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PubMed1977

Synthesis and adrenergic beta-blocking activity of some 1,3-benzodioxole derivatives.

A series of 1,3-benzodioxole derivatives was synthesized. We found four compounds (2,3,10 and 11 in Table IV) to have about the same order of beta-blocking activity as that of sotalol. In addition, it is of interest that some of the compounds (2-4) were found to have hypotensive activites, although they were about one-tenth of that of hydralazine. Sotalol did not produce any change in blood pressure, and propranolol raised the blood pressure.

Adrenergic beta-Antagonists↗
PubMed1979

Steric effects of substituents on phenethylamine hallucinogens. 3,4-(Methylenedioxy)amphetamine analogues alkylated on the dioxole ring.

The compounds 1-(2-methyl-1,3-benzodioxol-5-yl)-2-aminopropane and 1-(2,2-dimethyl-1,3-benzodioxol-5-yl)-2-aminopropane were synthesized and evaluated for pharmacologic effects in mice. These can be viewed as analogues of the known psychotomimetic agent 3,4-(methylenedioxy)amphetamine (MDA). Their hydrochloride salts were compared with MDA for their ability to increase spontaneous motor activity and to elicit behavioral effects. The former compounds was MDA-like in action, while the latter was not. The results suggest that one face of the molecule must be free of steric bulk to possess activity.

3,4-Methylenedioxyamphetamine↗
PubMed1979

Chemical characterization of 465 known or suspected carcinogens and their correlation with mutagenic activity in the Salmonella typhimurium system.

Since chemicals exhibiting mutagenic activity pose a potential hazard to their users, there is increasing acceptance of mutagenicity testing as an integral part of a premarketing toxicological evaluation of chemicals. In vitro testing has gained much notoriety as quick and relatively inexpensive means to assess the mutagenic potential of chemicals. However, the innovative use of microsomes to simulate metabolism has not changed the fact that in vitro activation cannot duplicate faithfully the metabolism that occurs in vivo. This shortcoming will express itself by the production of false negatives and possibly false positives during mutagenicity screening. This assertion is also borne out by a reanalysis of the ability of known animal carcinogens to cause mutations in the generally recognized premier in vitro system, the Salmonella-S-9 system. Although previous studies have suggested that a high percentage (greater than 85%) of all carcinogens will be mutagenic in this system, with no indication that false negatives are associated with certain chemical types, these findings are of uncertain practical value due to the limited number of chemical types that were considered. An analysis of 465 compounds with known or suspected carcinogenic activity indicates that about 58% have been adequately tested in Salmonella, that the testing has concentrated on certain chemical types and has neglected others, and that some categories of carcinogens exhibit individual correlations that are unsatisfactorily low by any standard. Poorly detected categories of carcinogens include: azonaphthols; carbamyls and thiocarbamyls; phenyls; benzodioxoles; polychlorinated aromatics, cyclics, and aliphatics; steroids; antimetabolites; and symmetrical hydrazines. Nonstandard procedures are necessary to optimize the testing of chemicals that are bactericidal, that are volatile, or that cross-link DNA. False negatives appear to arise for two reasons: an inability to devise an in vitro activation system that can be reliably used in a standard way; and an inability to detect the entire spectrum of mutational events that can lead to the induction of cancer.

Antimetabolites↗
PubMed2026

Targeting ALDH2 with Alda-1 to reverse cisplatin resistance in lung adenocarcinoma.

BACKGROUND: Cisplatin resistance remains a major obstacle in lung adenocarcinoma (LUAD) treatment. The role of Aldehyde dehydrogenase 2 (ALDH2), a detoxifying enzyme, in LUAD prognosis and chemoresistance is poorly understood. METHODS: We analyzed ALDH2's prognostic value using clinical cohorts, TCGA, and proteomic data. Cisplatin-resistant cell lines and xenograft models were used to assess the effect of the ALDH2 agonist Alda-1. Molecular mechanisms were investigated via gain/loss-of-function studies. RESULTS: High ALDH2 expression was significantly associated with improved survival in univariate analysis and correlated with a favorable genomic instability profile in LUAD. Pharmacological activation of ALDH2 with Alda-1 restored cisplatin sensitivity in resistant cells and potently enhanced cisplatin's efficacy in vivo. Mechanistically, ALDH2 activation upregulated PKC-ζ, leading to downregulation of the drug efflux pump MDR1. Proteomic analysis further linked low ALDH2 expression to a pro-chemoresistance signature. CONCLUSION: ALDH2 represents a potential prognostic biomarker associated with favorable outcomes in LUAD, particularly in patients receiving chemotherapy. Its activation via Alda-1 overcomes cisplatin resistance by targeting the PKC-ζ/MDR1 axis, presenting a novel therapeutic strategy.

Cisplatin↗
PubMed2024

Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on the oropharyngeal metagenome in adolescents with cystic fibrosis.

BACKGROUND: Triple modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and impacts upon the respiratory microbiome in people with Cystic fibrosis (pwCF) with advanced lung disease. However, adolescents with cystic fibrosis (CF) are less colonized with bacterial pathogens than adult pwCF but their microbiota already differs from healthy individuals. The aim of this study was to longitudinally analyze the impact of ETI on the respiratory metagenome in adolescents with predominantly mild CF lung disease. METHODS: In this prospective observational study, we included pwCF aged 12-20 years with at least one F508del mutation, who collected oropharyngeal swabs before and after initiation of ETI therapy twice per week to biweekly over three months. We performed whole metagenome shotgun sequencing, followed by host DNA filtering and taxonomic profiling. We used linear and additive mixed effects models adjusted for known confounders and corrected for multiple testing to study longitudinal development of the microbiome. We analyzed bacterial diversity, abundance, and strain-level phylogeny. RESULTS: We analyzed the metagenomic data of 297 swabs of 20 pwCF. Microbiome composition changed after initiation of ETI therapy. We observed a slight diversification of the microbiome over time (Inv Simpson, Coef 0.085, 95 %CI 0.003, 0.17, p = 0.04). Strain-level analysis and clustering showed that strain retention of the most frequent bacterial species is predominant even during ETI therapy. CONCLUSIONS: During three months of ETI therapy, commensal bacteria increased, which may help to prevent overgrowth of bacterial pathogens.

Humans↗
PubMed1979

[Comparative studies on the chemical modifications of Ehrlich ascites tumor cell membranes by hydrophobic drugs (cepharanthine, papaverine and cholesterol) (author's transl)].

Comparative studies were done on the actions of hydrophobic drugs (cepharanthine, papaverine and cholesterol) regarding chemical modifications of Ehrlich ascites tumor cell membranes. Changes in membrane potential monitored by using cyanine dye (diS-C3-(5)) were induced by cepharanthine and papaverine, but not by cholesterol. Increase in membrane permeability of K+ ions induced with lysolecithin was strongly inhibited in the order of papaverine, cholesterol and cepharanthine. Oxygen uptake by the cells was also strongly inhibited by papaverine, but the inhibitory effect by cepharanthine was little and cholesterol had no effect. Membrane fluidity was decreased in the order of cholesterol, cepharanthine and papaverine. From these results, it was suggested that papaverine maintained the compartmentation of K+ ion and membrane fluidity by regulating the intracellular mitochondrial metabolism or by inhibiting the membrane bound ATPase nucleotidase activity. The membrane stabilizing effect of cepharanthine and cholesterol probably was due to decrease in the membrane fluidity because of the hydrophobic association to the lipid bilayer of the cell membranes.

Alkaloids↗