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Department of Pharmaceutical Sciences, College of Pharmacy

Medicinal Chemistry Faculty

 
 
  Richard E. Lee, Ph.D.

Professor

Office location:
847 Monroe Ave
Johnson Bldg. Room 327B
Memphis, TN 38163
(901) 448-6018 tel
(901) 448-6828 fax
Email: relee@utmem.edu

CURRICULUM VITAE

Lab  Website

Ph.D., Organic Chemistry, University of Newcastle-upon-Tyne, UK, April 1993.
B.Sc., Chemistry, University of Newcastle-upon-Tyne, UK, June 1989

Professional Experience

Professor, 2008-present
Associate Professor, June 2005 - 2008.
Assistant Professor, May 2000- June 2005.
The University of Tennessee Health Science Center, College of Pharmacy, Department of Pharmaceutical Sciences

Research Fellow, August 1997-May 2000
Dr. C.E. Barry lab, Tuberculosis Research Section, National Institute of Allergy and Infectious Disease, National Institutes of Health.

Post Doctoral Research Fellow, April 1996-July 1997.
Dr. G.W.J. Fleet group, The Dyson Perrins Laboratory, The University of Oxford, UK

Post Doctoral Fellow, April 1993-April 1996.
Dr. P.J. Brennan group, The Mycobacterial Research Group, The Department of Microbiology, Colorado State University

Research

The major research focus of the laboratory is the design and synthesis of novel antimicrobial agents using an interdisciplinary approach and the latest technologies to tackle serious human infections. The typical research progression includes: target analysis and development; identification of candidate inhibitor scaffolds through database and literature searching; design and synthesis of hit identification and optimization libraries; lead optimization where possible through structure based drug design; in vitro testing; optimization of the pharmacological properties of the leads; and in vivo testing. Throughout this process we are aided by close collaborations with microbiologists, biochemists, structure biologists and clinical pharmacologists.  The core skills of the laboratory are organic synthesis, high throughput parallel synthesis, structure based drug design and microbiology.  There is also an active research interest in the laboratory in the analysis of natural products of bacterial origin that are pharmacologically active. The following are a selection of on going projects the laboratory:

Design and Synthesis M. tuberculosis cell wall biosynthesis inhibitors.
Tuberculosis is still a major cause of morbidity and mortality worldwide with the number of cases rising rapidly due to the HIV pandemic and the emergence of drug resistant strains. Tuberculosis possess a unique cell wall that provides many potential drug targets for the development of selective therapeutics.  In collaboration with Dr Michael McNeil and other workers at Colorado State University we are developing novel enzyme inhibitors against a panel of cell wall synthesis enzymes using a structure guided high throughput parallel synthesis approach followed by traditional medicinal chemistry optimization of the emerging leads.

Development of Novel Inhibitors of Dihyropteroate Synthase.
Dihydropteroate synthase is the target of the sulfonamide class of antibiotics.   However, problems have arisen that compromise their use due to the emergence of resistant strains in most of the organisms that they are used to treat.  In collaboration with Dr Stephen white at St Jude Children's Research Hospital we are using a structure based drug design approach to develop novel inhibitors of this enzyme that are not cross resistant to current sulfonamides.

Development of Nitrofuran antibiotics to treat tuberculosis.
One of the principal challenges of treating tuberculosis is developing therapies that are active against latent or slow growing organisms that are believed to live in a low oxygen environment.  It is this bacterial population that necessitates long treatment regimes for tuberculosis, thus faster acting treatments active against this population would significantly improve treatment options for this disease.  To target this population we are developing and optimizing a potent class of  nitrofuranyl amides as anti-tuberculosis agents.

Design and synthesis of inhibitors of Coenzyme A biosynthesis.
The continual onslaught of bacterial drug resistance coupled to the new science of genomics has lead researchers to propose that the development of non-classical antibacterial drug targets is of great importance. In a collaborative research project with Drs Rock and Jackowski at St. Jude Children’s Research Hospital we are exploring steps in Coenzyme A biosynthesis as non-classical antibacterial drug targets. The project involves the structure-based design and synthesis of inhibitors and anti-metabolites.

Whole cell HR-MAS NMR studies of live Mycobacteria
Until recently our current knowledge of the composition of the mycobacterial cell wall and other organic metabolites relied on tedious isolations in a destructive in a manner.  Recently, we developed whole cell high resolution magic angle spinning NMR technique to study the composition of these structures in live mycobacterial cells. Using this technique we were able to assign the majority of the spectrum and directly observe changes in cell wall composition due to drug treatment and from gene mutation.  We are currently applying this technique to study how all the macromolecules in the cell wall interact with each other and function as a chemical system.

Isolation and Characterization of Mycolactones.
Mycolactone is the major virulence determent of the mycobacteria species M. ulcerans, the causative cause of west Africa endemic disease Buruli ulcer.  This disease is characterized by large necrotic ulcers with the lack of inflammatory response. Most of the disease pathology is believed to be mediated by the lipid toxins the Mycolactones. Mycolactones are polyketides isolated from the acetone soluble fraction of the bacteria lipids.  In collaboration with Dr Pamela Small at the University of Tennessee Knoxville we are continuing to isolate and characterizing new mycolactones from fresh mycobacterial isolates and examine their immunosuppressive and anti tumor effects.

Keywords: Combinatoral Chemistry; Parallel Synthesis; Structure based drug design; High Throughput Screening; Antibiotics; Whole Cell MAS NMR; Mycolactone

Research Skills offered in the laboratory

Synthetic Chemistry of: Solid and Solution Phase Combinatorial Libraries, Parallel Synthesis; Structure Based Drug Design; Carbohydrate synthesis, Virtual screening; Biosynthetic Intermediates; Organo-Phosphates; Radiosynthesis; Fatty Acid Synthase Inhibitors; Prodrugs.

Structural analysis of Natural Products and Biosynthetic intermediates by: 1H, 13C, 31P and 2-Dimensional 500MHz NMR; Whole Cell MAS-NMR analysis; LC-MS-NMR; Electrospray, EI, FAB, APCI and GC-MS; GC, HPLC, TLC and HFC Column Chromatography.

Microbiology and Biochemical testing: Gene cloning and expression; MIC / MBC determinations against a wide panel of pathogenic organisms; Cell Free Enzymology; Cell culture; Stable and Radioactive Whole-Cell Isotopic Labeling; Gene, Lipid and Carbohydrate Profiling; High throughput screening;

Recent Publications

Structure-activity relationships and enzyme inhibition of pantothenamide-type pantothenate kinase inhibitors. KG Virga, YM Zhang, R Leonardi, RA Ivey, K Hevener, HW Park, S Jackowski, CO Rock, RE Lee Bioorg. Med. Chem. 2006 Feb 15;14(4):1007-20.

Synthesis and evaluation of cyclic secondary amine substituted phenyl and benzyl nitrofuranyl amides as novel antituberculosis agents. RP Tangallapally, R Yendapally, REB Lee, AJM Lenaerts, RE Lee. J. Med. Chem. 2005 Dec 29;48(26):8261-9.

Solid-phase synthesis development of a thymidinyl and 2’-deoxyuridinyl Ugi library for anti-bacterial agent screening. D Sun and RE Lee Tet. Lett. 2005; 46, 8497-01.

Synthesis of new and potent analogs of anti-tuberculosis agent 5-nitro-furan-2-carboxylic acid 4-(4-benzyl-piperazin-1-yl)-benzylamide with improved bioavailabilty. RP Tangallapally, REB Lee, AJM Lenaerts, RE Lee. Bioorg. Med. Chem. Lett 2006, 16, 2584-9.

Development of an etoposide prodrug for dual prodrug-enzyme antitumor therapy K.J Yoon, J Qi, JS. Remack, KG. Virga, M. J Hatfield, PM. Potter, RE Lee and M K. Danks Molecular Cancer Therapeutics 2006 Jun;5(6):1577-84.

Globally distributed mycobacterial fish pathogens produce a novel plasmid-encoded toxic macrolide, mycolactone F. Ranger BS, Mahrous EA, Mosi L, Adusumilli S, Lee RE, Colorni A, Rhodes M, Small PL. Infect Immun. 2006 Nov;74(11):6037-45

Acyl-Phosphates Initiate Membrane Phospholipid Synthesis in Gram-Positive Pathogens YJ Lu, Y-M Zhang, KD Grimes, J Qi, RE Lee, CO Rock Molecular Cell 2006 Sep 1;23(5):765-72

Monocyte and macrophage activation by lipoteichoic Acid is independent of alanine and is potentiated by hemoglobin. Hasty DL, Meron-Sudai S, Cox KH, Nagorna T, Ruiz-Bustos E, Losi E, Courtney HS, Mahrous EA, Lee R, Ofek I. J Immunol. 2006 May 1;176(9):5567-76.

Nitrofurans as Novel Anti-tuberculosis Agents: Identification, Development and Evaluation. RP Tangallapally, R Yendapally, AJ Daniels, REB Lee, RE Lee Curr Top Med Chem. 2007;7(5):509-26.

Topology and active site of plsy: the bacterial acylphosphate:glycerol-3-phosphate acyltransferase. Lu YJ, Zhang F, Grimes KD, Lee RE, Rock CO. J Biol Chem. 2007 Apr 13;282(15):11339-46.

Chemical Knockout of Pantothenate Kinase Reveals the Metabolic and Genetic Program Responsible for Hepatic Coenzyme A Homeostasis YM Zhang, S Chohnan, KG Virga, RD Stevens, OR Ilkayeva, BR Wenner, JR Bain, CB Newgard, RE Lee, CO Rock, and S Jackowski, Chem Biol. 2007 Mar;14(3):291-302.

Solid-Phase Synthesis of a Thymidinyl Dipeptide Urea Library, D Sun and RE Lee J. Comb. Chem. 2007 May-Jun;9(3):370-85

High-throughput solid-phase synthesis of nucleoside-based libraries in the search for new antibiotics, D. Sun, RE Lee High-Throughput Lead Optimization in Drug Discovery Ed.Tushar Kshirsagar, CRC press 2008, Vol. 3, Ch. 9, pp 215-238.

Crystal structure of the anthrax drug target, Bacillus anthracis dihydrofolate reductase BC Bennett, H Xu, RF Simmerman, RE Lee and CG Dealwis J. Med. Chem 2007 50(18):4374-81.

Discovery of Novel Isoxazolines as Anti-tuberculosis Agents RP Tangallapally , D Sun, Rakesh, N Budha, REB Lee, AJM Lenaerts, B Meibohm and RE Lee . Bioorg. Med. Chem. Lett . 2007; 17 :6638

Solid-phase synthesis and biological evaluation of a uridinyl branched peptide urea library. Sun D, Jones V, Carson EI, Lee RE, Scherman MS, McNeil MR, Lee RE. Bioorg Med Chem Lett. 2007; 17: 6899.

A rapid approach to lipid profiling of mycobacteria using 2D HSQC NMR maps. Mahrous EA, Lee RB, Lee RE. J Lipid Res. 2008 Feb;49(2):455-63

N-Substituted 3-Acetyl Tetramic acid Derivatives as Antibacterial Agents. R.Yendapally, J.G. Hurdle, EI Carson, RB Lee, RE Lee. J. Med. Chem. 2008 Mar 13;51(5):1487-91.

Biopharmaceutics, Pharmacokinetics and Pharmacodynamics of Antituberculosis Drugs. NR Budha, RE Lee and B Meibohm Curr Med Chem. 2008;15(8):809-25.

Design, Synthesis and Evaluation of Novel Ethambutol Analogues. R Yendapally and RE Lee Bioorg. Med. Chem. Lett. 2008 Mar 1;18(5):1607-11.

Pharmacokinetically-Guided Lead Optimization of Nitrofuranylamide Anti-Tuberculosis Agents. NR Budha, N Mehrotra, R Tangallapally, Rakesh, J Qi, AJ Daniels, RE Lee, and B Meibohm The AAPS Journal 2008;10(1):157-65

First Cultivation and Characterization of Mycobacterium ulcerans from the Environment. Portaels F, Meyers WM, Ablordey A, Castro AG, Chemlal K, de Rijk P, Elsen P, Fissette K, Fraga AG, Lee R, Mahrous E, Small PL, Stragier P, Torrado E, Van Aerde A, Silva MT, Pedrosa J. PLoS Negl Trop Dis. 2008 Mar 26;2(3):e178.

Synthesis, Optimization and Structure-Activity Relationships of 3,5-Disubstituted Isoxazolines as New Anti-tuberculosis Agents. Rakesh, D Sun, RB Lee, R Tangallapally, RE Lee European Journal of Medicinal Chemistry (in press).

Synthesis, Optimization and Structure-Activity Relationships of 3,5-Disubstituted Isoxazolines as New Anti-tuberculosis Agents. Rakesh, D Sun, RB Lee, R Tangallapally, RE Lee European Journal of Medicinal Chemistry. 2009 Feb;44(2):460-72

A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents  J Hurdle; RB Lee; N. Budha; M. Scherman; E. Carson; J. Qi, Jianjun; S Cho; A Lenaerts; S Franzblau; BM Meibohm, Bernd; RE Lee Journal of Antimicrobial Chemotherapy 2008 Nov;62(5):1037-45.

Quantitative structure–activity relationship studies on nitrofuranyl anti-tubercular agents KE Hevener, DM Ball, JK Buolamwini, RE. Lee  Bioorganic and Medicinal Chemistry 2008 Sep 1;16(17):8042-53.

Novel Acylphosphate Mimics that Target PlsY, an Essential Acyltransferase in Gram-Positive Bacteria.  KD Grimes, Y Lu, Y-M Zhang, VA Luna, JG Hurdle, EI Carson, J Qi, S Kudrimoti, CO Rock, RE Lee.  ChemMedChem 2008; 3 :1936-45.

Synthesis and Structure of Mycolactone E Isolated from Frog Mycobacterium.  Aubry S, Lee RE, Mahrous EA, Small PL, Beachboard D, Kishi Y. Org Lett. 2008, 10 (23), 5385–5388

Validation of Molecular Docking Programs for Virtual Screening against Dihydropteroate Synthase Hevener K; Zhao W; Ball D; Babaoglu K; Qi J; White S; Lee RE. J. Chem. Inf. Mod. 2009, 49 (2), 444–460.

Discovery, Synthesis, and Biological Evaluation of Piperidinol analogs With Anti-tuberculosis Activity D Sun, MS. Scherman, V Jones, JG Hurdle, LK Woolhiser,  SE Knudson, AJ Lenaerts, RA Slayden, MR McNeil RE Lee Bioorg Med Chem (in press)

 

Professional Memberships

 American Chemical Society Membership (1993-Present). Sub divisional Memberships: Carbohydrate Chemistry; Organic Chemistry and Medicinal Chemistry.   American Society of Microbiology (2000- present).

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