ABSTRACT
Oligodeoxyribonucleotides bearing boranephosphonate linkages (bpDNA) were shown to reduce a number of metal ions and form nanoparticles through a novel reaction pathway that leads to phosphate diesters or phosphate triesters in water or alcohols respectively. The synthetic utility of this reaction was further demonstrated through the synthesis of oligodeoxyribonucleotides containing phosphate triester linkages. This new reactivity also makes bpDNA promising for use in construction of DNA templated metallic nanostructures.
Subject(s)
Boron Compounds/chemical synthesis , DNA/chemistry , Gold/chemistry , Platinum/chemistry , Silver/chemistry , Thymidine/analogs & derivatives , Alcohols/chemistry , Cations , Magnetic Resonance Spectroscopy , Microscopy, Electron, Transmission , Molecular Mimicry , Nanoparticles/chemistry , Nanoparticles/ultrastructure , Oligodeoxyribonucleotides/chemical synthesis , Organophosphates/chemistry , Oxidation-Reduction , Solvents , Thymidine/chemical synthesis , Water/chemistryABSTRACT
Breast cancer resistance protein (BCRP) is a point of interest in drug-drug interaction safety testing. Therefore, a consensus probe that can be applied as victim in multiple experimental settings is of great benefit. Identification of candidates has been driven by the amount and quality of available clinical data, and as a result, drugs such as sulfasalazine and rosuvastatin have been suggested. In this article, the in vitro performance of 5 possible alternatives was evaluated: atorvastatin, chlorothiazide, dantrolene, topotecan, and teriflunomide, and benchmarked against sulfasalazine and rosuvastatin in reference in vitro assays for BCRP drug-drug interaction testing. Based on the results, teriflunomide is proposed as an alternate in vitro BCRP probe.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Neoplasm Proteins/metabolism , Animals , Biological Transport , Caco-2 Cells , Crotonates/metabolism , Crotonates/pharmacokinetics , Crotonates/pharmacology , Dogs , Drug Interactions , Humans , Hydroxybutyrates , Madin Darby Canine Kidney Cells , Nitriles , Toluidines/metabolism , Toluidines/pharmacokinetics , Toluidines/pharmacologyABSTRACT
Novel bromine-containing positively charged labels 5-bromo-1-ethyl-thiazolium (BET+) and 5-bromo-1-ethyl-pyridinium (BEP+) ions were studied for improving the interpretation of MS/MS spectra of peptides. 2,5-Dibromo-1-ethyl-thiazolium tetrafluoroborate (DBET) reacts in the order: epsilon->>alpha-amino group>>hydroxyl group of Tyr while 2,5-dibromo-1-ethyl-pyridinium tetrafluoroborate (DBEP) reacts preferably with thiol group of Cys>>hydroxyl group of Tyr. In this study a simple and fast CE/MS/MS method is presented for investigating the labeling reaction with these new reagents, where the difference in migration times of labeled and unlabeled peptides also gives us information about the position of labeling. These bromine-containing reagents simplify the MS/MS spectra of peptides: the charge of the derivatives increases the intensity of the corresponding ions, thus enhancing the sensitivity of the detection and the characteristic distribution of the bromine isotope (the 79Br and 81Br ratio is nearly one) facilitating the recognition. By eliminating the non-doubled peaks, clear and easily interpretable MS/MS spectra can be produced that contain only the labeled fragments.
Subject(s)
Bromine/chemistry , Peptide Fragments/chemistry , Peptides/analysis , Peptides/chemistry , Cysteine/chemistry , Electrophoresis, Capillary , Indicators and Reagents , Isotope Labeling/methods , Isotopes , Molecular Weight , Peptide Fragments/analysis , Peptides/chemical synthesis , Sequence Analysis , Spectrometry, Mass, Electrospray Ionization , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Tandem Mass Spectrometry , Tyrosine/chemistryABSTRACT
The purpose of this study was to characterize the uptake of carnitine, the physiological substrate, and the uptake of 3-(2,2,2-trimethylhydrazinium)propionate, a consensus substrate by rat Octn2 and human OCTN2 transporters as well as to characterize drug-mediated inhibition of l-carnitine uptake by the rat and human orthologs overexpressed in CHO-K1 cells. l-carnitine and 3-(2,2,2-trimethylhydrazinium)propionate were found to be a lower affinity substrate for rat Octn2 (KM = 32.66 ± 5.11 µM and 23.62 ± 4.99 µM respectively) than for human OCTN2 (KM = 3.08 ± 0.74 µM and 7.98 ± 0.63 µM). The intrinsic clearance (CLint) value for carnitine was higher for the human than for the rat transporter (22.82 ± 5.57 ml/min*mg vs 4.008 ± 0.675 ml/min*mg). For 3-(2,2,2-trimethylhydrazinium)propionate, in contrast, the CLint value for rat Octn2 was higher than for human OCTN2 (323.9 ± 72.8 ml/min*mg vs 65.11 ± 5.33 ml/min*mg). Furthermore, many pharmacologically important drugs were shown to affect l-carnitine transport by Octn2/OCTN2. The correlation between the IC50 datasets for the rat and human transporter resulted in an r value of 0.47 (p > 0.05). However, the greatest difference was less than seven-fold and 13 of 15 compounds yielded a difference less than 3-fold. Thus, the transporters from these two species showed an overlapping but somewhat different substrate and inhibitor specificity.
Subject(s)
Carnitine/pharmacology , Methylhydrazines/pharmacology , Solute Carrier Family 22 Member 5/antagonists & inhibitors , Animals , CHO Cells , Cells, Cultured , Cricetulus , Dose-Response Relationship, Drug , Humans , Kinetics , Male , Rats , Rats, Wistar , Solute Carrier Family 22 Member 5/genetics , Solute Carrier Family 22 Member 5/metabolism , Species Specificity , Structure-Activity RelationshipABSTRACT
8-Benzyloxymethyl-3,4,5-tribenzoyloxy-9-oxa-1-azabicyclo[4.2.1]nonane has been prepared as the single diastereoisomer 8 from an intramolecular 1,3-dipolar cycloaddition involving 2-(benzyloxy)acetaldehyde and omega-unsaturated hydroxylamine 7 derived from methyl alpha-D-glucopyranoside. The analogous 8-methoxycarbonyl 9-oxa-1-azabicyclo[4.2.1]nonane was afforded in a similar manner, from methyl D-galactopyranoside and methyl glyoxylate, as a 3:1 mixture of diastereoisomers 15 and 16. When conducted in achiral ionic liquid 17 this ratio increased to 8:1, and in chiral ionic liquid 18, compound 15 was formed exclusively.