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A New and Specific Method for the Monomethylation of Primary Amines

The reduction of monomeric methyleneamines, representing a convenient and highly specific procedure for the title reaction, is studied.

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Brief introduction of 5-(4-Hydroxyphenyl)isoxazole-3-carboxylic acid

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Pd(II)/Ag(I)-Promoted One-Pot Synthesis of Cyclic Ureas from (Hetero)Aromatic Amines and Isocyanates

A simple and facile one-pot reaction has been developed to afford a diverse range of N,N?-disubstituted benzimidazolones and imidazopyridinones containing two differently substituted N atoms. A cooperative Pd(II)/Ag(I) system promotes the sequential addition/intramolecular C-H amidation reaction of (hetero)aromatic amines and isocyanates, leading to the formation of two C-N bonds. A mechanism involving radical intermediates generated by single-electron transfer (SET) in the presence of a Ag2CO3 oxidant and Pd(OAc)2 Lewis acid is proposed. This protocol offers an operationally easy, simple, and robust approach with the use of readily available starting materials, good functional group tolerance, and high efficiency.

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Synthesis and biological evaluation of N-alkyl-N-(4-methoxyphenyl)pyridin- 2-amines as a new class of tubulin polymerization inhibitors

Based on our prior antitumor hits, 32 novel N-alkyl-N-substituted phenylpyridin-2-amine derivatives were designed, synthesized and evaluated for cytotoxic activity against A549, KB, KBVIN, and DU145 human tumor cell lines (HTCL). Subsequently, three new leads (6a, 7g, and 8c) with submicromolar GI50 values of 0.19-0.41 muM in the cellular assays were discovered, and these compounds also significantly inhibited tubulin assembly (IC50 1.4-1.7 muM) and competitively inhibited colchicine binding to tubulin with effects similar to those of the clinical candidate CA-4 in the same assays. These promising results indicate that these tertiary diarylamine derivatives represent a novel class of tubulin polymerization inhibitors targeting the colchicine binding site and showing significant anti-proliferative activity.

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Can You Really Do Chemisty Experiments About 5-(4-Methoxyphenyl)isoxazole-3-carboxylic acid

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Discovery of a novel class of potent HCV NS4B inhibitors: SAR studies on piperazinone derivatives

HTS screening identified compound 2a (piperazinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the HCV nonstructural protein NS4B. Extensive SAR studies were performed around 2a and the amide function and the C-3/C-6 cis stereochemistry of the piperazinone core were essential for HCV activity. A 10-fold increase in GT-1 potency was observed when the chiral phenylcyclopropyl amide side chain of 2a was replaced with p- fluorophenylisoxazole-carbonyl moiety (67). Replacing the C-6 nonpolar hydrophobic moiety of 67 with a phenyl moiety (95) did not diminish the GT-1 potency. A heterocyclic thiophene moiety (103) and an isoxazole moiety (108) were incorporated as isosteric replacements for the C-6 phenyl moiety (95), resulting in significant improvement in GT-1b and 1a potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development.

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Discovery of novel N -phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis

In this paper, we describe the screening of a 14640-compound library using a novel whole mycobacteria phenotypic assay to discover inhibitors of EthR, a transcriptional repressor implicated in the innate resistance of Mycobacterium tuberculosis to the second-line antituberculosis drug ethionamide. From this screening a new chemical family of EthR inhibitors bearing an N-phenylphenoxyacetamide motif was identified. The X-ray structure of the most potent compound crystallized with EthR inspired the synthesis of a 960-member focused library. These compounds were tested in vitro using a rapid thermal shift assay on EthR to accelerate the optimization. The best compounds were synthesized on a larger scale and confirmed as potent ethionamide boosters on M. tuberculosis-infected macrophages. Finally, the cocrystallization of the best optimized analogue with EthR revealed an unexpected reorientation of the ligand in the binding pocket.

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Mn(III)-based oxidative cyclization of N-aryl-3-oxobutanamides. facile synthesis and transformation of substituted oxindoles

The oxidation of 3-oxo-N-phenylbutanamides 1 with manganese(III) acetate in ethanol afforded dimeric 3,3′-biindoline-2,2′-dione derivatives 3-5. A similar reaction of N,2-disubstituted N-aryl-3-oxobutanamides 6 in acetic acid produced 3-acetylindolin-2-ones 7 bearing various substituents in good to excellent yields. The acetylindolinones 7 were easily deacetylated by treatment using neutral alumina in diethyl ether. Both the acetylindolinones 7 and deacetylated indolinones 8 were transformed by reduction into the substituted 1H-indoles.

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Iron-Catalyzed Selective N-Methylation and N-Formylation of Amines with CO2

We herein describe an efficient iron-catalyzed selective N-methylation and N-formylation of amines with CO2 and silane using mono-phosphine as ligand. With commercially available [CpFe(CO)2]2 as catalyst, Fe-catalyzed methylation of amines was achieved with triphenylphosphine as a ligand. Using tributylphosphine as a ligand, Fe-catalyzed formylation of amines was realized at a lower temperature. The method was successfully applied in the late-stage methylation and formylation of drug molecules containing amine moiety. (Figure presented.).

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Donor-acceptor interaction and photochemistry of polymethylene-linked bichromophores in solution

The ground-state and the excited-state spectroscopic properties of four series of polymethylene-linked anthracene-dialkylaniline bichromophores were compared as a probe to the relationship between energetics and distance in photoinduced electron transfer (PET). The results demonstrate that, when the energy level of the charge-transfer (CT) state is lowered below that of the localized excited state by appropriate substituents, there is a strong electron-donor-acceptor (EDA) interaction in the ground state which is absent in other bichromophores. Absorption and fluorescence excitation studies revealed that there is an unusually strong EDA interaction in the ground state of A-2 which is absent in other members in the A series.When A-2 is excited directly into this EDA absorption, it exhibits two CT emissions, one at 490 nm and the other at 605 nm. The quantum yield (tau(f))and the lifetime (Phi(f)) of the two emissions are dependent on the viscosity of the alkane solvent. The Phi(f) and the tau(f) of the 490 nm emission increased when the solvent viscosity was increased; however, those of the 605 nm emission remained essentially unchanged. The risetime of the 605 nm emission is 420 ps, but that of the 490 nm emission is instrument-function limiting. The results suggest that the two CT emissions may be derived from the two different conformations of the CT state. The 490 nm emission may be derived from the trans conformer of A-2, which is the major conformer at equilibrium. The EDA interaction in the trans conformer of A-2 may be treated as a type of through-sigma-bond interaction via the spacer between the n orbital of the anilino nitrogen and the pi orbital of the anthryl group. The direct excitation of A-2 from its EDA ground state to the CT state indicates that PET may occur in a sigma-linked bichromophoric system upon light absorption, thus reaching the limiting rate of a photochemical process.

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Three-component difluoroalkylamination of alkenes mediated by photoredox and iron cooperative catalysis

A three-component difluoroalkylamination of alkenes with BrCF2CO2Et and amines mediated by visible-light photoredox and iron cooperative catalysis is described. Electron rich, electron poor, and internal styrenes are all tolerated giving the desired products in good yields. The Csp3-Csp3 and Csp3-N bonds are simultaneously formed under mild conditions. A radical pathway is proposed by experimental studies.

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BICYCLIC COMPOUNDS HAVING ANTIMITOTIC AND/OR ANTITUMOR ACTIVITY AND METHODS OF USE THEREOF

The present invention provides bicyclic compounds, pharmaceutically acceptable salts, prodrugs, solvates, and hydrates thereof, having antimitotic activity, anti-multidrug resistance activity, such as for example P-glycoprotein inhibition, and antitumor activity, and which inhibit paclitaxel sensitive and resistant tumor cells. Also provided are methods of utilizing these compounds for treating tumor cells and inhibiting mitosis of cancerous cells.

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