piperidines and aniline

The nucleobase guanine in DNA (dG) and RNA (rG) has the lowest standard reduction potential of the bases, rendering it a major site of oxidative damage in these polymers. Mapping the sites at which oxidation occurs in an oligomer via chemical reagents utilizes hot piperidine for cleaving oxidized DNA and aniline (pH 4.5) for cleaving oxidized RNA. In the present studies, a series of time-dependent cleavages of DNA and RNA strands containing various guanine lesions were examined to determine the strand scission rate constants. The guanine base lesions 8-oxo-7,8-dihydroguanine (OG), spiroiminodihydantoin (Sp), 5-guanidinohydantoin (Gh), 2,2,4-triamino-2H-oxazol-5-one (Z), and 5-carboxamido-5-formamido-2-iminohydantoin (2Ih) were evaluated in piperidine-treated DNA and aniline-treated RNA. These data identified wide variability in the chemical lability of the lesions studied in both DNA and RNA. Further, the rate constants for cleaving lesions in RNA were generally found to be significantly smaller than for lesions in DNA. The OG nucleotides were poorly cleaved in DNA and RNA; Sp nucleotides were slowly cleaved in DNA and did not cleave significantly in RNA; Gh and Z nucleotides cleaved in both DNA and RNA at intermediate rates; and 2Ih oligonucleotides cleaved relatively quickly in both DNA and RNA. The data are compared and contrasted with respect to future experimental design.

Topics: Aniline Compounds; DNA; DNA Cleavage; Guanine; Kinetics; Molecular Structure; Oxidation-Reduction; Piperidines; RNA; RNA Cleavage; Time Factors

A series of novel N-arylmethyl substituted piperidine-linked aniline derivatives were designed, synthesized and evaluated for their anti-HIV activity in MT-4 cells. All the new compounds showed moderate to potent activities against wild-type (wt) HIV-1 with an EC₅₀ range from 0.022 to 2.1 μM. Among them, compound 5a6 (EC₅₀=0.022 ± 0.0091 μM, SI >10,770) was confirmed to be the most potent and selective inhibitor, which proved more potent than DDI and DLV in a cell-based assay against wt HIV-1, and more efficient than NVP in an RT (reverse transcriptase) assay. Besides, it is worth noting that compound 7a1 retained moderate inhibitory activity (EC₅₀=4.8 ± 0.95 μM) against the HIV-1 double RT mutant strain (K103N/Y181C). The preliminary structure-activity relationship was discussed and rationalized by molecular simulation.

Topics: Aniline Compounds; Anti-HIV Agents; Drug Design; HIV-1; Humans; Models, Molecular; Piperidines; Structure-Activity Relationship

OMAR analogs reference standards and their corresponding desmethylated precursors were synthesized from substituted anilines either in 4 and 5 steps with 27-32% and 24-31% yield, or in 3 and 4 steps with 21-30% and 19-28% yield, respectively. [(11)C]OMAR and its analog radioligands were prepared from their desmethylated precursors with [(11)C]CH(3)OTf through O-[(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 50-65% radiochemical yields based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB.

Topics: Aniline Compounds; Animals; Brain; Carbon Radioisotopes; Humans; Isotope Labeling; Ligands; Piperidines; Positron-Emission Tomography; Pyrazoles; Radiopharmaceuticals; Receptor, Cannabinoid, CB1; Structure-Activity Relationship

Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor (NR) superfamily and regulate development, growth, and metabolism. Upon binding thyroid hormone, TR undergoes a conformational change that allows the release of corepressors and the recruitment of coactivators, which in turn regulate target gene transcription. Although a number of TR antagonists have been developed, most are analogs of the endogenous hormone that inhibit ligand binding. In a screen for inhibitors that block the association of TRβ with steroid receptor coactivator 2 (SRC2), we identified a novel methylsulfonylnitrobenzoate (MSNB)-containing series that blocks this interaction at micromolar concentrations. Here we have studied a series of MSNB analogs and characterized their structure activity relationships. MSNB members do not displace thyroid hormone T3 but instead act by direct displacement of SRC2. MSNB series members are selective for the TR over the androgen, vitamin D, and PPARγ NR members, and they antagonize thyroid hormone-activated transcription action in cells. The methylsulfonylnitro group is essential for TRβ antagonism. Side-chain alkylamine substituents showed better inhibitory activity than arylamine substituents. Mass spectrum analysis suggested that MSNB inhibitors bind irreversibly to Cys-298 within the AF-2 cleft of TRβ to disrupt SRC2 association.

Topics: Aniline Compounds; HEK293 Cells; Hep G2 Cells; Humans; Methylamines; Nitrobenzoates; Nuclear Receptor Coactivator 2; Piperidines; Protein Binding; Receptors, Thyroid Hormone; Reverse Transcriptase Polymerase Chain Reaction; Structure-Activity Relationship

An operationally simple and concise synthesis of anilinoethanolamines, as NMDA NR2B receptor antagonist ifenprodil analogues, was developed via a copper-catalyzed amination of the corresponding bromoarene. Coupling was achieved with linear primary alkylamines, alpha,omega-diamines, hexanolamine and benzophenone imine, as well as with aqueous ammonia, in good yields using CuI and N,N-diethylsalicylamide, 2,4-pentadione or 2-acetylcyclohexanone as catalytic systems. Amination with ethylene diamine was efficient even in the absence of an additive ligand, whereas no reaction occurred with ethanolamine whatever the conditions used. The anilinoethanolamines were evaluated as NR2B receptor antagonists in a functional inhibition assay. Aminoethylanilines displayed inhibition effects close to that of ifenprodil.

Topics: Amination; Aniline Compounds; Bromine Compounds; Catalysis; Cell Line; Copper; Ethanolamine; Humans; Piperidines; Receptors, N-Methyl-D-Aspartate

The N arylation of primary and secondary aliphatic amines, anilines, and imidazoles with novel potassium aryl triolborates was carried out in the presence of a reoxidant and a catalytic amount of Cu(OAc)(2) (10 mol %). Aryl triolborates were found to be better reagents than aryl boronic acids or potassium aryl trifluoroborates as the former achieved high yields under mild conditions. Coupling of primary and secondary aliphatic amines to give N-aryl amines in excellent yields was performed under oxygen atmosphere. The reactions of anilines and imidazoles to provide N-aryl anilines and N-aryl imidazoles in good yields proceeded smoothly when trimethylamine N-oxide was used as an oxidant.

Topics: Amines; Aniline Compounds; Borates; Catalysis; Copper; Hydrogen; Imidazoles; Molecular Structure; Nitrogen; Piperidines

Microchip capillary electrophoresis (CE), coupled with indirect fluorescence detection was investigated for estimating the pK(a) values of non-fluorescent compounds. The CE method is based on the differences in electrophoretic mobility of the analyte as a function of the pH of the running buffer. Nine compounds were tested, including several of pharmaceutical importance, with pK(a) values from 10.3 to 4.6. All buffers contained 5-TAMRA as the fluorescent probe for indirect detection. Calculated pK(a) values agreed well with literature values obtained by traditional methods, differing not more than 0.2 from the literature value. The current work on single lane chips demonstrates the principle of microchip CE with indirect detection as a viable method for estimating pK(a) values. However, increased throughput will be required using a multilane chip to enable the approach to be used practically.

Topics: Aniline Compounds; Chemical Phenomena; Chemistry, Physical; Cimetidine; Electrophoresis, Microchip; Ethosuximide; Fluorescence; Fluorescent Dyes; Hydrogen-Ion Concentration; Piperidines; Prilocaine; Procaine; Pyridines; Ranitidine; Reproducibility of Results; Rhodamines; Sulfanilamide; Sulfanilamides; Uracil

Topics: Aniline Compounds; Coloring Agents; Piperidines; Procaine