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Drug-drug interactions (DDIs) are a common cause of adverse drug events (ADEs). The electronic medical record (EMR) database and the FDA's adverse event reporting system (FAERS) database are the major data sources for mining and testing the ADE associated DDI signals. Most DDI data mining methods focus on pair-wise drug interactions, and methods to detect high-dimensional DDIs in medical databases are lacking. In this paper, we propose 2 novel mixture drug-count response models for detecting high-dimensional drug combinations that induce myopathy. The "count" indicates the number of drugs in a combination. One model is called fixed probability mixture drug-count response model with a maximum risk threshold (FMDRM-MRT). The other model is called count-dependent probability mixture drug-count response model with a maximum risk threshold (CMDRM-MRT), in which the mixture probability is count dependent. Compared with the previous mixture drug-count response model (MDRM) developed by our group, these 2 new models show a better likelihood in detecting high-dimensional drug combinatory effects on myopathy. CMDRM-MRT identified and validated (54; 374; 637; 442; 131) 2-way to 6-way drug interactions, respectively, which induce myopathy in both EMR and FAERS databases. We further demonstrate FAERS data capture much higher maximum myopathy risk than EMR data do. The consistency of 2 mixture models' parameters and local false discovery rate estimates are evaluated through statistical simulation studies. [ABSTRACT FROM AUTHOR]

An in situ generated oxidation species of nickel quinolinylpropioamide intermediate was produced. Characterization by X‐ray absorption near edge structure (XANES) and EPR provides complementary insights into this oxidized nickel species. With aliphatic amides and isocyanides as substrates, a nickel‐catalyzed facile synthesis of structurally diverse five‐membered lactams could be achieved. Oxidized Ni species in‐depth: An in situ generated oxidation species of the nickel quinolinylpropioamide intermediate was produced. Characterization by XANES and EPR provided complementary insights into this oxidized nickel species. With aliphatic amides and isocyanides as substrates, a nickel‐catalyzed facile synthesis of structurally diverse five‐membered lactams could be achieved. [ABSTRACT FROM AUTHOR]

Recently, utilizing CO2 as a methylation reagent to construct functional chemicals has attracted significant attention. However, the conversion of CO2 is still a challenge due to its inherent inertness. In this study, we have developed a catalyst-free N-methylation of amines to prepare numerous methylamines using CO2 as a methyl source. By utilizing 2 eq. PhSiH3 as the reductant, amines could undergo N-methylation under 1 atm of CO2 in DMF at 90 °C. Aliphatic and aromatic amines were compatible, generating the desired products in up to 95% yield. [ABSTRACT FROM AUTHOR]

Direct radical additions to terminal alkynes have been widely employed in organic synthesis, providing credible access to the anti-Markovnikov products. Because of the Kharasch effect, regioselective control for the formation of Markovnikov products still remains a great challenge. Herein, we develop a transition-metal-free, visible light-mediated radical addition of S-nucleophiles to terminal alkynes, furnishing a wide array of α-substituted vinyl sulfones with exclusive Markovnikov regioselectivity. Mechanistic investigations demonstrated that radical/radical cross-coupling might be the key step in this transformation. This radical Markovnikov addition protocol also provides an opportunity to facilitate the synthesis of other valuable α-substituted vinyl compounds. [ABSTRACT FROM AUTHOR]

Nickel complexes, [Ni(H2BARTPP)](ClO4)2 (R=Ph for 1 or iPr for 2), supported by a pentadentate ligand H2BARTPP were synthesized and oxidized to form NiIII species having a N3S2 coordination environment to mimic the active site of the oxidized form of nickel superoxide dismutase (NiSODox). The NiIII species 2+ exhibited a rhombic signal with g values at 2.15, 2.12 and 2.02 similar to that of NiSODox. DFT calculations revealed that 2+ has an unpaired electron primarily located in the d [ABSTRACT FROM AUTHOR]

Two N3O2 pentadentate ligands, BMPP and BPPP, were prepared for synthesizing highly efficient nickel catalysts, [Ni(BMPP)(CH3CN)](ClO4)2 ( 1) and [Ni(BPPP)(CH3CN)](BPh4)(ClO4) ( 2), for thia-Michael addition of thiophenols to α,β-enones. X-ray structures of 1 and 2 revealed that a labile CH3CN molecule was bound to the nickel center of the catalysts. ESI-MS spectroscopy indicated that thiolate replaced the bound CH3CN molecule and coordinated to the nickel center during the catalytic cycle. [ABSTRACT FROM AUTHOR]

Recently, utilizing CO2 as a methylation reagent to construct functional chemicals has attracted significant attention. However, the conversion of CO2 is still a challenge due to its inherent inertness. In this study, we have developed a catalyst-free N-methylation of amines to prepare numerous methylamines using CO2 as a methyl source. By utilizing 2 eq. PhSiH3 as the reductant, amines could undergo N-methylation under 1 atm of CO2 in DMF at 90 °C. Aliphatic and aromatic amines were compatible, generating the desired products in up to 95% yield. [ABSTRACT FROM AUTHOR]

A strategy that combines electrochemical synthesis and photoredox catalysis was reported for the efficient synthesis of imines. This approach was demonstrated to be highly versatile in producing various types of imines, including symmetric and unsymmetric imines, by exploring the impact of different substituents on the benzene ring of the arylamine. Additionally, the method was specifically applied to modify N-terminal phenylalanine residues and was found to be successful in the photoelectrochemical cross-coupling reaction between NH 2 -Phe-OMe and aryl methylamines, leading to the synthesis of phenylalanine-containing imines. Therefore, this technique would present a convenient and efficient platform for synthesizing imines, with promising applications in chemical biology, drug development, and organic synthesis., (© 2023 Wiley-VCH GmbH.)

For the first time, simple N-tosyl aryl aldimines, prepared from the condensation of tosyl amide and aromatic aldehydes, can be used as substrates in the rhodium catalyzed 1,2-addition reaction using alkenylboron nucleophiles. In the presence of 1.5 mol % of [RhCl(1e)]2, enantioselective addition of various potassium alkenyltrifluoroborates to aryl aldimines furnished the corresponding chiral allylic amines in 73-96% yield and 72->99.5% ee. Notably, this method efficiently provides the di-, tri-, and tetrasubstituted allylic N-tosyl amines with high asymmetric induction.

In order to understand the mechanisms of drug-drug interaction (DDI), the study of pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenetics (PG) data are significant. In recent years, drug PK parameters, drug interaction parameters, and PG data have been unevenly collected in different databases and published extensively in literature. Also the lack of an appropriate PK ontology and a well-annotated PK corpus, which provide the background knowledge and the criteria of determining DDI, respectively, lead to the difficulty of developing DDI text mining tools for PK data collection from the literature and data integration from multiple databases.To conquer the issues, we constructed a comprehensive pharmacokinetics ontology. It includes all aspects of in vitro pharmacokinetics experiments, in vivo pharmacokinetics studies, as well as drug metabolism and transportation enzymes. Using our pharmacokinetics ontology, a PK corpus was constructed to present four classes of pharmacokinetics abstracts: in vivo pharmacokinetics studies, in vivo pharmacogenetic studies, in vivo drug interaction studies, and in vitro drug interaction studies. A novel hierarchical three-level annotation scheme was proposed and implemented to tag key terms, drug interaction sentences, and drug interaction pairs. The utility of the pharmacokinetics ontology was demonstrated by annotating three pharmacokinetics studies; and the utility of the PK corpus was demonstrated by a drug interaction extraction text mining analysis.The pharmacokinetics ontology annotates both in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. The PK corpus is a highly valuable resource for the text mining of pharmacokinetics parameters and drug interactions.