Stuart T. Caldwell

Selective uncoupling of individual mitochondria within a cell using a mitochondria-targeted photoactivated protonophore

Depolarization of an individual mitochondrion or small clusters of mitochondria within cells has been achieved using a photoactivatable probe. The probe is targeted to the matrix of the mitochondrion by an alkyltriphenylphosphonium lipophilic cation and releases the protonophore 2,4-dinitrophenol locally in predetermined regions in response to directed irradiation with UV light via a local photolysis system. This also provides a proof of principle for the general temporally and spatially controlled release of bioactive molecules, pharmacophores, or toxins to mitochondria with tissue, cell, or mitochondrion specificity.

Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1.

The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood. Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.

Organocatalysts immobilised onto gold nanoparticles: application in the asymmetric reduction of imines with trichlorosilane

Gold nanoparticles functionalised with a valine-derived formamide have been developed as effective homogenous catalysts for the asymmetric reduction of ketimine 1 with trichlorosilane (< or = 84% ee) in toluene. This methodology both simplifies the recovery of the catalyst and its separation from the product, as the nanoparticles can be readily removed and subsequently recycled by precipitation from the reaction mixture.

Controlled Self‐Assembly of Organic Nanowires and Platelets Using Dipolar and Hydrogen‐Bonding Interactions

Synergistic dipole-dipole and hydrogen-bonding interactions are used to assemble nanostructured materials. Precipitation of a hydrogen-bonding donor-acceptor molecule 8-[[p-[bis(ethyl)amino]phenyl]azo]-isobutylflavin (ABFL) yields nanowires approximately 50-150 nm in diameter and lengths of several millimeters. Precipitation of the non-hydrogen-bonding analog, methylated ABFL (MABFL), generates micrometer-sized hexagonal platelets that are 5-10 microm in length, 1-5 microm in width, and 0.1-0.5 microm thick. The structural similarity of the two molecules allows intermediate morphologies to be formed via co-precipitation. Doping experiments demonstrate efficient control over nanowire length and diameter due to the disruption of the hydrogen bonding within the nanowires.

LCST: a powerful tool to control complexation between a dialkoxynaphthalene-functionalised poly(N-isopropylacrylamide) and CBPQT4+ in water

We describe the application of the LCST of a naphthalene-functionalised polyNIPAM derivative as a convenient, tuneable and reversible method to disrupt complex formation with CBPQT(4+) in water.

Isotopic Labelling of Quercetin 4′-O-β-d-Glucoside

[2-13C]-Quercetin-4′-O-β-glucoside was synthesised in four steps and 28% yield from barium [13C]-carbonate. This short route will be applicable to the synthesis of radiolabelled quercetin-4′-O-β-d-glucoside from barium [14C]-carbonate. The most important feature is control of the regiochemistry and stereochemistry of glycosylation before introduction of the isotopic label. The synthesis also uses only benzyl protecting groups allowing global deprotection in the last step.

Naphthoxanthenyl, a New Stable Phenalenyl Type Radical Stabilized by Electronic Effects

Naphthoxanthenyl 1 is a new stable phenalenyl-type radical. Electrochemical studies indicate that 1 has two reversible redox processes that occur on comparatively short time scales. Crystals containing 1 can be grown by electrocrystallization, suggesting that they are conductive.

Model systems for flavoenzyme activity: intramolecular self-assembly of a flavin derivative via hydrogen bonding and aromatic interactions

We have synthesised a flavin derivative incorporating functionalities that promote intramolecular self-assembly via hydrogen bonding and aromatic interactions.

Novel methods for the synthesis of three-, four-, five-, six- and seven-membered, saturated and partially unsaturated carbocycles

Reviewing the literature from May 1998 to April 1999. Previous Review: J. Chem. Soc., Perkin Trans. 1, 1998, 983.

A Prototypical Small-Molecule Modulator Uncouples Mitochondria in Response to Endogenous Hydrogen Peroxide Production

A high membrane potential across the mitochondrial inner membrane leads to the production of the reactive oxygen species (ROS) implicated in aging and age‐related diseases. A prototypical drug for the correction of this type of mitochondrial dysfunction is presented. MitoDNP‐SUM accumulates in mitochondria in response to the membrane potential due to its mitochondria‐targeting alkyltriphenylphosphonium (TPP) cation and is uncaged by endogenous hydrogen peroxide to release the mitochondrial uncoupler, 2,4‐dinitrophenol (DNP). DNP is known to reduce the high membrane potential responsible for the production of ROS. The approach potentially represents a general method for the delivery of drugs to the mitochondrial matrix through mitochondria targeting and H2O2‐induced uncaging.