the development of peptic ulcer. The dehydroleucodine (DhL), its active principle, significantly prevents the formation of gastric lesions induced by the exposure of the rats to absolute ethanol orally administered. The stomachs of control and experimental rats (after ethanol and pretreated with DhL) were removed, opened along the greater curvature and studied under stereo microscope and with light and scanning electron microscope. Absolute ethanol produced focal visible hemorrhagic lesions, extensive hyperemia, vascular stasis, cell disruption, and necrosis of the mucosa. Abundant mass of mucus was observed with scanning. The stomachs of rats pretreated with DhL showed a reduction of lesions. No hemorrhage and hyperemia were observed. The epithelia of the mucosa had a cobblestone appearance, similar to control rats and was covered by a fine layer of mucus. The mechanism of the protective action of DhL is unknown although it seems to be related to endogenous prostaglandins (PG).

The gastric cytoprotective effect of several sesquiterpene lactones.

The aerial part of Artemisia douglasiana, used in folk medicine as a cytoprotective agent against the development of peptic ulcer, was studied, its active principle dehydroleucodine [1] isolated, and its pharmacological properties analyzed. In order to establish whether or not the reported activity is particular to sesquiterpene lactones, the study of the cytoprotective activity of several related guaianolides and pseudoguaianolides from plants was undertaken. Ludartin [3], 8-angeloyloxy-3-hydroxyguaia-3(15),10(14),11(13)-trien-6,12- olide [4], hymenin [5], mexicanin I [6], helenanin [7], and 9-O-desacetylsparthulin-2-O-angelate [8] were found to exhibit protection. Desacetoxymatricarin [2] did not show cytoprotective activity. The results obtained from the different sesquiterpene lactones studied suggest that the presence of the alpha-methylene-gamma-lactone moiety is, in principle, a requirement for the observed antiulcerogenic activity.