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Frederick Villamena

​Frederick A. Villamena, PhD

Associate Professor

126A Tzagournis Medical Research Facility
420 W. 12th Avenue
Columbus, OH 43210
Phone: (614) 292-8215
Frederick.Villamena@osumc.edu
 
Education:
PhD - Georgetown University
Post Doctoral Work: Johns Hopkins University
  
Curriculum Vitae

Research Interest

Free Radical Detection
Free radicals have been implicated in the pathogenesis of various diseases, or as mediators in a number of vital cellular functions. One of my major research interests is the advancement of free radical detection and identification by electron paramagnetic resonance (EPR) spectroscopy through the development of new spin traps and probes for chemical, biological and biomedical imaging applications. The spin trapping technique, using nitrone spin traps and EPR, has been widely employed for the identification of free radicals. We envision that spin traps with improved spin trapping properties will aid us in the detection and identification of free radicals in cells and animal models, and ultimately contribute towards the understanding of some of the fundamental mechanisms leading to oxidative stress or damage in biological systems.
Mechanisms of Oxidative Stress
Understanding the origin of radical production in cellular systems can lead to new therapeutic strategies for the reversal and prevention of oxidative stress, and for protection against environmental-induced cardiovascular injury. Exogenously introduced chemical agents such as toxins, particulates, metal ions or ionizing radiation can induce (or may attenuate) radical production in cells. The location of radical production, whether extracellular or intracellular, remains unclear and may exhibit different pathophysiological affects. For example, extracellularly generated superoxide radical anion may affect adjacent cells and inactivate NO in the vasculature. On the other hand, intracellularly generated superoxide may cause dysfunction of the cells that produce it. Therefore, knowledge of the location of radical generation in cellular systems under pathophysiological condidtions may help develop strategies to protect cells against radical-mediated injury.
Design of Synthetic Antioxidants
The introduction of the nitrone-based, disodium 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059), the first drug that had reached phase III clinical trials in the US in the treatment of acute ischemic stroke, has provided opportunities for the development of new and more robust pharmacological agents for the prevention of neurodegenerative diseases and ischemia-reperfusion injuries. However, the specific mechanism of nitrone bioactivity remains obscure but current findings by others indicate that this involves modulation of the intracellular redox state, suppression of gene transcription (in particular that of NF-kappa B-regulated cytokines and iNOS), and prevention of mitochondrial dysfunction. Our research focus involves interdisciplinary approach towards the development of novel synthetic antioxidants with improved pharmacological properties encompassing theoretical, synthetic, biochemical, and in-vitro/in-vivo studies.
 

Representative Publications

Liu Y, Song Y, Rockenbauer A, Sun J, Hemann C, Villamena FA, Zweier JL. (2011) Synthesis of trityl radical-conjugatyed disulfid biradicals for measurement of thiol concentration. J Org Chem 76:3853-3860.
Shah Z, Pineda C, Kampfrath T, Miaseyeu A, Ying Z, Racoma I, Deiuliis J, Xu X, Sung Q, Moffatt-Bruce S, Villamena F, Rajagopalan S. (2011) Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways. Vascul Pharmacol [Epub ahead of print].
Kim SU, Liu Y, Nash KM, Zweier JL, Rockenbauer A, Villamena FA. (2010) Fast reactivity of a cyclic nitrone-calix[4]pyrrole conjugate with superoxide radical anion: Theoretical and experimental studies (+). J Am Chem Soc [Epub ahead of print].
Liu Y, Villamena FA, Song Y, Sun J, Rockenbauer A, Zweier JL. (2010) Synthesis of (14)N- and (15)N-labeled trityl-nitroxide biradicals with strong spin-spin interaction and improved sensitivity to redox status and oxygen. J Org Chem [Epub ahead of print].
Durand G, Poeggeler B, Ortial S, Polidori A, Villamena FA, Boker J, Hardeland R, Pappolia MA, Pucci B. (2010) Amphiphilic amide nitrones: a new class of protective agents acting as modifiers of mitochondrial metabolism. J Med Chem 53:4849-4861.
Liu Y, Villamena FA, Rockenbauer A, Zweier JL (2010) Trityl-nitroxide biradicals as unique molecular probes for the simultaneous measurement of redox status and oxygenation. Chem Commun (Camb) 46:628-630.
Villamena FA (2010) Superoxide radical anion adduct of 5,5-dimethyl-1-pyrroline N-oxide. 6. Redox properties. J Phys Chem A 114:1153-1160.
Han Y, Liu Y, Rockenbauer A, Zweier Jl, Durand G, Villamena FA (2009) Lipophilic beta-cyclodextrin cyclic-nitrone conjugate: synthesis and spin trapping studies. J Org Chem 74:5369-5380.
Durand G, Prosak RA, Han Y, Ortial S, Rockebauer A, Pucci B, Villamena FA (2009) Spin trapping and cytoprotective properties of fluorinated amiphiphilic carrier conjugaes of cyclic versus linear nitrones. Chem Res Toxicol 22:1570-1581.
Villamena FA. Superoxide radical anion adduct of 5,5-dimethyl-1-1pyrroline N-oxide. 5. Thermodynamics and kinetics of unimolecular decomposition. J Phys Chem A 113:6398-6403, 2009.
Villamena, F.A., Xia, S., Merle, J.K., Lauricella, R., Tuccio, B., Hadad, C.M., Zweier, J.L. Role of intramolecular H-Bond and electrostatics on the reactivity of superoxide radical anion with cyclic nitrones. J Am Chem Soc 2007, (in press).
Lu, D., Villamena, F.A., Zhang, G., Nadas, J., Zweier, J.L., Johnson, W., Cardounel, A.J., Wang, P.G. Caged RNSOs: The next generation of S-Nitrosothiols. J Am Chem Soc 129:5503-5514, 2007.
Villamena, F.A., Locigno, E.J., Rockenbauer, A., Hadad, C.M., Zweier, J.L. Theoretical and experimental studies of the spin trapping of inorganic radicals by 5,5-dimethyl-1-pyrroline N-oxide (DMPO). 2. Carbonate radical anion. J Phys Chem A 111:384-391, 2007.
Locigno, E.J., Zweier, J.L., Villamena, F.A. Nitric oxide release form the unimolecular decomposition of the superoxide radical anion adduct of cyclic nitrones in aqueous medium. Org Biomol Chem 3:3320-3227, 2007.
Villamena, F.A., Merkle, K.J., Hadad, C.M., Zweier, J.L. Superoxide radical anion adduct of 5,5-Dimethyl-1-pyrroline N-oxide (DMPO). 1. The thermodynamics of formation and its acidity. J Phys Chem A 109:6083-6088, 2005.
Velayutham, M., Villamena, F.A., Navamal, M., Fishbein, J.C., Zweier, J.L. Glutathione mediated formation of oxygen free radicals by the major metabolite of oltipraz. Chem Res Toxicol 18:970-975, 2005.
Villamena, F.A., Hadad, C., M., Zweier, J.L. Comparative DFT study of the spin trapping of methyl, mercapto, hydroperoxy, superoxide, and nitric oxide radicals by various substituted cycline nitrones. J Phys Chem A 109:1662-1674, 2005.
Villamena F., Rockenbauer, A., Gallucci, J., Velayutham, M., Hadad, C.H., Zweier, J.L. Spin trapping by 5-carbamoyl-5-methyl-1-pyrroline N-oxide (AMPO): Theoretical and experimental studies. J Org Chem 69:7994-8004, 2004.
Villamena, F., Hadad, C., Zweier, J. Theoretical study of the spin trapping of hydroxyl radical by cyclic nitrones: A density functional theory approach. J Am Chem Soc 126: 1816-1829, 2004.
Villamena, F. and Zweier, J. Detection of reactive oxygen and nitrogen species by EPR spin-trapping technique. Antioxidant and Redox Signaling 6:619-629, 2004.
Villamena, F., Hadad, C., Zweier, J. Kinetic study and theoretical analysis of hydroxyl radical trapping and spin adduct decay of alkoxycarbonyl- and dialkoxyphosphoryl-nitrones in aqueous media. J Phys Chem A 107:4407-4414, 2003.
Zweier, J.L. and Villamena, F.A. Chemistry of free radicals in biological systems. In: Oxidative Stress and Cardiac Failure. Eds: Kukin, M.L. and Fuster, V., Futura Publishing Co., New York, 67-95, 2003.
Methachit, N., McGrath C, Stewart, J., Blans, P., Villamena, F., Zweier, J., Fishbein, J.C. Thiolytic chemistry of alternative precursors to the major metabolite of the cancer chemopreventive oltipraz. J Org Chem 67:9406-9413, 2002.
Villamena, F., Zweier, J., Superoxide radical trapping and spin adduct decay of 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide (BocMPO): Kinetics and theoretical analysis. J Chem Soc, Perkins Trans. 2. 130-1344, 2002.


The Davis Heart and Lung Research Institute, Investigator