» Research Group web page » Syracuse University Magazine Feature » BioSym Technologies signs $5 million research agreement with Syracuse University		Robert Doyle Assistant Professor of Chemistry (2005) and Faculty of Biochemistry (2006) Adjunct Professor of Biology (2008) Inorganic chemistry, bioconjugate chemistry, molecular biology, chemical biology rpdoyle@syr.edu phone: 315-443-3584 / fax: 315-443-4070 Office: CST 2-006 Education: • B.A., 1998, Trinity College, Dublin, Ireland • Ph.D., 2002, Trinity College, Dublin, Ireland • Postdoctoral Fellow, 2002-2003, Australian National University • Postdoctoral Fellow, 2003-2005, Yale University Honors & Awards: • Enterprise Ireland Fellowship, 1998 • RSC Fellowship, 2002 • Rudolph Anderson Foundation Fellowship, 2004 • Ewing Marion Kauffman Foundation Award, 2008 Courses: CHE 103: Chemistry in the Modern World CHE 139*: Honors General Chemistry CHE 600: Metals in Biology & Medicine CHE 422/622*: Advanced Inorganic Laboratory CHE 450: Independent Research CHE 400/600*: Bioinorganic Chemistry   * denotes current Spring '08 course

Tribute Lectures: Christopher Walsh, John Fenn, W.A. Van der Donk, Stephen J. Lippard

Research Interests Research in my group focuses on the roles metal ions play in biology, medicine, and materials science. The overall goal is to develop research that offers a unique perspective between the disparate areas of biological chemistry and materials science. This is an exciting time for chemistry with more and more chemists utilizing the tools of molecular biology to study metalloproteins and with greater availability of cutting edge instrumentation such as Superconducting Quantum Interference Devices (SQUID). Work in our Lab involves:

1. The study of metal transport and uptake proteins in Prokaryotic organisms, including the mechanistic and structural characterization of a putative metal-citrate transporter from Streptomyces coelicolor A3(2). We are systematically figuring out how this unusual protein functions. To do this, we have overexpressed and isolated pure protein in E. coli, begun mutagenesis studies and extensive functional and kinetic studies in Streptomyces coelicolor A3(2). In addition we are working with Professor Gino Cingolani (Upstate Medical University, NY) to try to obtain crystal structures. The long-term goal of this work is to understand the possible role these proteins may have in disease pathogenesis in bacteria such as B. anthracis or M. tuberculosis. We are also interested in developing and utilizing these systems in metal bioremediation. [Josh Lensbouer (all facets of project), Joe Sirianni (E. coli overexpression), Ami Patel (mutagenesis), Suzanne Vroman (mutagenesis)]

Streptomyces coelicolor A3(2) single colony. Courtesy of the John Innes Centre, Norwich, UK.

Figure 1. Model of the predicted membrane topology of Sccit predicted by the TMHMM topology prediction program. C-terminal region is predicted to be outside the membrane with the N-terminal region inside. Boxes indicate transmembrane helices. Connecting loops are sized to portray general size (relative number of residues per loop). Residues to be mutated initially are marked. G446 is present in S. coelicolor and both CitM and CitH from B. subtilis. The arginine residue is postulated to be solvent exposed, through a membrane-traversing loop, and available for substrate binding (shaded oval; See Inset).

2a.) The synthesis of transition metal-based anti-cancer bioconjugates. The use of transition metals as therapeutics has long been left fallow by the pharmaceutical industry, which cites metal toxicity. Our goal is to demonstrate that this issue can be overcome by taking advantage of naturally occurring in vivo delivery systems. We are interested in using folic acid for example, to transport Ga and Tc into cells. In addition to transporting metals we tether nucleotide and nucleoside based anti-cancer compounds and peptide drugs to both folic acid and thiamin. We have successfully increased the in vitro cytotoxicity of AZT by ~20 fold against a drug resistant ovarian cancer cell line (A2780/AD) using this method, and in vivo studies are being conducted in collaboration with Prof. Dawn Post (Dept. of Neurosurgery, Upstate Medical University, NY). [Anthony Vortherms (Nucleosides), Nerissa Viola (Ga and Tc), Hester Dang (Nucleosides), Amy Rabideau (Tc)]

Nerissa with her mammalian cells (chinese hamster ovary cells)		Amy working with Tc in hot cell at Nuclear Reactor, Hamilton, Ontario

Along with the design, synthesis, purification and characterization of new therapeutics comes in vitro testing. We maintain stocks of CHO cells and human cancer cells (Breast, Ovarian, Nasopharyngeal) and screen our new compounds ourselves. 2b.) We are interested in methods to deliver proteins and peptides orally and have been utilizing vitamin and polymer based methods. Shown here is a B12-insulin system we built that has greater in vivo glucose lowering ability than free insulin when administered orally [Amanda Petrus, Dr. Timothy Fairchild (Department of Exercise Science), Dr. Ruth Weinstock (Joslin Diabetes Centre)]. B12-Insulin conjugate coupled at B12 ribose –OH goup and insulin BK29. B12-Insulin conjugate bound to B12 uptake protein TCII (Insulin in red; B12 in yellow)
3.) The synthesis and characterization of molecular materials based on paramagnetic metal ions complexed with organic radicals. The aim is to synthesize stable materials with high critical temperatures or with 'switching' properties for use in molecular devices. Currently we are interested in modifying galvinoxyl based organic radicals for this purpose. In addition we are looking at the fundamental VPO mechanism involved in the conversion of butane to maleic anhydride. We are interested in using a 'building-block' approach to producing homo- and hetero-nuclear systems. This work is in collaboration with Professor Miguel Julve, University of Valencia, Spain. [Tayo Ikotun, Beth Higbee]	3D-channels in nickel pyrophosphate coordination complex
Overall this work encompasses a broad view of inorganic chemistry and biology and uses techniques that are the cornerstone of chemical and biochemical research. Each project is designed to educate students through challenging, applied research involving in-demand and cutting edge techniques from light- and air-sensitive synthesis and low temperature magnetic susceptibility studies to in vivo protein expression and mutagenesis. In addition, each student is responsible for all aspects of the project from design, through synthesis, purification, characterization, radiochemistry, in vitro assays (Enzyme inhibition, DNA binding/scission/unwinding, WSK, Ox-stress, Caspase), to in vivo testing.

Patents Doyle RP, Oral Insulin Delivery, Non-provisional Patent Filed March 4th 2008 Doyle RP and Ikotun OF, Pyrophosphate therapeutics for the treatment of drug-resistant tumors Patent pending Filed May 2008 Doyle RP and Fairchild TJ, Non-invasive delivery of neuropeptides for the treatment of obesity Patent pending Filed June 2008 Doyle RP and Lensbouer JJ, Targeting Iron uptake in pathogenic bacteria Filed June 2008 Selected Publications (SU Grads and/or Undergrads are underlined) (* is corresponding author)   Doyle RP*, Ikotun OF, Higbee EM, Pyrophosphate based coordination complexes with nanomolar activity for the treatment of drug-resistant tumors, in prep   Doyle RP*, Vortherms AR, Dang H, Methotrexate based nucleotide bioconjugates: Evidence of in-tandem toxicity in doxorubicin resistant A2780/AD ovarian cancer cells, in prep   Doyle RP*, Ikotun OF, Higbee EM, Oullette W, Lloret F, and Julve M, Synthesis and structural and magnetic characterization of {[(phen)2Cu]2(μ-HP2O7)(μ-Cl)}•2H2O submitted 2008 Doyle RP, Nadia Marino, Teresa F. Mastropietro, Donatella Armentano, Giovanni De Munno, Francesc Lloret and Miguel Julve, Spin Canting in an Unprecedented Three-Dimensional Pyrophosphate- and 2,2’-Bipyrimidine-Bridged Cobalt(II) Framework, submitted Chem Commun 2008 Doyle RP*, Lensbouer JJ, Patel A and Sirianni JP, Functional Characterization and metal ion specificity of the Metal-Citrate complex transporter from Streptomyces coelicolor A3(2), J. Bacteriology published online as JB ACCEPTS June 13 2008 Nerissa Viola-Villegas, Amy E. Rabideau, Justin Cesnavicius, Jon E. Zubieta and Doyle RP*, Synthesis, Characterization, Cytotoxicity and in vitro uptake of a Rhenium (I) bisquin complex targeting the folate receptor, In Press ChemMedChem 2008 Doyle RP*, Ikotun OF, Ouellette W, Julve M, Lloret F, Synthesis, characterization, Thermal and magnetic characterization of a pyrophosphate bridged cobalt(II) complex Eur. J. Inorg. Chem 2691-2697 2008 Doyle RP*, Petrus AP and Fairchild TJ, Delivery of Proteins and Peptides through the Vitamin B12 Uptake Pathway, accepted In press Angew. Chemie. Int. Ed. 2008 Doyle RP, Boddy CN, Dixson DD, Offer J, Burlina F, Chassaing G, Dawson P, Orthogonal ligation: a three piece assembly of a PNA-peptide-PNA conjugate Chem Commun 2785-2787 2008 Tinoco A, Lucchesse B, Peterson C, Doyle RP, Valentine AM* On the Evolutionary significance and Metal binding characteristics of a Monolobal Transferrin from Ciona intestinalis, Proceedings of the National Academy (USA), 105, 3268-3273, 2008 Selected as a 'Faculty of 1000' paper Doyle RP*, Viola-Villegas NA and Vortherms AR, Delivering Gallium to Cancer Cells through the folate receptor Drug Targets Insight (invited paper) 3, 13-25, 2008 > full article Doyle RP*, Vortherms AR, Sinko PJ, Gao D and Debrah O, Synthesis, Characterization and In Vitro Assay of Folic Acid conjugates of 3`-azido-3`-deoxythymidine (AZT): Towards Targeted AZT based Anti-Cancer Therapeutics Nucleosides, Nucleotides and Nucleic Acids 25; 173-185, 2008 Doyle RP*, Petrus AP, Vortherms AR and Fairchild TJ, Vitamin B12 as a Carrier for the Oral Delivery of Insulin, ChemMedChem 2, 1717-1721, 2007. > read abstract Selected for Journal Cover: See Cover Art Selected as a 'Faculty of 1000' paper - designated a "must read" Angewandte Chemie 'Spotlight' article. See: Angew. Chemie. Int. Ed., 2007, 46, p8936 A ChemMedChem most accessed article Media Reports: CBS, NBC, FOX, The Post-Standard, News-Medical.Net, In-Pharma Technologist, NYSTAR News Apollo Biotech Newsletter, Diabetes-News, somewhereville.com, National Review of Medicine, Diabetes Australia Doyle RP*, Bauer TH, Cano J, Lloret F, Nieuwenhuyzen M and Julve, M, Metamorphosis of a butterfly: Synthesis, structural, magnetic and DFT characterisation of a ferromagnetically coupled tetranuclear copper(II) cluster Dalton Trans. 44, 5140, 2007 > full article Selected for Journal Cover: See Cover Art Doyle RP*, Levin B and Sirianni J, Isolation of DNA from Bacillus subtilis using the Wizard PLUS SV Miniprep DNA purification system, eNOTES July 2007 > full article Doyle RP*, Ikotun OF, Oullette W, Lloret F, and Julve M, Synthesis and structural and magnetic characterization of {[(phen)2Ni]2(μ-P2O7)}•27H2O and {[(phen)2Mn]2(μ-P2O7)}•13H2O: Rare examples of coordination complexes with the pyrophosphate ligand Inorg. Chem., 48, 6668, 2007 Doyle RP*, Ikotun OF, Oullette W, Lloret F, and Julve M, Synthesis, X-ray structure, thermal and magnetic properties of the first Neutral ferromagnetically coupled six coordinate dichloro-bridged nickel(II) dimer Eur J. Inorg. Chem., 14: 2083, 2007 > read abstract » View all Publications