Synthesis of enantioenriched spirocyclic 2-arylpiperidines via kinetic resolution.

Kinetic resolution of N-Boc-spirocyclic 2-arylpiperidines with spiro substitution at C-4 was achieved with high enantiomeric ratios using the chiral base n-BuLi/sparteine. Cyclopropanation or metallaphotoredox catalysis were used to access the piperidines, which could be further functionalised without loss of enantiopurity, highlighting their use as potential 3D fragments for drug discovery.

Chirality: a key parameter in chemical probes.

Many small molecule bioactive and marketed drugs are chiral. They are often synthesised from commercially available chiral building blocks. However, chirality is sometimes incorrectly assigned by manufacturers with consequences for the end user ranging from: experimental irreproducibility, wasted time on synthesising the wrong product and reanalysis, to the added cost of purchasing the precursor and resynthesis of the correct stereoisomer. Further on, this could lead to loss of reputation, loss of funding, to safety and ethical concerns due to potential in vivo administration of the wrong form of a drug. It is our firm belief that more stringent control of chirality be provided by the supplier and, if needed, requested by the end user, to minimise the potential issues mentioned above. Certification of chirality would bring much needed confidence in chemical structure assignment and could be provided by a variety of techniques, from polarimetry, chiral HPLC, using known chiral standards, vibrational circular dichroism, and x-ray crystallography. A few case studies of our brushes with wrong chirality assignment are shown as well as some examples of what we believe to be good practice.

The effect of flavonoids on the reduction of cupric ions, the copper-driven Fenton reaction and copper-triggered haemolysis.

Flavonoids are considered beneficial, but they may exhibit pro-oxidative effects likely due to metal reducing properties. For the first time, 24 structurally related flavonoids were compared for copper reduction, and modulation of the copper-triggered Fenton reaction and lysis of erythrocytes. The vast majority of flavonoids reduced cupric ions; their behaviour ranged from progressive gradual reduction through bell-shaped, neutral, to a blockade of spontaneous reduction. Similarly, different behaviours were observed with the Fenton reaction. Flavone was the only flavonoid that potentiated copper-triggered haemolysis (155 ± 81 % at twice the amount of Cu2+), while 18 flavonoids were at least partly protective in some concentrations. Only 5-hydroxyflavone did not reduce Cu2+ and behaved as an antioxidant in both assays (reduction of 60 ± 10 % and 88 ± 1%, respectively, at an equimolar ratio with Cu2+). In conclusion, relatively subtle structural differences resulted in very different anti/prooxidant behaviour depending on the model.

Recent developments in enantio- and diastereoselective hydrogenation of N-heteroaromatic compounds.

The enantioselective and diastereoselective hydrogenation of N-heteroaromatic compounds is an efficient strategy to access chirally enriched cyclic heterocycles, which often possess highly bio-active properties. This strategy, however, has only been established in recent times. This is in part due to the challenges of the high stability of the aromatic compounds and the presence of heteroatoms that have the potential to poison the chiral catalysts. Additionally, N-heteroaromatic compounds are a structurally diverse family of substrates, each group showing distinct reactivity in hydrogenation. Advances in recent years have allowed various N-heteroaromatic compounds, including pyridines, indoles, quinolines, isoquinolines, quinoxalines and imidazoles, to be hydrogenated with good to excellent enantioselectivity under appropriate reaction conditions. Transition-metal catalysis, utilising iridium, ruthenium, rhodium, and palladium complexes, has been found to play an important role in this field. More recently, organocatalysis has been shown to be efficient for the hydrogenation of certain N-heteroaromatic compounds. This review provides an analysis of the recent developments in the enantioselective and diastereoselective hydrogenation of N-heteroaromatic compounds. The importance of these molecules and their applications to drug discovery has been highlighted throughout the review.

Asymmetric Synthesis of 2-Arylindolines and 2,2-Disubstituted Indolines by Kinetic Resolution.

Kinetic resolution of 2-arylindolines (2,3-dihydroindoles) was achieved by treatment of their N-tert-butoxycarbonyl (Boc) derivatives with n-butyllithium and sparteine in toluene at -78 °C followed by electrophilic quench. The unreacted starting materials together with the 2,2-disubstituted products could be isolated with high enantiomer ratios. Variable temperature NMR spectroscopy showed that the rate of Boc rotation was fast (ΔG≠ ≈57 kJ/mol at 195 K). This was corroborated by DFT studies and by in situ ReactIR spectroscopy. The enantioenriched N-Boc-2-arylindolines were converted to 2,2-disubstituted products without significant loss in enantiopurity. Hence, either enantiomer of the 2,2-disubstituted products could be obtained with high selectivity from the same enantiomer of the chiral ligand sparteine (one from the kinetic resolution and the other from subsequent lithiation-trapping of the recovered starting material). Secondary amine products were prepared by removing the Boc group with acid to provide a way to access highly enantioenriched 2-aryl and 2,2-disubstituted indolines.

Augmentation of Anticancer Drug Efficacy in Murine Hepatocellular Carcinoma Cells by a Peripherally Acting Competitive N-Methyl-d-aspartate (NMDA) Receptor Antagonist.

The most common solid tumors show intrinsic multidrug resistance (MDR) or inevitably acquire such when treated with anticancer drugs. In this work, we describe the discovery of a peripherally restricted, potent, competitive NMDA receptor antagonist 1l by a structure-activity study of the broad-acting ionotropic glutamate receptor antagonist 1a. Subsequently, we demonstrate that 1l augments the cytotoxic action of sorafenib in murine hepatocellular carcinoma cells. The underlying biological mechanism was shown to be interference with the lipid signaling pathway, leading to reduced expression of MDR transporters and thereby an increased accumulation of sorafenib in the cancer cells. Interference with lipid signaling pathways by NMDA receptor inhibition is a novel and promising strategy for reversing transporter-mediated chemoresistance in cancer cells.

Iron reduction potentiates hydroxyl radical formation only in flavonols.

Flavonoids, substantial components of the human diet, are generally considered to be beneficial. However, they may possess possible pro-oxidative effects, which could be based on their reducing potential. The aims of this study were to evaluate the ability of 26 flavonoids to reduce ferric ions at relevant pH conditions and to find a possible relationship with potentiation of hydroxyl radical production. A substantial ferric ions reduction was achieved under acidic conditions, particularly by flavonols and flavanols with the catecholic ring B. Apparently corresponding bell-shaped curves displaying the pro-oxidant effect of flavonols quercetin and kaempferol on iron-based Fenton reaction were documented. Several flavonoids were efficient antioxidants at very low concentrations but rather inefficient or pro-oxidative at higher concentrations. Flavonols, morin and rutin were progressively pro-oxidant, while 7-hydroxyflavone and hesperetin were the only flavonoids with dose-dependent inhibition of hydroxyl radical production. Conclusively, administration of flavonoids may lead to unpredictable consequences with few exceptions.

Copper(I)-catalyzed cycloaddition of silver acetylides and azides: incorporation of volatile acetylenes into the triazole core.

Silver acetylides and organic azides react under copper(I) catalysis to afford 1,4-disubstituted 1,2,3-triazoles. Mechanistic studies implicate a process involving transmetallation to copper acetylides prior to cycloaddition. This work demonstrates that silver acetylides serve as suitable precursors for entry into copper-mediated coupling reactions. This methodology allows the incorporation of volatile and difficult-to-handle acetylenes into the triazole core.