6′,7′‐Dihydroxybergamottin in grapefruit juice and Seville orange juice: Effects on cyclosporine disposition, enterocyte CYP3A4, and P‐glycoprotein

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109869/1/cptclpt1999363.pd

Increased Helicobacter pylori-associated gastric cancer risk in the Andean region of Colombia is mediated by spermine oxidase

Helicobacter pylori infection causes gastric cancer, the third leading cause of cancer death worldwide. More than half of the world’s population is infected, making universal eradication impractical. Clinical trials suggest that antibiotic treatment only reduces gastric cancer risk in patients with non-atrophic gastritis (NAG), and is ineffective once preneoplastic lesions of multifocal atrophic gastritis (MAG) and intestinal metaplasia (IM) have occurred. Therefore, additional strategies for risk stratification and chemoprevention of gastric cancer are needed. We have implicated polyamines, generated by the rate-limiting enzyme ornithine decarboxylase (ODC), in gastric carcinogenesis. During H. pylori infection, the enzyme spermine oxidase (SMOX) is induced, which generates hydrogen peroxide from the catabolism of the polyamine spermine. Herein, we assessed the role of SMOX in the increased gastric cancer risk in Colombia associated with the Andean mountain region when compared with the low-risk region on the Pacific coast. When cocultured with gastric epithelial cells, clinical strains of H. pylori from the high-risk region induced more SMOX expression and oxidative DNA damage, and less apoptosis than low-risk strains. These findings were not attributable to differences in the cytotoxin-associated gene A oncoprotein. Gastric tissues from subjects from the high-risk region exhibited greater levels of SMOX and oxidative DNA damage by immunohistochemistry and flow cytometry, and this occurred in NAG, MAG and IM. In Mongolian gerbils, a prototype colonizing strain from the high-risk region induced more SMOX, DNA damage, dysplasia and adenocarcinoma than a colonizing strain from the low-risk region. Treatment of gerbils with either α-difluoromethylornithine, an inhibitor of ODC, or MDL 72527 (N[superscript 1,]N[superscript 4]-Di(buta-2,3-dien-1-yl)butane-1,4-diamine dihydrochloride), an inhibitor of SMOX, reduced gastric dysplasia and carcinoma, as well as apoptosis-resistant cells with DNA damage. These data indicate that aberrant activation of polyamine-driven oxidative stress is a marker of gastric cancer risk and a target for chemoprevention.National Institutes of Health (U.S.) (Grant P01CA028842)Vanderbilt Digestive Disease Center (Grant P30DK058404

Novel Pt(II) and Pd(II) complexes with polyamine analogues: Synthesis and vibrational analysis

A vibrational spectroscopy study (infrared and Raman) is reported for the biogenic polyamine analogues norspermidine (NSpd), N(1),N(11)-bis(ethyl)norspermine (BENSpm) and N(1)-cyclo-propylmethyl-N(11)-ethylnorspermine (CPENSpm), as well as for their newly synthesised Pt(II) and Pd(II) complexes. Attending to the potential antineoplastic properties of this kind of systems, their full conformational characterization is essential for understanding the molecular basis of their cytotoxic activity and the mechanisms through which they are transported into the cell. The all-trans geometry was found to be favoured for all the alkylated polyamines, in their totally protonated state, while their polynuclear complexes presented a stable geometry very similar to that previously obtained for the analogous chelates with spermidine (M(3)Spd(2)) and spermine (M(2)Spm), comprising two or three cisplatin-like (MCl(2)NH(2)) moieties

QSAR study on the contribution of log P and E(s) to the in vitro antiprotozoal activity of glutathione derivatives.

A series of N-S-blocked glutathione monoester and diester derivatives based on N-benzyloxycarbonyl-S-(2,4-dinitrophenyl)glutathione were evaluated for activity against the pathogenic parasites Trypanosoma brucei brucei, Trypanosoma cruzi, and Leishmania donovani in vitro.Only monoesters 7-9 with a log P value of >2.7 were active inhibitors of T.b. brucei bloodstream form trypomastigotes. Diester compounds 10-15 and 17-27 in most cases were better inhibitors of T.b. brucei than monoester compounds, and some displayed high activity against T. cruzi 14 and L. donovani 17, 19, 29. Compounds 14, 24, and 25 were the most active compounds identified against T.b. brucei having ED(50) values of <0.4 microM. Analysis of the inhibition data (ED(50)) vs calculated log P and E(s) values provided evidence to support membrane penetration and steric factors as the key component in the activity of these compounds. The optimum values for log P and E(s) determined were 5.8 and -0.70, respectively. A QSAR equation relating log(1/ED(50)) vs log P and E(s) was determined and interpreted within the proposed mechanism of activity for these compounds