Faculty
Research Areas
Undergraduate Research

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Faculty



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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 |
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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. |
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| 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)] |
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Nerissa with her mammalian cells
(chinese hamster ovary cells) |
Amy working with Tc in hot cell at
Nuclear Reactor, Hamilton, Ontario |
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| 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) |
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| 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
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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)
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Doyle RP*, Ikotun
OF, Higbee EM, Pyrophosphate
based coordination complexes
with nanomolar activity for
the treatment of drug-resistant
tumors, in prep
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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
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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
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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
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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
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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
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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