Matthew A. Jones
University of Canterbury
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Featured researches published by Matthew A. Jones.
Angewandte Chemie | 2009
Andrew D. Abell; Matthew A. Jones; James M. Coxon; James D. Morton; Steven G. Aitken; Stephen B. McNabb; Hannah Y.-Y. Lee; Janna M. Mehrtens; Nathan A. Alexander; Blair G. Stuart; Axel T. Neffe; Roy Bickerstaffe
The design and elaboration of a series of macrocyclic templates that exhibit a propensity to adopt a beta-strand-like peptide-backbone conformation led to potent and selective inhibitors of calpain 2. Macrocycle 1 retarded calcium-induced opacification in an ovine-lens culture assay and is a lead compound for the development of a drug for cataract treatment. Cbz=carbobenzyloxy.
Journal of Organic Chemistry | 2009
Andrew D. Abell; Nathan A. Alexander; Steven G. Aitken; Hongyuan Chen; James M. Coxon; Matthew A. Jones; Stephen B. McNabb; Andrew Muscroft-Taylor
We report the synthesis of macrocycles 1-6 via ring closing metathesis of dienes 7-12. Addition of chlorodicyclohexylborane to thermal and microwave assisted RCM of dienes 8 and 9 markedly improves the yield. The geometric isomers of macrocycles 1-3 and 5 have been assigned using X-ray crystallography and NMR.
Investigative Ophthalmology & Visual Science | 2013
James D. Morton; Hannah Y.-Y. Lee; Josh D. McDermott; Lucinda J. G. Robertson; Roy Bickerstaffe; Matthew A. Jones; James M. Coxon; Andrew D. Abell
PURPOSEnWe used sheep with an autosomal dominant gene for cortical cataract as an animal model to evaluate novel macrocyclic calpain inhibitors with potential for the medical treatment of human cataract.nnnMETHODSnThe macrocyclic aldehyde, CAT811, identified previously as a calpain inhibitor that prevents calcium-induced opacification in cultured sheep lenses, was tested for its ability to protect cytoskeletal proteins from calpain proteolysis. CAT811 and its alcohol analogue, CAT505, were formulated separately into ointments, and each was applied twice daily to the right eye of sheep with early cataracts for five months. Progress of cataracts in the sheep was determined by ophthalmologic examination and comparison with a matched sample of sheep treated similarly with ointment that did not contain the active ingredient.nnnRESULTSnThe novel macrocyclic aldehyde, CAT811, was able to inhibit calpain proteolysis of lens cytoskeletal proteins at micromolar concentrations. When applied topically to the eyes of sheep, CAT811 was able to slow cataract development by 27% in the initial three months of treatment (P < 0.05). Its alcohol analogue, CAT505, was not able to slow cataractogenesis significantly.nnnCONCLUSIONSnThe inherited sheep cataract provides a reproducible model of cortical cataract over a time scale of several months. The data reported here, using this model, demonstrated the potential of the macrocyclic calpain inhibitor, CAT811, to act as a therapeutic for treatment of cortical cataract.
Journal of Medicinal Chemistry | 2011
Blair G. Stuart; James M. Coxon; James D. Morton; Andrew D. Abell; McDonald Dq; Steven G. Aitken; Matthew A. Jones; Roy Bickerstaffe
Studies of 17 analoges of 3 (SJA6017) in an in silico calpain model are reconciled to measured IC(50) values against ovine calpain. The studies validate the potential of the model and criteria established for inhibition as a tool to select structures for synthesis to test as calpain inhibitors. Using this screening methodology of virtual libraries led us to synthesize several inhibitors including macrocycle 33, which in vitro sheep eye lens culture experiments showed to substantially slow opacification.
Clinical and Experimental Ophthalmology | 2008
Hannah Yy Lee; James D. Morton; Lucinda J. G. Robertson; Joshua D McDermott; Roy Bickerstaffe; Andrew D. Abell; Matthew A. Jones; Janna M. Mehrtens; James M. Coxon
Purpose:u2002 The aim of this study is to evaluate the therapeutic potential of a newly synthesized calpain inhibitor, CAT0059, using a naturally occurring in vivo sheep cataract model.
Bioorganic & Medicinal Chemistry | 2008
Matthew A. Jones; James D. Morton; James M. Coxon; Stephen B. McNabb; Hannah Y.-Y. Lee; Steven G. Aitken; Janna M. Mehrtens; Lucinda J. G. Robertson; Axel T. Neffe; Shigeru Miyamoto; Roy Bickerstaffe; Karl Gately; Jacqueline M. Wood; Andrew D. Abell
A series of N-heterocyclic dipeptide aldehydes 4-13 have been synthesised and evaluated as inhibitors of ovine calpain 1 (o-CAPN1) and ovine calpain 2 (o-CAPN2). 5-Formyl-pyrrole 9 (IC(50) values of 290 and 25nM against o-CAPN1 and o-CAPN2, respectively) was the most potent and selective o-CAPN2 inhibitor, displaying >11-fold selectivity. The amino acid sequences of o-CAPN1 and o-CAPN2 have been determined. Because of the lack of available structural information on the ovine calpains, in silico homology models of the active site cleft of o-CAPN1 and o-CAPN2 were developed based on human calpain 1 (h-CAPN1) X-ray crystal structure (PDB code 1ZCM). These models were used to rationalise the observed SAR for compounds 4-13 and the selectivity observed for 9. The o-CAPN2 selective inhibitor 9 (CAT0059) was assayed in an in vitro ovine lens culture system and shown to successfully protect the lens from calcium-induced opacification.
Chemistry & Biodiversity | 2012
Hongyuan Chen; Wanting Jiao; Matthew A. Jones; James M. Coxon; James D. Morton; Roy Bickerstaffe; Ashok D. Pehere; Ondrej Zvarec; Andrew D. Abell
Two new series of 15‐membered macrocyclic peptidomimetics, in which the P1 and P3 residues of the peptide backbone are linked by a bridge containing a 1,4‐disubstituted 1H‐imidazole, are reported. The structure with an aldehyde at the C‐terminus and the imidazole at P3, i.e., 4c, shows significant inhibitory activity against calpain 2, with an IC50 value of 238u2005nM. The macrocyclic aldehyde with the imidazole at the alternative P1 position, i.e., 5c, is significantly less active. The relative activities are linked to the ability of the component macrocycles to mimic a β‐strand geometry that is known to favor active‐site binding. This ability is defined by conformational searches and docking studies with calpain.
Australian Journal of Chemistry | 2009
Matthew A. Jones; James M. Coxon; Stephen B. McNabb; Janna M. Mehrtens; Nathan A. Alexander; Seth A. Jones; Hongyuan Chen; Clémence Buisan; Andrew D. Abell
A high-yielding, short, and scalable synthesis of a potent calpain 2 inhibitor (CAT811) is reported. The key step in the sequence involves an intramolecular macrocyclization of a 6-iodonorleucine residue to the side chain of tyrosine.
Peptides | 2005
Andrew D. Abell; Karina M. Brown; James M. Coxon; Matthew A. Jones; Sigeru Miyamoto; Axel T. Neffe; Janna M. Nikkel; Blair G. Stuart
In the course of the development of calpain inhibitors, we report the synthesis of eight-membered cyclic pseudo dipeptides closely related to the known inhibitor SJA6017. The ring closure was effected by metathesis of the diallyl-substituted dipeptides 6 and 7. The formation of the dipeptides under kinetic control leads to the preferential formation of the unlike diastereomer 7 over the like diastereomer 6. The relative configuration of the diastereomers was determined by NMR and modeling studies of the related cyclic compounds 8 and 9 and their derivatives. The compounds proved not to inhibit calpain.
Protein and Peptide Letters | 2009
Seth A. Jones; Matthew A. Jones; Stephen B. McNabb; Steven G. Aitken; James M. Coxon; Andrew D. Abell
A series of Val-Leu based peptidic aldehydes containing either a furan or thiophene at the N-terminus was prepared and assayed against ovine m-calpain. In general, potency is favoured by a 2-substituted (rather than 3-substituted) heterocycle, a thiophene rather than a furan, and a shorter chain length at the N-terminus. Molecular docking experiments provide some rationale for these observations.