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Dr Richard Wheelhouse

PositionReader in Medicinal Chemistry
LocationICT 3.20
DepartmentSchool of Pharmacy and Medical Sciences
Telephone+44 (0) 1274 234710
EmailR.T.Wheelhouse@bradford.ac.uk
ORCID0000-0002-2250-3384

Research Interests (key words only)

Medicinal Chemistry, cancer, heterocyclic chemistry, tetrazines, prodrugs, biophysics, NMR, ITC, temperature-scanning UV spectrophotometry, RNaseH, DNA RNA hybrids, tetraplex DNA, i-motif DNA.

Teaching and Supervisory Responsibilities

  • PhD Student: Aya Kabariti
  • PH-4046L Student Selected Component – Pharmacy Special Studies. Mdule leader; leader of Research Project and Innovative Therapeutics strands.
  • CR-4003D Cancer Pharmacology. Lectures on DNA as a target in anticancer drug discovery.
  • PH-1216U Foundation Studies in Pharmacy 2 (Life Cycle of a Medicine). Author and leader of two units on introductory organic and medicinal Chemistry.

Highfield NMR training and system management for the Centre for Chemical and Structural Analysis.

Member of the University recommended list of chairs for research degree viva voce examinations.

Personal Academic Tutor, 18 MPharm students.

Administrative Responsibilities

Study Abroad coordinator, Bradford School of Pharmacy.

Study History

BSc, PhD (Leicester), CChem, FRSC

Professional History

  • 2009 April–Sept, Visiting Research Scientist, Brown Cancer Center, University of Louisville, Kentucky, USA
  • 2006–2008, Head, Division of Pharmaceutics and Pharmaceutical Chemistry, Bradford School of Pharmacy
  • 1998– Bradford School of Pharmacy
  • 1996–1998 Research Fellow, Drug Dynamics Institute, College of Pharmacy, The University of Texas at Austin, USA
  • 1992–1995 Senior Research Fellow, Cancer Research Campaign Experimental Cancer Chemotherapy Research Group, Cancer Research Laboratories, The University of Nottingham, UK
  • 1990–1992 Research Associate,  Cancer Research Campaign Experimental Cancer Chemotherapy Research Group, Aston University,  Birmingham, UK

Professional Activities

  • Editorial Board Member (Chemistry) Scientific Reports, Nature Publishing Group, 2016-18
  • Honorary Member, Faculty of Pharmacy, University of Khartoum, Sudan
  • Fellow of the Royal Society of Chemistry (2007)
  • EPSRC Peer Review College since 2006

External Examiner

  • Curriculum Reform Panel (BPharm), Faculty of Pharmacy, University of Khartoum, Sudan. February 2016
  • University of Manchester, School of Chemistry,  September 2011 (PhD)
  • University of Manchester, Manchester Interdisciplinary Biocentre,  April 2011 (PhD)
  • University of Leeds, School of Chemistry, July 2008 (PhD), Spring 2010 (PhD)
  • Heriot Watt University, Chemistry, School of Engineering and Physical Sciences, Nov. 2009 (PhD)
  • University of Bath, School of Pharmacy and Pharmacology, Nov 2007 (PhD)

Research Areas

  • Medicinal Chemistry
  • Biophysics
  • Anticancer Drugs
  • Drug-Nucleic Acid Interactions
  • Imidazotetrazines
  • NMR
  • UV

Current Projects

Imidazotetrazine Prodrugs

The imidazotetrazine is a fascinating group in Medicinal Chemistry. Our work so far (CRUK funded) has concerned the development of new tetrazine anticancer agents that overcome some of the limitations of the archetypal agent Temodal,  the lone member of this drug class. 

Our new agents havein vitro activity independent of the DNA mismatch repair and O6-alkylguanine-DNA alkyl transferase constraints that compromise tumour response to temozolomide; a (Q)SAR study has allowed fine tuning of the activity of these agents.  Representatives of two classes of novel agent are now under in vivo investigation. 

Targeting Unusual Nucleic Acid Structures

We have a long-standing interest in targeting unusual nucleic acid structures: e.g. triplexes, tetraplexes (G-tetraplex and i-motif) and DNA·RNA hybrids.  As well as the design and synthesis of new ligands, the associated biophysics is conducted in house. 

This is a continuing collaboration with Professor Brad Chaires, Brown Cancer Center, University of Louisville, KY, USA.  New sequence- and structure-selective ligands for DNA·RNA hybrids have applications as inhibitors of RNaseH to control HIV infectivity and telomerase (anti-cancer).  Our discovery of a new ligand with RNAseH inhibitory activity was reported in Angewandte Chemie in 2010.

Research Collaborations

  • Dr Roger Phillips, Department of Pharmacy, University of Huddersfield, Cancer Pharmacology
  • Professor J. Brad Chaires, Brown Cancer Center, University of Louisville, KY, USA.  Drug–Nucleic Acid Biopysics
  • Dr Jann Sarkaia, Mayo Clinic, Rochester MD, USA.  Evaluation of anti-tumour agents
  • Professor John Hartley, CL Cancer Institute, London. Drug-DNA reactivity and selectivity
  • Dr Alonzo Ross, UMASS Medical School, Boston MA, USA. Evaluation of anti-tumour agents
  • Dr Colin Wright, Bradford School of Pharmacy.  DNA-binding natural products and NMR

Publications

See Dr Wheelhouse's publications on Bradford Scholars.

Papers and Chapters

  • Preclinical Anti-cancer Activity and Multiple Mechanisms of Action of a Cationic Silver Complex Bearing N-heterocyclic Carbene Ligands. S.J. Allison, M. Sadiq, E. Baronou, P.A. Cooper, C. Dunnill, N.T. Georgopoulos, A. Latif, S. Shepherd, S.D. Shnyder, I.J. Stratford, R.T. Wheelhouse, C. Willans and R.M. Phillips. Cancer Letters (2017) 397. dx.doi.org/10.1016/j.canlet.2017.04.041

  • Stabilization of a Bimolecular Triplex by 3'-S-Phosphorothiolate Modifications: an NMR and UV Thermal Melting Investigation. K. Evans, I. Bhamra, R.T. Wheelhouse, J.R.P. Arnold, R. Cosstick, and J. Fisher Chem. Eur. J (2015) 21, 7278–7284. DOI: 10.1002/chem.201500369. PubMed PMID:25802084
  • Evaluation of Novel Imidazotetrazine Analogues Designed to Overcome Temozolomide Resistance and Glioblastoma Regrowth. Y.P. Ramirez, A.C. Mladek, R.M. Phillips, M. Gynther, J. Rautio, A.H. Ross, R.T. Wheelhouse, J.N. Sakaria, Mol. Cancer Ther. (2015) 14, 111–119. doi: 10.1158/1535-7163.MCT-14-0113. PubMed PMID: 25351918
  • The Medicinal Chemistry of Imidazotetrazine Prodrugs. C.L. Moody and R.T. Wheelhouse Pharmaceuticals (2014) 7, 797–838
  • Synthesis and Quantitative Structure–Activity Relationship of Imidazotetrazine Prodrugs with Activity Independent of O6-Methylguanine-DNA-methyltransferase, DNA Mismatch Repair and p53. D. Pletsas, E.A.E. Garelnabi, L. Li, R.M. Phillips, R.T. Wheelhouse. J. Med. Chem (2013) 56, 7120–7132
  • Glioblastoma Multiforme Therapy and Mechanisms of Resistance. Y. Ramirez, J.L. Weatherbee, R.T. Wheelhouse and A.H. Ross Pharmaceuticals (2013) 6 1475–1506
  • Strategy for Imidazotetrazines with Anticancer Activity Independent of MGMT and MMR.  E.A. E. Garelnabi, D. Pletsas, L. Li, K. Kiakos, N. Karodia, J.A. Hartley, R.M. Phillips and R.T. Wheelhouse. ACS Med. Chem. Lett. (2012) 3, 965–968
  • Minor Structural Modifications to Alchemix Influence Mechanism of Action and Pharmacological Activity. Q.M.A. Abdallah, R.M. Phillips, H. Abdel-Rahman, J. Etzad, R.T. Wheelhouse, J.A. Hartley, L.H. Patterson, K. Pors Biochem Pharmacol. (2012) 83, 1514–1522
  • Metabolism of Cryptolepine and 2-Fluorocryptolepine by Aldehyde Oxidase.  J.G. Stell, R.T. Wheelhouse and C.W. Wright.  J. Pharm. Pharmacol. (2012) 64 237–243
  • Probing the Molecular Recognition of a DNA·RNA Hybrid Duplex.  R.T. Wheelhouse,* N.C. Garbett, N.J. Buurma and J.B. Chaires. Angew. Chem. Int. Ed. (2010) 49 3207–3210
  • Drug Binding to DNA·RNA Hybrid Structures.  R.T. Wheelhouse and J. B. Chaires. Drug-DNA Interactions Protocols, 2nd Ed., Ed K.R. Fox, Methods in Molecular Biology, Springer, (2010), Chapter 4, pp. 55–70
  • Heterocyclic N-oxidation Using Urea-Hydrogen Peroxide: a Safe, Convenient and Effective source of Hydrogen Peroxide.  D. Rong, V.A. Phillips, R.T. Wheelhouse.  Topics in Chemistry and Materials Science, Volume 3.  Current Issues in Organic Chemistry.  Heron Press, Sofia, Bulgaria. (2009) ISBN 978-954-580-271-3, pp 63–71
  • A Cytotoxic Diterpenoid form Croton membranaceus, the Major Constituent of Anticancer Herbal Formulations in Ghana.  M.T. Bayor, J.S.K. Ayim, G. Marston, R.M. Phillips, S.D. Shnyder, R.T. Wheelhouse, and C.W. Wright.  Nat. Prod. Commun. (2008) 3, 1875–1878
  • A Safe, Convenient and Efficient Method for the Preparation of Heterocyclic N-Oxides Using Urea⋅hydrogen peroxide. D. Rong, V.A. Phillips, R. Sánchez Rubio, Ma Ã. Castro, R.T. WheelhouseTetrahedron. Lett. (2008) 49 6933–6935
  • Inhibition of Cobalamine-dependent Methionine Synthase by Substituted Benzo-fused Heterocycles. E.C. Banks, S.W. Doughty, S.M. Toms, R.T. Wheelhouse, A. Nicolaou. FEBS J. (2007) 274 287–299

 Conference Presentations

  • Probing Imidazotetrazine Prodrug Activation Mechanisms. C.L. Moody, L. Ahmad, A. Ashour, R.T. Wheelhouse. G2PA 25th Medicinal Chemistry Conference, Liverpool, September 2017

  • Mechanisms of Action of Silane-substituted Anti-cancer Imidazotetrazines. H.S. Summers, T.D. Bradshaw, M.F.G. Stevens, R.T. Wheelhouse. G2PA 25th Medicinal Chemistry Conference, Liverpool, September 2017

  • Does an intercalated clinical placement make a difference to learning gain? R.T. Wheelhouse. Manchester Pharmacy Education Conference 2017

  • A Molecular Profile of Tumours Responsive to New Imidazotetrazine (Temozolomide Analogue) Prodrugs. Y.P. Ramirez, A.C. Mladek, C.L. Moody, R.M. Phillips, A.H. Ross, J.N. Sakaria, R.T. Wheelhouse. ELRIG Drug Discovery '14, Manchester, September 2014
  • Synthesis and SAR of New Imidazotetrazine Prodrugs. Royal Society of Chemistry Organic Division
North East Regional Meeting, University of Huddersfield, March 2013
  • Imidazotetrazines with Potential Against Temozolomide-resistant Glioma.  Y.P. Ramirez, A.C. Mladek, C.L. Moody, A.H. Ross, J.N. Sakaria, R.M. Phillips, R.T. Wheelhouse.* BACR-EORTC PAMM Group winter meeting, Cardiff, January 2013
  • Cytotoxicity of a Novel Bi-functional Temozolomide Analog, DP68, is Independent of MGMT Status in Glioblastoma Models. A.C. Mladek, Y. Ramirez, D. Pletsas, R.T. Wheelhouse, R.M. Phillips, A.H. Ross, K. Knudson, J.N. Sarkaria. Proceedings of the American Association for Cancer Research (2013) abstract 4476
  • Exploring Novel Temozolomide Analogues to Overcome Glioblastoma Resistance., Y.P. Ramirez, A.C. Mladek, R.M. Phillips, R.T. Wheelhouse, J.N. Sarkaria, A.H. Ross. 24th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Dublin, November 2012. Eur. J. Cancer (2012) 48(6S) 36

  • NMR Studies of DNA triplexes.  K. Evans, R.T. Wheelhouse, R. Costick, J. Fisher.  ANZMAG Conference, Torquay, Australia, 2011
  • DNA Sequence and Structure Binding Preferences in a Family of Cryptolepine Analogues. A.J. Pardal, T. Ibrahim, H. Chan, C.W. Wright and R.T. Wheelhouse Royal Society of Chemistry, Nucleic Acids Forum, London, July 2011
  • Targeting DNA·RNA Hybrids. R.T. Wheelhouse, H.R. Evans, N.C. Garbett, J.B. Chaires. Royal Society of Chemistry, Nucleic Acids Forum, Liverpool, July 2010
  • Imidazotetrazinone Prodrugs (Temozolomide analogues) with Activity Independent of Mismatch Repair and Alkyltransferase. R.T. Wheelhouse, D. Pletsas, L. Li, E.A.E. Garelnabi, R.M. Phillips. 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Berlin, November 2010. Eur. J. Cancer (2010) 8(7S) 138.
  • Investigating a Novel Antitumor Molecular Target using a Chemical Proteomic StrategyH.R. Evans, D. Rong, R.M. Phillips, C.W. Sutton and R.T. Wheelhouse.  Yorkshire Cancer Research Annual Scientific Meeting, Harrogate July 2010
  • New Applications of Imidazotetrazines – Taming Alkyldiazonium Ions.  E.A.E. Garelnabi, D. Pletsas, R.M. Phillips, R.T. Wheelhouse. British Association for Cancer Research 50th Anniversary Meeting, Edinburgh, June 2010
  • Targeting DNA·RNA Hybrids – a Route to Inhibitors of RNAse H and Telomerase.  R.T. Wheelhouse, H.R. Evans, N.C. Garbett, J.B. Chaires. British Association for Cancer Research 50th Anniversary Meeting, Edinburgh, June 2010
  • New temozolomide analogs with activity independent of mismatch repair and alkyltransferase. R.T. Wheelhouse, D. Pletsas, L. Li, E.A.E. Garelnabi, R.M. Phillips. Proceedings of the American Association for Cancer Research(2010) LB-177
  • Investigating a Novel Antitumor Molecular Target using a Chemical Proteomic StrategyH.R. Evans, D. Rong, R.M. Phillips, C.W. Sutton and R.T. Wheelhouse.AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, Boston, November 2009.  Mol. Cancer Ther. (2009) 8(12 Suppl) A204
  •  N-Nitrosocarbamates in the Synthesis of 3-(2-Aminoethyl)imidazotetrazines. E.A.E. Garelnabi, D. Pletsas and R.T. Wheelhouse.42nd IUPAC Congress: Chemistry Solutions, Glasgow, UK, August 2009
  • Novel small molecule inhibitors of telomerase. A. Adekunle, A., H.R. Evans, V.A. Phillips, D. Pletsas, R.T. Wheelhouse, S.M. Parkin, D.A.L. Watt, D.T.S. Sharpe, R.M. Phillips.  20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, October 2008 Geneva, Switzerland.  Eur. J. Cancer (2008) 6 (Supl) 139
  • Heterocyclic N-oxidation Using Urea-Hydrogen Peroxide: a Safe, Convenient and Effective source of Hydrogen Peroxide.  D. Rong, V.A. Phillips, R.T. Wheelhouse.  2nd International Symposium on Organic Chemistry, Sofia, Bulgaria, December 2008
  • A Safe, Convenient and Efficient Method for the Preparation of Heterocyclic N-Oxides Using Urea·Hydrogen Peroxide.  D. Rong, R.T. Wheelhouse, Tetrahedron Symposium, San Francisco, CA, USA, July 2008

Impact

Patents:

  • Aminoalkyl Imidazotetrazines for Treatment of Cancer. D. Pletsas and R.T. Wheelhouse. International Publication Number WO2009127815 (A1) October 2009. 58 pages
  • Porphyrin Compounds as Telomerase Inhibitors.  R.T. Wheelhouse and L.H. Hurley.  US Patent No. 6087493.  International Publication Number WO 98/33503

Visiting Lecturer:

  • Visiting Lectures: Department of Pharmacy, University of Malta, April 2015
  • Dipartimento di Scienza e Technologica del Farmaco Università di Torino, Italy July 2014
  • Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Italy, July 2014
  • Dipartimento di Scienza e Technologie Biologiche Chimiche e Farmaceutiche Università Degli Studi di Palermo, Italy, July 2014
  • Academy of Pharmaceutical Sciences, Edinburgh, September 2013
  • School of Pharmacy, University of Eastern Finland, April 2013
  • Royal Society of Chemistry Organic Division, NE Regional Meeting, Huddersfield, March 2013
  • BACR-EORTC PAMM group Meeting, Cardiff, January 2013
  • Royal Society of Chemistry, Nucleic Acids Forum, Liverpool, July 2010
  • Department of Chemistry, Grand Valley State University, Michigan, USA, June 2009
  • Department of Chemistry, Hope College, Holland, Michigan, USA, June 2009
  • James Graham Brown Cancer Center, Louisville, Kentucky, USA, May 2009
  • School of Pharmacy and Life Sciences, The Robert Gordon University, Aberdeen, UK, October 2008
  • Facultad Quimica, Universidad De Salamanca, Spain, May 2008
  • Facultad Farmacia, Universidad De Salamanca, Spain, May 2008

In the News/Media

January 2015

  • News archive 

January 2012

  • Yorkshire Post - "Drug to act as chemo carrier"

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