ABSTRACT
Transmissible spongiform encephalopathies (TSEs) are thought to arise from aggregation of a protease resistant protein denoted PrP(Sc), which is a misfolded isoform of the normal cellular prion protein PrP(C). Using virtual high-throughput screening we have selected structures analogous to acridine, 2-methyquinoline and 2-phenylquinazoline as potential therapeutic candidates for the treatment of TSEs. From the synthesis and screening of constructed libraries we have shown that an electron-rich aromatic ring attached through an amine linker to the position para to the ring nitrogen is beneficial to both binding to PrP(C) and the suppression of PrP(Sc) accumulation for acridine and 2-methylquinoline analogues. 2-Phenylquinazoline analogues appear to utilise a different mode of action by binding at a different location and/or pose. We report IC50s in the nanomolar range.
Subject(s)
Acridines/chemical synthesis , Acridines/pharmacology , Prions/antagonists & inhibitors , Quinaldines/chemical synthesis , Quinaldines/pharmacology , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Acridines/chemistry , Animals , Binding, Competitive , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Mice , Molecular Structure , Quinaldines/chemistry , Quinazolines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The peak intensities obtained when 2,5-dihydroxybenzoic acid (DHB) was used as a 'classic' matrix were measured using substance P (SP) and betacyclodextrin (BCD) as analytes. Enhancements in peak intensities were observed going from 1:1 MeOH/H2O to dimethylforamide (DMF) as matrix solvents. Also non-covalent interactions between SP and solvent and DHB were observed suggesting close interactions between matrix, solvent and analyte in the gas-phase. Peak enhancements were previously reported with 'superDHB' (DHB and 2-hydroxy-5-methoxybenzoic acid at 10% v/v). Co-addition of structural analogues and their respective absorption coefficients were determined. It was found that other analogues used as co-matrices could give analyte peak enhancement similar to reported for sDHB with the additional benefit that some analogues could act as matrices with DHB addition. No direct correlation was observed between absorption coefficient and the ability of the molecule to act as a 'good' UV MALDI matrix.
Subject(s)
Solvents/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/instrumentation , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Substance P/analysis , Substance P/chemistry , beta-Cyclodextrins/analysis , beta-Cyclodextrins/chemistryABSTRACT
The palladium-catalyzed reaction of pinacolone with tert-butyldimethyl(3-(2-bromophenyl)allyloxy)silane results in direct formation of 1-vinyl-3-tert-butyl-1H-isochromene. This is the result of a ketone arylation followed by an intramolecular cyclization of the enolate with the allylic system. The use of a lithium diamide base appears to be essential for success. The tert-butyldimethylsilyl protecting group is also an essential choice as it furnishes the appropriate reactivity to promote allylic substitution after the aryl coupling process. The use of more effective leaving groups, such as acetate, results in reaction of the allylic group, and no aryl coupling is observed. Through the appropriate selection of phosphine ligand and solvent, either the cyclized isochromene product or the noncyclized intermediate may be formed selectively. A short combinatorial study of the scope and limitations of the reaction, involving 24 ketones, is described.
ABSTRACT
Bryostatins are a class of antineoplastic compounds isolated from the bryozoans Bugula neritina. A wide range of scientific research is currently underway, studying different aspects of the bryostatins. In this review we try to summarize the latest findings, including all the topics involved, from marine biology to medicinal chemistry.
Subject(s)
Antineoplastic Agents , Bryozoa/chemistry , Lactones , Protein Kinase C/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Bryostatins , Bryozoa/metabolism , Clinical Trials as Topic , Drug Screening Assays, Antitumor , Enzyme Activation , Humans , Lactones/chemical synthesis , Lactones/chemistry , Lactones/metabolism , Lactones/therapeutic use , Macrolides , Molecular Structure , Neoplasms/drug therapy , Protein Kinase C/chemistryABSTRACT
BACKGROUND: Individuals entering prison are known to have high rates of human immunodeficiency virus (HIV) infection, and inmates are known to engage in high-risk behavior. This suggests the potential for intraprison spread of HIV infection, but this has not been documented. METHODS: All prisoners (N = 556) in the Florida Department of Corrections who had been continuously incarcerated since 1977 were identified. The medical records of these prisoners were reviewed to determine whether they had been tested for HIV infection and, if tested, whether the results were positive. Results were considered positive if there were reactions to two enzyme-linked immunosorbent assays confirmed by Western blot assay. If an individual tested positive, the medical record was reviewed to determine whether the patient had been treated for conditions consistent with HIV infection. RESULTS: Eighty-seven of the 556 prisoners had undergone testing for HIV infection. Of the tested inmates, 18 (21%) were found to be positive for HIV infection. Eight of these individuals had no HIV-related conditions, and 10 had HIV-related symptoms. CONCLUSIONS: The results present strong evidence for intraprison transmission of HIV infection. Given that most inmates serve relatively short sentences, there is a strong possibility that prison-acquired HIV infection will be carried into the "free world." Preventive programs in prisons may be very important in controlling HIV infection in our society.
