11 research outputs found

    Formation of quaternary centres by copper catalysed asymmetric conjugate addition to Ăź substituted cyclopentenones with the aid of a quantitative structure-selectivity relationship

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    A new asymmetric conjugate addition method was developed for β-substituted cyclopentenones to form quaternary centres using alkylzirconocene nucleophiles giving up to 97% yield and 92% ee. Key to the reaction’s success was the design of suitable phosphoramidite ligands which was aided by a linear quantitative structure-selectivity relationship (QSSR). QSSR models were created from the ligand screening data (a total of 36 ligands) which revealed important electronic and steric requirements and led to the synthesis of more enantioselective ligands. DFT calculations of competing transition structures enable the interpretation of the electronic and steric terms present in the QSSR models

    Enantioselective conjugate addition catalyzed by a copper-phosphoramidite complex: Computational and experimental exploration of asymmetric induction

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    The stereochemical role of the phosphoramidite ligand in the asymmetric conjugate addition of alkylzirconium species to cyclic enones has been established for the first time through experimental and computational studies. Systematic, synthetic variation of the modular ligand established that the configuration of the binaphthol backbone is responsible for absolute stereocontrol, whereas modulation of the amido substituents leads to dramatic variations in the level of asymmetric induction. Chiral amido substituents are not required for enantioselectivity, leading to the discovery of a new family of easily synthesized phosphoramidites based on achiral amines that deliver equal levels of selectivity to Feringa’s ligand. A linear correlation between the length of the aromatic amido groups and experimentally determined enantioselectivity was uncovered for this class of ligand, which, following an optimisation, leading to the highly selective ligands (up to 94% ee) with naphthyl rather than phenyl groups. An electronic effect of sterically similar aromatic substituents was investigated through NMR and DFT studies, showing that electron rich aryl groups allow better Cu-coordination. An interaction between the metal center and an aromatic group is responsible for this enhanced affinity and leads to a more tightly-coordinated transition structure leading to the major enantiomer. These studies illustrate the use of parametric quantitative structure-selectivity relationships to generate mechanistic models for asymmetric induction and catalyst structures that may be further probed by experiment and computation. This integrated approach leads to the rational modification of chiral ligands to achieve enhanced levels of selectivity

    Enantioselective conjugate addition catalyzed by a copper-phosphoramidite complex: Computational and experimental exploration of asymmetric induction

    No full text
    The stereochemical role of the phosphoramidite ligand in the asymmetric conjugate addition of alkylzirconium species to cyclic enones has been established for the first time through experimental and computational studies. Systematic, synthetic variation of the modular ligand established that the configuration of the binaphthol backbone is responsible for absolute stereocontrol, whereas modulation of the amido substituents leads to dramatic variations in the level of asymmetric induction. Chiral amido substituents are not required for enantioselectivity, leading to the discovery of a new family of easily synthesized phosphoramidites based on achiral amines that deliver equal levels of selectivity to Feringa’s ligand. A linear correlation between the length of the aromatic amido groups and experimentally determined enantioselectivity was uncovered for this class of ligand, which, following an optimisation, leading to the highly selective ligands (up to 94% ee) with naphthyl rather than phenyl groups. An electronic effect of sterically similar aromatic substituents was investigated through NMR and DFT studies, showing that electron rich aryl groups allow better Cu-coordination. An interaction between the metal center and an aromatic group is responsible for this enhanced affinity and leads to a more tightly-coordinated transition structure leading to the major enantiomer. These studies illustrate the use of parametric quantitative structure-selectivity relationships to generate mechanistic models for asymmetric induction and catalyst structures that may be further probed by experiment and computation. This integrated approach leads to the rational modification of chiral ligands to achieve enhanced levels of selectivity

    The efficacy of the Quercetin analogue LY294002 in immortalized cancer cell lines is related to the oxygenic and metabolic status of cells

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    Purpose: LY294002, a promising drug for chemotherapy, suppresses the activity of Phosphatidylinositol 3-Kinase (PI3K) which is pivotal to a number of processes such as proliferation, metabolism, and apoptosis. The compound has, however, been seen to have very variable efficacy in vivo. Methods: Proliferation and viability of two immortalized cells with divergent bioenergetic profiles was determined using crystal violet staining, and the 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Oxygen consumption rates were determined using MitoXpress-Xtra probes, and lactate generation was assessed with pH-Xtra probe and BM-lactate strips. Immunoblotting was performed with phospho-Akt-Ser 473 and Akt-pan primary antibodies. Results: U87 cells were shown to have a glycolytic metabolism, whereas RD cells exhibited a more aerobic metabolism. In both lines, hypoxia was shown to increase lactate production, and LY294002 reduced lactate production. The drug decreased cell proliferation and viability under all conditions, but the effect was greatest in U87 cells under normoxic conditions. Conclusion: Metabolic analysis showed a link between a glycolytic cell status and LY294002 induced cell death. However, in both cell lines the drug was also less effective under hypoxic conditions, as would be found in a tumour in vivo. Furthermore, in the presence of LY294002 the phosphorylation status of Akt, a target of PI3K, was found to be related to both the mechanism of cell respiration, and the oxygenic status of the cells.</p

    Mechanistic investigation of Rh(i)-catalysedasymmetric Suzuki–Miyaura coupling withracemic allyl halides

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    Understanding how catalytic asymmetric reactions with racemic starting materials can operate would enable new enantioselective cross-coupling reactions that give chiral products. Here we propose a catalytic cycle for the highly enantioselective Rh(I)-catalysed Suzuki–Miyaura coupling of boronic acids and racemic allyl halides. Natural abundance 13C kinetic isotope effects provide quantitative information about the transition-state structures of two key elementary steps in the catalytic cycle, transmetallation and oxidative addition. Experiments with configurationally stable, deuterium-labelled substrates revealed that oxidative addition can happen via syn- or anti-pathways, which control diastereoselectivity. Density functional theory calculations attribute the extremely high enantioselectivity to reductive elimination from a common Rh complex formed from both allyl halide enantiomers. Our conclusions are supported by analysis of the reaction kinetics. These insights into the sequence of bond-forming steps and their transition-state structures will contribute to our understanding of asymmetric Rh–allyl chemistry and enable the discovery and application of asymmetric reactions with racemic substrates

    The efficacy of the Quercetin analogue LY294002 in immortalized cancer cell lines is related to the oxygenic and metabolic status of cells

    No full text
    Purpose: LY294002, a promising drug for chemotherapy, suppresses the activity of Phosphatidylinositol 3-Kinase (PI3K) which is pivotal to a number of processes such as proliferation, metabolism, and apoptosis. The compound has, however, been seen to have very variable efficacyandnbsp;in vivo. Methods: Proliferation and viability of two immortalized cells with divergent bioenergetic profiles was determined using crystal violet staining, and the 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Oxygen consumption rates were determined using MitoXpress-Xtra probes, and lactate generation was assessed with pH-Xtra probe and BM-lactate strips. Immunoblotting was performed with phospho-Akt-Ser 473 and Akt-pan primary antibodies. Results: U87 cells were shown to have a glycolytic metabolism, whereas RD cells exhibited a more aerobic metabolism. In both lines, hypoxia was shown to increase lactate production, and LY294002 reduced lactate production. The drug decreased cell proliferation and viability under all conditions, but the effect was greatest in U87 cells under normoxic conditions. Conclusion: Metabolic analysis showed a link between a glycolytic cell status and LY294002 induced cell death. However, in both cell lines the drug was also less effective under hypoxic conditions, as would be found in a tumourandnbsp;in vivo. Furthermore, in the presence of LY294002 the phosphorylation status of Akt, a target of PI3K, was found to be related to both the mechanism of cell respiration, and the oxygenic status of the cells.</p

    Expanding the medicinal chemistry synthetic toolbox

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    The key objectives of medicinal chemistry are to efficiently design and synthesize bioactive compounds that have the potential to become safe and efficacious drugs. Most medicinal chemistry programmes rely on screening compound collections populated by a range of molecules derived from a set of known and robust chemistry reactions. Analysis of the role of synthetic organic chemistry in subsequent hit and lead optimization efforts suggests that only a few reactions dominate. Thus, the uptake of new synthetic methodologies in drug discovery is limited. Starting from the known limitations of reaction parameters, synthesis design tools, synthetic strategies and innovative chemistries, here we highlight opportunities for the expansion of the medicinal chemists’ synthetic toolbox. More intense crosstalk between synthetic and medicinal chemists in industry and academia should enable enhanced impact of new methodologies in future drug discovery. © 2018 Springer Nature Limited. All rights reserved
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