Prof D. Vaughan Griffiths

BSc PhD(Nott) CChem FRSC : Professor of Organic Chemistry at Queen Mary, University of London.

School of Biological & Chemical Sciences
Queen Mary, University of London
Walter Besant Building, Mile End Road, London E1 4NS, UK

Tel. +44 (0) 20 7882 5389
Fax. +44 (0) 20 7882 7427
E-mail : D.V.Griffiths@qmul.ac.uk

Research Interests

These can be divided into three main areas.

•  The development of new radiopharmaceutical agents for imaging and therapy

•  Mechanistic and synthetic studies in organophosphorus chemistry.

•  The synthesis of novel functionalised polydentate ligands with potential biomedical applications.

The development of new radiopharmaceutical agents for imaging and therapy

We have been collaborating with Amersham plc (formerly Nycomed Amersham plc, and now trading under the name GE Healthcare) for over 20 years on the development of a range of new radiopharmaceutical agents for imaging and therapy, particularly those based on the isotope Tc-99m which are used for medical imaging. This has involved the synthesis of novel functionalised polydentate ligands containing a combination of phosphorus, nitrogen, sulphur and oxygen donor atoms, often linked to biological targeting units. By using our expertise in applying NMR techniques for monitoring reaction pathways we have been able to develop efficient synthetic schemes to such ligands minimising unwanted side reactions which would otherwise complicate purification. This work has ranged over an extremely wide area of organic chemistry and has necessitated the development of new synthetic methods to some of the target molecules. Our research to date has identified several potential bone imaging agents and has contributed to the development of the commercially successful medical imaging agents CeretecT, for studying blood flow in the brain and for detecting deep seated sites of infection ( via labelled white blood cells), and MyoviewT, for detecting abnormalities in the blood flow in heart muscle. We have also worked on a range of other projects including those for imaging hypoxic tissue, kidney function and the D2 receptors in the brain.

We have recently extended our studies to include the development of routes to imaging agents suitable for PET studies.

The application of n.m.r. techniques to mechanistic and synthetic studies in organophosphorus chemistry.

Many organophosphorus compounds are known to be biologically active and there is therefore considerable interest in the synthesis of such compounds. We have been interested for some time in the way in which trivalent phosphorus compounds react with electrophilic organic compounds and the nature of the intermediates involved. NMR spectroscopy is particularly well suited for this type of work and it is often possible to identify the reaction pathways followed and the types of reactive intermediate involved by monitoring the reactions of the phosphorus compound with the organic molecules over a range of conditions. We have then been able to exploit this information to develop novel synthetic routes to some interesting new products.

In the reactions of trivalent phosphorus compounds with electrophilic acetylenes, for example, we found the nature of the products to be very sensitive to the ratio of the reactants and the reaction temperature. However, by controlling these conditions and by adding trapping agents to intercept particular intermediates we were able to prepare some novel systems in high yield.

We have also shown that under appropriate conditions dialkyl aroylphosphonates can be made to undergo reaction with trialkyl phosphites to give some novel products. In the absence of additional electrophiles, the initially formed zwitterionic quasi-phosphonium salt intermediate undergo cleavage of the C-O bond adjacent to the aryl ring to give highly reactive carbene intermediates. These are then usually trapped by phosphite to give novel ylidic phosphonates, although for the carbene generated from the furan-2-oylphosphonate system carbene we have observed subsequent ring-opening of the heterocyclic ring system to give an alkynylphosphonate as the preferred reaction pathway. In contrast, if there is a suitable ortho substituent present on the aroyl ring there is the potential for an intramolecular reactions to occur between the carbene centre and the substituent. We have demonstrated this with a range of 2-substituted-benzoylphosphonates where in many cases we observe the formation of cyclic systems, this in some cases being accompanied by interesting rearrangements. Current work is concerned with studying the reaction of trialkyl phosphites with substituted heteroaroylphosphonates and with substituted benzoylphosphonates possessing ortho-substitutents which contain electrophilic centres, both of which should result in the formation of novel products.

The synthesis of novel functionalised polydentate ligands with potential biomedical applications.

As noted above our work on the development of new radiopharmaceutical imaging agents has involved the synthesis of a very wide range of functionalised polydentate ligand systems containing phosphorus, nitrogen, oxygen and sulphur donor atoms. More recently we have been broadening our synthetic work on ligand synthesis into other collaborative projects involving non-radioactive imaging techniques and the modelling of the active sites of certain metalloenzymes.

Selected References

1. Functionalised Ligands

'Bone seeking complexes of technetium-99m for labelling in bone-imaging studies', (with J. D. Kelly) PCT Int. Appl. 1988, 20 pp, WO 8800061, [C.A. 109(5):34594f]

'Preparation of cationic complexes of technetium-99m with bidentate phosphine and arsine ligands for heart imaging', (with K. W. Chiu, J. D. Kelly, I. A. Latham, and P. G. Edwards) Eur. Pat. Appl. 1989, 52 pp, EP 311352, [C.A. 112(17):154491d]

'Synthesis of Complexes of Tc-99m Possessing Cationic Substituents for Evaluation as Myocardial Imaging Agents', (with D. J. Tonkinson, J. F. Burke, B. Higley and J. D. Kelly) in M. Nicolini, G. Bandoli and U. Mazzi (eds.) "Technetium and Rhenium in Chemistry and Nuclear Medicine, 3", 353-364, Cortina International, Verona, 1990.

Technetium-99m Complexes of Functionalised Diphosphines for Myocardial Imaging', (with J. D. Kelly, B. Higley, C. M. Archer, L. R. Canning, K. W. Chiu, B. Edwards, A. M. Forster, H. K. Gill, I. A. Latham, P. Webbon, P. G. Edwards, D. J. Tonkinson, P. M. Mahoney, D. C. York, J. R. Dilworth and A. Lahiri) in M. Nicolini, G. Bandoli and U. Mazzi (eds.) "Technetium and Rhenium in Chemistry and Nuclear Medicine, 3", 405-412, Cortina International, Verona, 1990.

Preparation of technetium-99m complexes with mercaptoethylammonio-ethylphosphines and related compounds as imaging agents', (with K. W. Chiu, J. D. Kelly, and J. R. Dilworth) Eur. Pat. Appl. 1990, 18 pp, EP 386873, [C.A. 115(5):49973b]

'Cationic complexes of technetium 99m and ligands therefor', (with J. D. Kelly, K. W. Chiu, and J. R. Dilworth) Eur. Pat. 1993, 18pp, EP 0 386 873 B1

'Metal Chelating Compounds', (with C. Archer, G. R. Bower, H. K. Gill, A. L. M. Riley, A. E. Storey, and J. R. Canning) PCT Int. Appl. 1994, 75 pp, WO 94/22816

Synthesis of Polydentate Tripodal Phosphorus-Capped Ligands with Potential Biomedical Applications', (with J. R. Dilworth, J. M. Hughes, S. Morton, C. M. Archer, and J. D. Kelly) in M. Nicolini, G. Bandoli and U. Mazzi (eds.) "Technetium in Chemistry and Nuclear Medicine, 4", SGEditoriali, Padova, 1995, 173-175.

New Hydrophilic Ligands for 99m Tc,-based Radiopharmaceuticals' (with P. Duncanson, J. M. Hughes, P. A. Pitman, A. M. Tran, C. M. Archer, L. R. Canning, H. K. Gill, J. D. Kelly, and A. E. Storey) in M. Nicolini, G. Bandoli and U. Mazzi (eds.) "Technetium in Chemistry and Nuclear Medicine, 4", SGEditoriali, Padova, 1995, 177-179.

'Low Lipophilicity Technetium-99m Complexes for Radiopharmaceutical Applications' (with P. Duncanson, J. M. Hughes, P. A. Pitman, A. M. Tran, C. M. Archer, L. R. Canning, H. K. Gill, J. D. Kelly, and A. E. Storey) in M. Nicolini, G. Bandoli and U. Mazzi (eds.) "Technetium in Chemistry and Nuclear Medicine, 4", SGEditoriali, Padova, 1995, 259-263.

'Synthesis of 2-Mercapto- and 2-Hydroxy-Substituted Diphenylphosphines for use as Dianionic Bidentate Ligands and Polydentate Ligand Precursors' (with J. R. Dilworth, and J. M. Hughes) Phosphorus, Sulfur, and Silicon , 1996, 111 , 108.

'Uptake of technetium-99m nitrido dithiocarbamate complexes by tumour cells', (with M. A. Stalteri, S. J. Parrott, J. R. Dilworth, and S. J. Mather) Nucl. Med. Commun. , 1997, 18 , 870-877.

'The Synthesis and Characterisation of Rhenium Dithiocarbamate Complexes. The X-ray Crystal Structures of [ReO(O(OH)C 6 H 4 )(S 2 CNEt 2 ) 2 ], [Re(PPh 2 C 6 H 4 S-2) 2 (S 2 CNEt 2 )].CH 3 COCH 3 and [ReO(PPh(C 6 H 4 S-2) 2 )(S 2 CNEt 2 ) 2 ].', (with J. R. Dilworth, S. J. Parrott and Y. Zheng) J. Chem. Soc. Dalton Trans. , 1997, 2931-2936.

'The Synthesis and Studies of a 15-Crown-5 Complex of the Sodium Salt of 2­Nitroimidazole' (with P. Duncanson and J.R. Miller) Tetrahedron , 1997, 53 , 13177-13182.

'The Synthesis of 1-Amino-2-Hydroxy- and 2-Amino-1-Hydroxy-Substituted Ethylene-1,1-Bisphosphonic Acids and their N­Methylated Derivatives', (with J. W. Brown, J. C. Caesar, S. A. Cumming, J. M. Hughes, J. D. Kelly and S. P. Swetnam) Tetrahedron , 1997, 53 , 17815-17822.

'Amidine-functionalised Methylenebisphosphonates as potential 99mTc-based Bone Imaging Agents', J. C. Caesar, D. V. Griffiths , J. D. Kelly and C. F. Ruddock, in M. Nicolini, G. Bandoli and U. Mazzi (eds.) "Technetium in Chemistry and Nuclear Medicine 5", SGEditoriali, Padova, 1999, 637-640.

'Carboxyl-functionalised Bis(amine oxime) Ligands as potential 99mTc-based Kidney Imaging Agents', S. Archer, D. V. Griffiths and N. A. Powell, in M. Nicolini, G. Bandoli and U. Mazzi (eds.) "Technetium in Chemistry and Nuclear Medicine 5", SGEditoriali, Padova, 1999, 717-720.

'Structural and Functional Models for Copper-based Nitrite Reductase', S. C. Davies, M. C. Durrant, D. L. Hughes, R. L. Richards, P. Arnold and D. V. Griffiths , Material Structure in Chemistry, Biology, Physics and Technology , 1998, 5 , 389.

'Radiolabelled Bisphosphonates and Method', A.M. Gibson, M. Mendizabal, R. Pither, S.E. Pullan, D.V. Griffiths , P. Duncanson, Patent WO 01/09146, Feb. 2001

'Synthesis and Biodistribution Studies of the 99m Technetium Oxo-Complexes of a Series of Substituted Bis(Aminoethanethiol) Ligands incorporating N -Alkylated-piperidin-4-yl Ring Systems', D. V. Griffiths, J. F. Burke, J. C. Caesar, B. Higley, P. M. Mahoney, D. J. Tonkinson. In M. Nicolini, G. Bandoli and U. Mazzi (eds.) "Technetium in Chemistry and Nuclear Medicine", SGEditoriali, Padova, 2002, 535-537 .

"Copper nitrite complexes of tripodal ligands derived from 1,1,1-tris(2-pyrdiyl)methylamine" P. J. Arnold, S. C. Davies, M. C. Durrant, D. V. Griffiths, D. L. Hughes and P. C.Sharpe, Inorg. Chim. Acta. , 2003, 348 , 143-149

"Nucleophilic addition to dimethylvinylphosphine sulfide as a convenient route to polydentate ligands containing the 2-dimethylphosphinoethyl unit." D. V. Griffiths and H. J. Groombridge, ICPC16, Birmingham International Conference Centre, July 2004.

"Nucleophilic addition to dimethylvinylphosphine sulfide as a convenient route to polydentate ligands containing the 2-dimethylphosphinoethyl unit." D. V. Griffiths, H. J. Groombridge, P. M. Mahoney, S. P. Swetnam, G. Walton and D. C. York, Tetrahedron , in press.

2. Organophosphorus Chemistry

'The Reactions of Carbene Intermediates from the Reaction of Trialkyl Phosphites with Dialkyl Benzoylphosphonates : Intramolecular Cyclisations of 2-Substituted Dialkyl Benzoylphosphonates', (with P. A. Griffiths, K. Karim and B. J. Whitehead) J. Chem. Soc., Perkin Trans. I , 1996, 555-561.

'Dimethyl 2-iodobenzoylphosphonate; an unusual example of a crystalline a­ketophosphonate', (with J. E. Harris and J. R. Miller), Acta Cryst. C , 1997, C53 , 1462-1464.

'Reactions of carbene intermediates from the reaction of trialkyl phosphites with dialkyl benzoylphosphonates: preparation and reactions of dimethyl 2-(N-tert-butyl-N-methylamino)benzoylphosphonate and dimethyl 2-(methylamino)benzoylphosphonate', (with J. E. Harris and B. J. Whitehead) J. Chem. Soc., Perkin Trans. I , 1997, 2545-2548.

'Dialkyl phosphonates and tetraalkyl bisphosphonates from the decomposition of quasiphosphonium ylidic phosphonates in aqueous conditions', (with J. E. Harris and K. Karim) J. Chem. Soc., Perkin Trans. I , 1997, 2539-2544.

'The Reactions of Aroylphosphonates with Trialkyl Phosphites', D. V. Griffiths , Zilele Academice Timisene , 1999, 6a , 1-

'Intramolecular cyclisation of 2-vinyl- and 2-allylbenzoylphosphonates with trimethyl phosphite via carbene intermediates', D. V. Griffiths , J. E. Harris, K. Karim and B. J. Whitehead , Arkivoc, 2000, 1( 3), 296-303

'The Reactions of Trialkylsilyl-containing Phosphites with Electrophilic Organic Compounds', D. V. Griffiths and P. Duncanson, Phosphorus, Sulfur, Silicon and Relat. Elements, 2002, 177 , 2213-2214 s.

"The reaction of heteroaroylphosphonates with triaklyl phosphites." D. V. Griffiths, M. Salt and H. V. Taylor, ICPC16, Birmingham International Conference Centre, July 2004.

"Cyclisation reaction of aroylphosphonates with triaklyl phosphites via anionic intermediates." Y-K Cheong, P. Duncanson, D. V. Griffiths, T. Imirniyaz and M. J. Salt, ICPC16, Birmingham International Conference Centre, July 2004.

"Novel ylides from the reaction of halogeno-substituted furan-2,5-diones with trivalent phosphorus compounds." P. Duncanson and D. V. Griffiths, ICPC16, Birmingham International Conference Centre, July 2004.

Last update : March 2005

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