Novel antioxidant compounds

The autoxidation process, mechanism of action of radical-trapping antioxidants and the problem of textile yellowing are described and reviewed. Structures implicit in the function of an antioxidant by promotion of radical stabihsation are identified and textile yellowing is attributed largely to reactions of antioxidants with NO2. The reaction of ethanolic solutions of 2,6-di-r-butyl-4-methylphenol (BHT) with several concentrations of gaseous NO2 are investigated. The main products are 2,6-dir-butyl-4-methyl-4-hydroxy-2,5-cyclohexadienone (MQOL) and 2,6-di-r-butyl-4-methyl-4-nitro-2,5-cyclohexadienone (MQN). Additional products are observed when lower- concentrations of BHT and NO2 are employed. The major product, MQN, is shown to be unstable in aqueous ethanohc solutions and the yellowing component of the reaction solutions is identified as 2,6-di-r-butyl-4-nitrophenol (NP).Two methods for screening potential compounds for antioxidant activity involving the inhibition of BHT product formation and the NO2-/NO3-ratio are described. They indicate that kojic acid, maltol and 2,5-dimethyl-4-hydroxyfuranone possess similar degrees of antioxidant activity to BHT. This is shown to be consistent with antioxidant function being promoted by the structural features identified.A quantitative NO2-yellowing test is described which allows rapid determination of the yellowing indices (OUYI) of test compounds. The results support the use of kojic acid and maltol as alternatives to BHT.An investigation of kojic acid indicates that it is both nitrosated by gaseous NO2, and undergoes a complicated series of reactions. Investigations with 3-methylcyclopentane-1,2-dione confirm that cychc 1,2-diones both reduce and trap gaseous NO2, a possible strategy for reducing yellowing.The foregoing studies indicate possible structural requirements for a NO2yellowing antioxidant and the synthesis of several N-(3,5-di-r-butyl-4-hydroxyphenyl) cyclic imides has been accomplished. This has provided a group of new compounds which show similar antioxidant activity to BHT, but are less prone to NO2-yellowing than 4-substituted hindered phenols possessing labile hydrogen atoms. Studies on the solvolysis of these cyclic imide compounds suggest that sufficient stability to obtain a commercially useful antioxidant may be imparted by the bulky alkyl substituents in the imide ring, as in the case of N-(3,5-di-f-butyl-4-hydroxyphenyl)-3,3-dimethylglutarimide and N-(3,5-di-tbutyl-4-hydroxyphenyl)-2,3-diethyl-2,3-dimethylsuccinimide which have been successfully prepared

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Integrated Synthesis and Testing of Substituted Xanthine Based DPP4 Inhibitors: Application to Drug Discovery

A novel integrated discovery platform has been used to synthesize and biologically assay a series of xanthine-derived dipeptidyl peptidase 4 (DPP4) antagonists. Design, synthesis, purification, quantitation, dilution, and bioassay have all been fully integrated to allow continuous automated operation. The system has been validated against a set of known DPP4 inhibitors and shown to give excellent correlation between traditional medicinal chemistry generated biological data and platform data. Each iterative loop of synthesis through biological assay took two hours in total, demonstrating rapid iterative structure–activity relationship generation

Rapid Discovery of a Novel Series of Abl Kinase Inhibitors by Application of an Integrated Microfluidic Synthesis and Screening Platform

Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure–activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC₅₀ > 8 against Abl kinase  both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases

Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort (Nature, (2020), 583, 7814, (90-95), 10.1038/s41586-020-2265-1)

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Whole-genome sequencing of patients with rare diseases in a national health system

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare