Prof Colin J Suckling

Research in Heterocyclic, Biological and Medicinal Chemistry

Pteridine and related chemistry

In structural terms, current research centres on heterocyclic compounds and their applications in medicinal chemistry. The extension of our long-standing work (with Dr Colin Gibson) in the synthesis andbiological properties of pteridines has led to the development of methods for the synthesis of highly functionalised pterins, especially at position 6, in both solution and solid phase formats. [see references] Compounds have been designed to be inhibitors of the biosynthesis of folic acid and their evaluation is currentlyunderway; particular targets are dihydroneopterin aldolase and dihydropteroatesynthase. In addition to pteridines, the synthesis of 7-deazaguanines has also been developed. These compounds are intended to interact with the first enzyme in the folic acid biosynthesis pathway, GTP-cyclohydrolase I. This enzyme catalyses a complex, multi-step reaction and some of our compounds appear to act as inhibitors and pseudo substrates. The mechanism of these reactions remains to be investigated. Scheme 1 shows the early stages of the biosynthesis of folic acid with some of our compounds (in blue) alongside the substrates and target enzymes. The long term possibility is that these studies will lead to the discovery of new antibacterial or anti-infective agents. We have also been aware of the importance of nitric oxide biosynthesis in brain, the immune response, and endothelial function. Withrespect to the last, we were excited to find recently that one of our library of compounds acted as a stimulator of nitric oxide synthesis in rat aortic rings (with Professor R. Wadsworth, Physiology & Pharmacology). This unusual discovery, in which the Strathclyde compound acts presumably as a mimic of the naturally occurring cofactor, tetrahydrobiopterin, opens further possibilities for the application of our syntheses of pteridines.

Scheme1

Minor Groove Binders

The search for novel anti-infective and anticancer drugs ranges over many types of compound. Following earlier work into the synthesis of compounds that bind into the minor groove of DNA (based upon the well-known N-methylpyrrole amino acid monomer), we have extended our studies to develop compounds including a wide range of alternative heterocyclic rings and alkyl substituents (with Professor RogerWaigh, Pharmaceutical Sciences). [see references] For reasons of commercial significance, the detailed structures of these compounds cannot be disclosed until early 2003 but Scheme2 is illustrative. However we have been gratified to find that some of our compounds containing novel structural features have antibacterial activity against such key organisms as MRSA and Cryptosporidium as well as against a number of fungi including Aspergillus and Candida. Moreover, nmr studies have given us strong insight into the detailed binding of our compounds with DNA. The chief synthetic chemical problems to be solved relate to the efficient solid phase synthesis of compounds containing the new heterocyclic monomers and, in some cases, to the monomers themselves. These problems are being addressed in partnership with LINK Technologies, a local biotech company, through the Teaching Company Scheme. There are also major structural and biochemical problems to be tackled. Some of our active compounds have very potent and specific binding patterns to DNA; in order to make further progress in targeting specific genes, the structural basis for this must be understood. Having discovered significant antibacterial and antifungal activity we are also keen to confirm and extend preliminary results that indicate interference with the action of cytokines in some cell types.

Scheme 2

Other research projects

Other research reported recently [see references] includes the synthesis of compounds as potential modulators of steroid biosynthesis (with Dr Keith Suckling,GlaxoSmithKline); results of biological evaluation are awaited. An investigation of the potential of chloroperoxidase as a one-pot, double oxidantof activated alkenes (with Professor Iain Hunter, Pharmaceutical Sciences) led to some interesting outcomes that are capable of further development.

Recent papers

Pteridine Chemistry

On the mechanism of action of GTP transforming enzymes. M.J. Dufton, C.L. Gibson, S.Athmani, A.R. Pitt, and C.J. Suckling, Bioorg.Med.Chem.Lett. , 1997, 7, 779-784.

A novel synthesis of 8-substituted 7-deazaguanines. C.L. Gibson, K.Paulini, and C.J.Suckling, J.Chem.Soc.,Chem.Commun., 1997, 371-372.

Studies oninhibition of folate biosynthesis: synthesis of 6-substituted pterins C.L.Gibson, A. Lang, C.J. Suckling, and M.J. Rice in Chemistry and Biology of Pterins and Folates 1997 eds. W.Pfleiderer and H. Rokos Blackwell Science, Berlin pp. 11-16.

On the mechanism of action of GTP transforming enzymes M.J.Dufton, C.L. Gibson, A.R. Pitt, S. Athmani, and C.J. Suckling Ibid pp 35 - 40. 

The synthesis of 7-substituted 7-deazaguanines C.L. Gibson, K. Ohta, and C.J. Suckling J.Chem.Soc.Perkin Trans.1, 1998, 3025-3031. 

The synthesis of highly functionalised 6-substituted pterins C.L. Gibson, A. Lang, K. Ohta,M.J. Rice, and C.J. Suckling J.Chem.Soc.,PerkinTrans.1, 1999, 163-169. 

Synthesis of Pyrimidine Libraries: Development of Solid Phase Methodology McCluskey, C.L.Gibson, and C.J. Suckling Solid PhaseSynthesis and Combinatorial Chemical Libraries, Mayflower Press, 2001 , 359-360. 

Solution and solid phase synthesis of pteridines, purines and related compounds. S. La Rosa,P.H. Boyle, C.L. Gibson, D. Guiney, and C.J. Suckling The Chemistry and Biology of Pteridines and Folates, 2002, 25-29. 

Synthesis of Pteridines with C-2 and C-6 functional group diversity. D. Guiney, P.H. Boyle,C.L. Gibson, S. La Rosa, and C.J. Suckling Ibid., 31-35. 

Strategies for the synthesis of pteridines and related compounds with high diversity C.L.Gibson, P.H. Boyle, D. Guiney, S. La Rosa, and C.J. Suckling Ibid.421-425. 

A traceless synthesis of pteridines. C.L. Gibson, S.La Rosa, and C.J. Suckling TetrahedronLett. 2003, 44, 1267-1270. 

Syntheses of highly functionalised pteridines. D. Guiney,C.L. Gibson and C. J. Suckling Org.Biomol.Chem., 2003, 664-675. 

A prototype solid phase synthesis of pteridines andrelated heterocyclic compounds. C.L. Gibson, S. La Rosa, and C.J. Suckling, Org.Biomol.Chem., 2003, 1909-1918. 

The Synthesis of 7-deazaguanines as potentialinhibitors of guanosine triphosphate cyclohydrolase 1. C.L. Gibson, S. La Rosa, K. Ohta, P.H. Boyle, F.Leurquin, A. Lemaçon^c and C.J. Suckling. Tetrahedron, in press

Minor groove binders

Design and Synthesis of extended lexitropsins with good solubility and potentially improved tissue penetration characteristics. A.I. Khalaf, A.R. Pitt, M. Scobie,C.J. Suckling, J. Urwin, R.D. Waigh, S.C. Young, R.V. Fishleigh and K.R. Fox, J.Med.Chem. 2000, 43, 3257-3266. 

The synthesis of some head-to-head linked DNA minor groove binders. A.I. Khalaf .A.R. Pitt,M. Scobie, C.J. Suckling, J. Urwin, R.D. Waigh, S.C. Young, R.V. Fishleigh andK.Fox, Tetrahedron, 2000, 56, 5225-5239. 

The synthesis of some indole-containing amino acids as linkers for the construction of DNAminor groove binders. A.I. Khalaf.A.R. Pitt, M. Scobie, C.J. Suckling, J. Urwin, R.D. Waigh, S.C. Young, R.V.Fishleigh, J.Chem.Res, (S) 2000,264-265; (M), 2000 , 0751-0770. 

Minor groove binders substituted by lipophilic groups.C.J. Suckling, R.D. Waigh, A.I. Khalaf, J. Parkinson, and I.S. Hunter, 19^th International Congress onHeterocyclic Chemistry Abstracts, Elsevier, 2003, 98.

Distamycin analogues with enhanced lipophilicity:synthesis and antimicrobial activity.  A.I.Khalaf, A.J. Drummond, B. Pringle, I. McGroarty, G.G. Skellern, R.D.Waigh, C.J. Suckling, Submitted to J.Med. Chem. 

Other projects in bioorganic chemistry

The synthesisof some novel oxy and fluoro cholesterol analogues as probes of cholesterolbiosynthesis and metabolism. A.R. Pitt, C.J. Suckling, K.E. Suckling, and M.Thomas, J.Chem.Soc.,Perkin Trans.1, 1999 , 3191-3198. 

Theselectivity and mechanism of action of the catalytic antibody H-11, A.I.Khalaf, S. Linaza, A.R. Pitt, W.H. Stimson, and C.J. Suckling, Tetrahedron, 2000, 56, 489-495. 

Unexpected dealkylation during nucleophilic substitution – synthesis of 2- N,N-dialkylamino- benzoxazoles andbenzothiazoles, A.I. Khalaf, R.G. Alvarez, C.J. Suckling and R.D. Waigh, Tetrahedron, 2000, 56, 8567-8571.  

A novel transformation of benzofurans and related compounds catalysed by achloroperoxidase., R.G. Alvarez, I.S. Hunter, C.J. Suckling, M.Thomas, andU.Vitinius. Tetrahedron, 2001, 57, 8581-8587. 

DNA binding of a short lexitropsin. Nahoum G. Anthony, Keith R. Fox, Blair Johnston, A.I. Khalaf, S. P. Mackay, I.S. McGroarty, J.A. Parkinson, G.G. Skellern, C.J. Suckling, R.D. Waigh. Bioorg. Med. Chem. Lett. In press.