Andrew J. McCarroll
University of Nottingham
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Featured researches published by Andrew J. McCarroll.
Journal of Medicinal Chemistry | 2008
Mai-Kim Cheng; Chetna Modi; Jennifer C. Cookson; Ian Hutchinson; Robert Heald; Andrew J. McCarroll; Sotiris Missailidis; Farial A. Tanious; W. David Wilson; Jean-Louis Mergny; Charles A. Laughton; Malcolm F. G. Stevens
The growth-inhibitory activities of an extensive series of quaternized quino[4,3,2- kl]acridinium salts against tumor cell lines in vitro have been measured and their biological properties interpreted in the light of differential binding to different DNA isoforms. Selectivity for quadruplex DNA binding and stabilization by compounds were explored through an array of methods: UV absorption and fluorescence emission spectroscopy, surface plasmon resonance, and competition dialysis. Quadruplex DNA interaction was further characterized through FRET and DNA polymerase arrest assays. Telomerase inhibition, inferred from the TRAP assay, is attributed to quadruplex stabilization, supported by the strong correlation (R(2) = 0.81) across the series between quadruplex DNA binding affinity and TRAP inhibition potency. Growth inhibition potency in the NCI60 human tumor cell line panel is more marked in compounds with greater DNA duplex binding affinity (R(2) = 0.82). Quantification of relative quadruplex and duplex binding affinity constants puts some of these ligands among the most selective quadruplex DNA interactive agents reported to date.
Bioorganic & Medicinal Chemistry | 2012
Amy S. Capes; Stephen Patterson; Susan Wyllie; Irene Hallyburton; Iain T. Collie; Andrew J. McCarroll; Malcolm F. G. Stevens; Julie A. Frearson; Paul G. Wyatt; Alan H. Fairlamb; Ian H. Gilbert
Graphical abstract
Organic and Biomolecular Chemistry | 2010
Andrew J. McCarroll; Charles S. Matthews; Geoffrey Wells; Tracey D. Bradshaw; Malcolm F. G. Stevens
4-Ethynyl-4-hydroxycyclohexa-2,5-dien-1-one 5 undergoes cycloaddition reactions with a range of substituted azides in the presence of copper salts to form 1,4-disubstituted triazoles 8-11 bearing the 4-hydroxycyclohexa-2,5-dien-1-one (quinol) pharmacophore; one example of an isomeric 1,5-disubstituted triazole 12 was formed from 5 and benzyl azide in the presence of a ruthenium catalyst. Compounds were screened for growth-inhibitory activity against five cancer cell lines of colon, breast and lung origin, but were overall less potent than the benzothiazolyl- and indolyl-substituted quinols 2 and 3.
Organic and Biomolecular Chemistry | 2004
Ian Hutchinson; Andrew J. McCarroll; Robert A. Heald; Malcolm F. G. Stevens
Cyclisation of 9-(benzotriazol-1-yl)acridine to the pentacycle 8H-quino[4,3,2-kl]acridine in a range of low-boiling solvents is mechanistically distinct from previously published photochemical (carbene) and thermolytic (radical) cyclisations. Fragmentation of the triazole ring of to a diazonium intermediate, and its subsequent heterolysis (-N(2)) and cyclisation is facilitated by solvation of intermediate zwitterionic species. Derivatives of 2- and 3-aminoquinoacridines methylated in the 8-position can be converted to 8,13-dimethylquino[4,3,2-kl]acridinium iodide salts with methyl iodide and were required for biological examination as potential telomerase inhibitors. The chloro group in 3-chloro-8-methyl-8H-quino[4,3,2-kl]acridine can be replaced efficiently by benzylamino, 4-morpholinyl and cyano substituents in palladium(0) mediated reactions.
Molecular Cancer Therapeutics | 2009
Charles S. Matthews; Andrew J. McCarroll; Malcolm F. G. Stevens; Anne Monks; Tracey D. Bradshaw
The novel quinol PMX 290 is an experimental anti‐tumor agent with potent activity against colon, renal and breast tumor cell lines in vitro (GI50 Treatment of HCT116 colon or TK‐10 renal carcinoma cells with PMX 290 leads to the induction of a distinct vacuolar phenotype 4 – 6h after addition of the compound. These perinuclear vacuoles were identified as swollen endoplasmic reticulum (ER) as their membranes stain positively with a fluorescent ER dye. Furthermore when a fluorescent analogue of PMX 290 is added to cells it co‐localized with the ER dye. Microarray data from HCT116 cells treated with PMX 290 demonstrated the induction of a panel of mRNAs for genes involved in ER stress. These included GADD34, TRIB3, DNAJB9, BiP and CHOP as well as several genes upregulated by ATF4. Uncharacteristically for a quinol there was no increase in thioredoxin reductase mRNA levels although other markers of oxidative stress were upregulated (e.g. heme oxygenase 1). The gene array results suggest that the PERK‐eIF2alpha ER stress pathway is activated by PMX 290. Upon activation by ER stress PERK phosphorylates eIF2alpha which switches off general translation and allows the expression of the transcription factor ATF4. This switch to reduced protein synthesis and expression of ATF4 transcribed chaperone proteins lowers the load on ER and increases protein folding efficiency thus alleviating ER stress. A transient increase in eIF2aplha phosphorylation and a concurrent increase in BiP levels were detected byWestern blot in response to PMX 290 in HCT116 cells. In conclusion, ER stress appears to play an important role in the anti‐tumor activity of PMX 290 and represents a novel mechanism of action for this class of compound. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B164.
Molecular Cancer Therapeutics | 2009
Malcolm F. G. Stevens; Ian Hutchinson; Andrew J. McCarroll; Marc Geoffery Hummersone; Huw El Williams
Antitumor properties of the potent G‐quadruplex ligand 3,11‐difluoro‐6,8, 13‐trimethyl‐8H‐quino[4,3,2‐kl]acridinium methosulfate (RHPS4) are driven by telomere uncapping events. RHPS4 has good selectivity for quadruplex DNA over duplex DNA as measured by surface plasmon resonance (Kquad 1.1 × 107 M−1); Kdup 3.4 × 105 M−1). In preclinical models of solid tumor xenografts RHPS4 potentiates the activity of camptothecins but good response is dependent on the timing of the drug sequence employed. These experiments teach how an agent of this novel class might be used clinically in combination with chemotherapeutic agents. Although RHPS4 has several ‘drug‐like’ qualities (synthetic accessibility, water solubility, cellular uptake), a preliminary toxicological study revealed that the compound is a potent hERG inhibitor (IC50 0.2 M) and has additional receptor interactions, notably with muscarinic M1, M2 and M3 receptors. In an anaesthetized guinea pig cardiac model RHPS4 increased QTcB interval at doses of 5 and 10 mg/kg. Modifications to the peripheral substituents around the pentacyclic core have identified agents with differing on‐ and off‐target effects. Removal of the N(13)‐methyl group of RHPS4 to generate an uncharged molecule drastically reduced affinity for the target quadruplex DNA coupled with reduced pharmacological liabilities; increasing the size of the onium group at N(13) from Me to Et reduced affinity for quadruplex DNA (Kquad 0.6 × 106 M−1) and increased hERG inhibition (IC50 0.04 M). After a significant redesign program two isomeric compounds have been identified, 2‐ and 3‐acetylamino‐8,13‐dimethyl‐8H‐quino[4,3,2‐kl]acridinium iodides with ‘win‐win’ profiles ‐ better selectivity for quadruplex DNA and markedly reduced hERG liability (for the 2‐acetylamino compound Kquad 2.4 × 107 M−1; Kdup 3.8 × 105 M−1; hERG IC50 3.7 M): for the 3‐acetylamino isomer Kquad 2.5 × 107 M−1; Kdup 4.4 × 105 M−1; hERG IC50 18 M). Molecular modeling studies on the favored 3‐acetylamino derivative indicate that the pentacyclic core acts as a surrogate K+ stabilizing the G‐quadruplex structure with the acetylamino side‐chain projecting into a quadruplex groove. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C171.
Journal of Medicinal Chemistry | 2007
Andrew J. McCarroll; Tracey D. Bradshaw; Andrew D. Westwell; Charles S. Matthews; Malcolm F. G. Stevens
Biochemical and Biophysical Research Communications | 2006
Eng-Hui Chew; Charles S. Matthews; Jihong Zhang; Andrew J. McCarroll; Thilo Hagen; Malcolm F. G. Stevens; Andrew D. Westwell; Tracey D. Bradshaw
Organic and Biomolecular Chemistry | 2004
Ian Hutchinson; Andrew J. McCarroll; Robert Heald; Malcolm F. G. Stevens
Archive | 2008
Malcolm Francis Graham Stevens; David Cousin; Sharon A. Jennings; Andrew J. McCarroll; John Gareth Williams; Marc Geoffery Hummersone; Jihong Zhang