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Charles E. McKenna

Professor of Chemistry
Organic and Bioorganic Chemistry

Ph.D., 1971, University of California at San Diego
B.A., 1966, Oakland University
Office: LJS 268
Phone: (213) 740-7007
Fax: (213) 740-0930
Email: mckenna@usc.edu
 Group Homepage


Research Focus

 

Synthesis of Bisphosphonates: Drugs and Imaging Probes

The complex formed from crystallization of human farnesyl pyrophosphate synthase (hFPPS) from a solution of racemic [6,7-dihydro-5H-cyclopental[c]pyridin-7-yl(hydroxy)methylene]bis( phosphonic acid) (NE-10501, 8), a chiral analog of the anti-osteoporotic drug risedronate, contained the R enantionmer in the enzyme active site. This enantiospecificity was assessed by computer modeling of inhibitor-active site interactions using Autodock 3. The compound 8 complex exhibited only one Mg2+ (vs. 2 typically found with similar inhibitors), which could contribute to its 100-fold higher IC50. An improved synthesis of 8 is described, which decreases the number of steps from 12 to 8 and increases the overall yield by 17-fold.

We report the synthesis of the first fluorescently labeled conjugates of risedronate (1), using an epoxide linker strategy enabling conjugation of 1 via its pyridyl nitrogen with the label (carboxyfluorescein). Unlike prior approaches to create fluorescent bisphosphonate probes, the new linking chemistry did not abolish the ability to inhibit protein prenylation in vitro, while significantly retaining hydroxyapatite affinity. The utility of a fluorescent 1 conjugate in visualizing osteoclast resorption in vitro was demonstrated.


Nucleotide Analogues: A "Toolkit" to Study DNA Polymerase

The mechanism of DNA polymerase -catalyzed nucleotidyl transfer consists of chemical steps involving primer 3'OH deprotonation, nucleophilic attack, and pyrophosphate leaving-group elimination, preceded by dNTP binding which induces a large-amplitude conformational change for Watson-Crick nascent base pairs. Ambiguity in the nature of the rate-limiting step and active-site structural differences between correct and incorrect base-paired transition states remain obstacles to understanding DNA replication fidelity. Analogues of dGTP where the - bridging oxygen is replaced with fluorine-substituted methylene groups have been shown to probe the contribution of leaving-group elimination to the overall catalytic rate (Biochemistry 46, 461-471). Here, the analysis is expanded substantially to include a broad range of halogen substituents with disparate steric and electronic properties. Evaluation of linear free energy relationships for incorporation of dGTP analogues opposite either template base C or T reveals a strong correlation of log(kpol) to leaving group pKa. Significantly different kpol behavior is observed with a subset of the analogues, with magnitude dependent on the identity of the nascent base pair. This observation, and the absence of an analogous effect on ground state analogue binding (Kd values), points to active-site structural differences at the chemical transition state. Reduced catalysis with bulky halo-containing substrates is manifested in the fidelity of T-G incorporation, where the CCl2-bridging analogue shows a 27-fold increase in fidelity over the natural dGTP. Solvent pH and deuterium isotope effect data are also used to evaluate mechanistic differences between correct and mispaired incorporation.


Synthesis of Peptidomemitic Prodrugs of Cidofovir

Cidofovir (HPMPC, 1), a broad-spectrum antiviral agent, is currently used to treat AIDS-related human cytomegalovirus (HCMV) retinitis and has recognized therapeutic potential for orthopox virus infections, but is limited by its low oral bioavailability. Cyclic cidofovir (2) displays decreased nephrotoxicity compared to 1, while also exhibiting potent antiviral activity. Here we describe in detail the synthesis and evaluation as prodrugs of four cHPMPC dipeptide conjugates in which the free POH of 2 is esterified by the Ser side chain alcohol group of an X-L-Ser(OMe) dipeptide: 3 (X = L-Ala), 4 (X = L-Val), 5 (X = L-Leu), and 6 (X = L-Phe). Perfusion studies in the rat establish that the mesenteric permeability to 4 is more than 20-fold greater than to 1, and the bioavailability of 4 is increased 6-fold relative to 1 in an in vivo murine model. In gastrointestinal and liver homogenates, the cHPMPC prodrugs are rapidly hydrolyzed to 2. Prodrugs 3, 4, and 5 are nontoxic at 100 µM in HFF and KB cells and in cell-based plaque reduction assays had IC50 values of 0.1-0.5 µM for HCMV and 10 µM for two orthopox viruses (vaccinia and cowpox). The enhanced transport properties of 3-6, conferred by incorporation of a biologically benign dipeptide moiety, and the facile cleavage of the Ser-O-P linkage suggest that these prodrugs represent a promising new approach to enhancing the bioavailability of 2.

When the X-L-Ser(OMe) dipeptide is conjugated with 2, a new chiral center is formed at the phosphorus atom resulting in two diastereomers. They can be detected individually by 31P NMR and separated by RP-HPLC. Geometry optimization using a 3-21G* basis set on Spartan '02 predicts a substantial difference in polarity between the two diastereomers (5.72 D vs 13.17 D). As the diastereomers are presumably separated on the C-18 HPLC column due to their differing hydrophobicity, the less hydrophobic compound is likely the R isomer, which is calculated to have a larger dipole moment than the S isomer (the slower eluting compound). It will be of future interest to determine whether this significant difference in ground state polarities is reflected in the relative rates of enzyme-mediated activation processes.


Selected publications

 

2014

Oertell K, Chamberlain BT, Wu Y, Ferri E, Kashemirov BA, Beard WA, Wilson SH, McKenna CE, Goodman MF, "The Transition-State in DNA Polymerase β Catalysis: Rate-limiting Chemistry Altered by Base-Pair Configuration", Biochemistry2014, 53 (11), pp 1842–1848.

I.S. Krylov, C.E. McKenna, “Enzymatically activated phosphate and phosphonate prodrugs”, Chapter in: "Enzyme technology for biotechnology and pharmaceutical applications", Vol. 2, eds.  J.R. McCarthy, G. Yang, W.-K. Yeh, Wiley Interscience, New York, NY, in press (2014).

 

2013

Vermeer JA, Jansen ID, Marthi M, Coxon FP, McKenna CE, Sun S, de Vries TJ, Everts V. "Jaw bone marrow-derived osteoclast precursors internalize more bisphosphonate than long-bone marrow precursors." Bone. 2013, 57, 242-51. 

Ni F, Lee CC, Hwang CS, Hu Y, Ribbe MW, McKenna CE. "Reduction of fluorinated cyclopropene by nitrogenase." J Am Chem Soc. 2013, 135, 10346-10352.

Emadali A, Rousseaux S, Bruder-Costa J, Rome C, Duley S, Hamaidia S, Betton P, Debernardi A, Leroux D, Bernay B, Kieffer-Jaquinod S, Combes F, Ferri E, McKenna CE, Petosa C, Bruley C, Garin J, Ferro M, Gressin R, Callanan MB, Khochbin S. "Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers." EMBO Mol Med. 2013, 5 (8), 1180–1195.

Krylov IS, Kashemirov BA, Hilfinger JM, McKenna CE. "Evolution of an amino acid based prodrug approach: stay tuned." Mol. Pharm. 2013, 10, 445-58. (cover)

Hokugo A, Sun S, Park S, McKenna CE, Nishimura I. "Equilibrium-dependent bisphosphonate interaction with crystalline bone mineral explains anti-resorptive pharmacokinetics and prevalence of osteonecrosis of the jaw in rats." Bone2013, 53, 59-68.

 
2012

Arora DKSyed IMachhadieh BMcKenna CEKowluru A. "Rab-geranylgeranyl transferase regulates glucose-stimulated insulin secretion from pancreatic β cells." Islets2012, 4, 354-358.

Ward SE, Kim HS, Komurov K, Mendiratta S, Tsai PL, Schmolke M, Satterly N, Manicassamy B, Forst CV, Roth MG, García-Sastre A, Blazewska KM, McKenna CE, Fontoura BM, White MA. "Host modulators of H1N1 cytopathogenicity". PLoS One. 2012, 7 (8).

Oertell K, Wu Y, Zakharova VM, Kashemirov BA, Shock DD, Beard WA, Wilson SH, McKenna CE, Goodman MF. "Effect of β,γ-CHF and β,γ-CHCl dGTP halogen atom stereochemistry on the transition-state of DNA polymerase β". Biochemistry. 2012, 51, 8491-8501.

Roelofs AJ, Stewart C, Sun S, Blazewska KM, Kashemirov BA, McKenna CE, Russell RGG, Rogers MJ, Lundy MW, Ebetino FH, Coxon FP. "Influence of bone affinity on skeletal distribution of fluorescently-labeled bisphosphonate analogues". J Bone Miner Res. 2012, 27(4), 835-47.

Y. Wu, V.M. Zakharova, B.A. Kashemirov, M.F. Goodman, V.K. Batra, S.H. Wilson, C.E. McKenna. "β,γ-CHF- and CHCl-dGTP diastereomers: synthesis, discrete 31P NMR signatures and absolute configurations of new stereochemical probes for DNA polymerases”, J Am Chem Soc. 2012134 (21), 8734–8737.

J. Turek, F.H. Ebetino, M.W. Lundy, S. Sun, B.A. Kashemirov, C.E. McKenna, M.A. Gallant, L.I. Plotkin, T. Belido, X. Duan, R.G.G. Russell, D. Burr, M. Allen. “Bisphosphonate Binding Affinity Affects Drug Distribution in Both Intracortical and Trabecular Bone of Rabbits”, Calcif Tissue Int. 2012, 90, 202-210

V.K. Batra, D.D. Shock, W.A. Beard, C.E. McKenna, S.H. Wilson. “Binary complex crystal structure of DNA polymerase β reveals multiple conformations of the templating 8-oxoguanine lesion”, Proc Natl Acad Sci U S A. 2012, 109, 113-118.

I.S. Krylov, V.M. Zakharova, M. Serpi, R. Haiges, B.A. Kashemirov, C.E. McKenna. “The structure of cyclic nucleoside phosphonate ester prodrugs: an inquiry”, J Org Chem. 2012, 77, 684-689.

B.T. Chamberlain, V.K. Batra, W.A. Beard, A.P. Kadina, D.D. Shock, B.A. Kashemirov, C.E. McKenna. “Stereospecific Formation of a Ternary Complex of (S)-α,β-fluoromethylene-dATP with DNA Pol β”, ChemBioChem. 2012, 13,  528-530.

2011

V.M. Zakharova, I.S. Krylov, M. Serpi, B. Kashemirov, C.E. McKenna. “Approaches to Tyrosine-Linked Peptidomimetic Prodrugs of (S)-HPMP-Based Acyclic Nucleoside Phosphonates”, Phosphorus Sulfur Silicon Relat Elem. 2011, 186, 968-969.

E. Gaidamauskas, D.C. Crans, H. Parker, K. Saejueng, B.A. Kashemirov, C.E. McKenna. “Quantification of foscarnet with chromogenic and fluorogenic chemosensors: indicator displacement assays based on metal ion coordination with a catechol ligand moiety”, New J Chem. 2011, 35, 2877-2883.

M.M. Williams, I.S. Krylov, V.M. Zakharova, M. Serpi, L.W. Peterson, M. Krecmerova, B.A. Kashemirov, C.E. McKenna. “Cyclic and acyclic phosphonate tyrosine ester prodrugs of acyclic nucleoside phosphonates”, Czech Coll Symp Ser. 2011, 12, 167-170.

A.J. Roelofs, C.A. Stewart, S. Sun, K.M. Blazewska, B.A. Kashemirov, C.E. McKenna, R.G.G. Russell, M.J. Rogers, M.W. Lundy, F.H. Ebetino, F.P. Coxon. “Influence of bone affinity on the skeletal distribution of fluorescently‚Äźlabeled bisphosphonates in vivo”, J Bone Miner Res. 2011.

V.M. Zakharova, M. Serpi, I.S. Krylov, L.W. Peterson, J.M. Breitenbach, K.Z. Borysko, J.C. Drach, M. Collins, J.M. Hilfinger, B.A. Kashemirov, C.E. McKenna. “Tyrosine-based 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) prodrugs: synthesis, stability, antiviral activity, and in vivo transport studies”, J Med Chem. 2011, 54, 5680-5693.

D.A. Mustafa, B.A. Kashemirov, C.E. McKenna. “Microwave-assisted synthesis of nitrogen-containing 1-hydroxymethylene bisphosphonate drugs”, Tetrahedron Lett. 2011, 52, 2285-2287.

K.M. Blazewska, R. Haiges, B.A. Kashemirov, F.H. Ebetino, C.E. McKenna. “A serendipitous phosphonocarboxylate complex of boron: when vessel becomes reagent”, Chem Commun (Camb). 2011, 47, 6395-6397.

K.M. Blazewska, F. Ni, R. Haiges, B.A. Kashemirov, F.P. Coxon, C.A. Stewart, R. Baron, M.J. Rogers, M.C. Seabra, F.H. Ebetino, C.E. McKenna. “Synthesis, stereochemistry and SAR of a series of minodronate analogues as RGGT inhibitors”, Eur J Med Chem. 2011, 46, 4820-4826.

S. Sun, K.M. Blazewska, B.A. Kashemirov, A.J. Roelofs, F.P. Coxon, M.J. Rogers, F.H. Ebetino, M.J. McKenna, C.E. McKenna. “Synthesis and characterization of novel fluorescent nitrogen-containing bisphosphonate imaging probes for bone active drugs”, Phosphorus Sulfur Silicon Relat Elem. 2011, 186, 970-971.

B.T. Chamberlain, J. Osuna, B.A. Kashemirov, C.E. McKenna. “Synthesis and Sensing of Biphosphonophosphate Alkyl Monoesters: A Novel Class of Compounds for the Study of Nucleoside 5’-Triphosphate Chemistry”, Phosphorus Sulfur Silicon Relat Elem. 2011, 186, 966-967.

B.T. Chamberlain, T.G. Upton, B.A. Kashemirov, C. McKenna. “α-Azido bisphosphonates: synthesis and nucleotide analogues”, J Org Chem. 2011, 76, 5132-5136.

S. Sun, C.E. McKenna. “Farnesyl pyrophosphate synthase modulators: a patent review (2006 - 2010)”, Expert Opin Ther Pat. 2011, 21 1433-1451.

L.W. Peterson, J.S. Kim, P. Kijek, S. Mitchell, J. Hilfinger, J. Breitenbach, K. Borysko, J.C. Drach, B.A. Kashemirov, C.E. McKenna. “Synthesis, transport and antiviral activity of Ala-Ser and Val-Ser prodrugs of cidofovir”, Bioorg Med Chem Lett. 2011, 21, 4045-4049.

F.H. Ebetino, A.M. Hogan, S. Sun, M.K. Tsoumpra, X. Duan, J.T. Triffitt, A.A. Kwaasi, J.E. Dunford, B.L. Barnett, U. Oppermann, M.W. Lundy, A. Boyde, B.A. Kashemirov, C.E. McKenna, R.G. Russell. “The relationship between the chemistry and biological activity of the bisphosphonates”, Bone. 2011, 49, 20-33.

2010

X. Tian, R. U. Jin, A. J. Bredemeyer, E. J. Oates, K. M. Blazewska, C. E. McKenna, J. C. Mills. “RAB26 and RAB3D are direct transcriptional targets of MIST1 that regulate exocrine granule maturation.” Mol. Cell. Biol. 2010, 30, 1269-1284.

H. Zhang, W. Pang, M. S. Marma, C. Y. Lee, S. Kamal-Bahl, E. S. Kim, C. E. McKenna. “Label-free detection of protein-ligand interactions in real time using micromachined bulk acoustic resonators.” Appl. Phys. Lett. 2010, 96, ARTN 123702.

J. L. F. Bala, B. A. Kashemirov, C. E. McKenna. “Synthesis of a Novel Bisphosphonic Acid Alkene Monomer.” Synthetic Commun 2010, 40, 3577-3584.

V. K. Batra, L. C. Pedersen, W. A. Beard, S. H. Wilson, B. A. Kashemirov, T. G. Upton, M. F. Goodman, C. E. McKenna. “Halogenated β,γ-methylene- and ethylidene-dGTP-DNA ternary complexes with DNA polymerase β: structural evidence for stereospecific binding of the fluoromethylene analogues.” J. Am. Chem. Soc. 2010, 132, 7617-7625.

C. E. McKenna, B. A. Kashemirov, L. W. Peterson, M. F. Goodman. “Modifications to the dNTP triphosphate moiety: from mechanistic probes for DNA polymerases to antiviral and anti-cancer drug design.” Biochim. Biophys. Acta 2010, 1804, 1223-1230.

C. E. McKenna, B. A. Kashemirov, K. M. Blazewska, I. Mallard-Favier, C. A. Stewart, J. Rojas, M. W. Lundy, F. H. Ebetino, R. A. Baron, J. E. Dunford, M. L. Kirsten, M. C. Seabra, J. L. Bala, M. S. Marma, M. J. Rogers, F. P. Coxon. “Synthesis, chiral high performance liquid chromatographic resolution and enantiospecific activity of a potent new geranylgeranyl transferase inhibitor, 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid.” J. Med. Chem. 2010, 53, 3454-3464.

J. J. Pan, B. A. Kashemirov, J. Lee, C. E. McKenna, F. J. Devlin, P. J. Stephens. “Electronic circular dichroism of monomethyl [16O,17O,18O]-phosphate and [16O,17O,18O]-thiophosphate revisited.” Bioorg. Chem. 2010, 38, 7-16.

L. W. Peterson, M. Sala-Rabanal, I. S. Krylov, M. Serpi, B. A. Kashemirov, C. E. McKenna. “Serine side chain-linked peptidomimetic conjugates of cyclic HPMPC and HPMPA: synthesis and interaction with hPEPT1.” Mol Pharm 2010, 7, 2349-2361.

G. K. Surya Prakash, M. Zibinsky, T. G. Upton, B. A. Kashemirov, C. E. McKenna, K. Oertell, M. F. Goodman, V. K. Batra, L. C. Pedersen, W. A. Beard, D. D. Shock, S. H. Wilson, G. A. Olah. “Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis-(difluoromethylene)triphosphoric acid.” Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 15693-15698.

K. Fu, Q. Xu, J. Czernuszka, C. E. McKenna, F. H. Ebetino, R. G. Russell, J. T. Triffitt, Z. Xia. “Prolonged osteogenesis from human mesenchymal stem cells implanted in immunodeficient mice by using coralline hydroxyapatite incorporating rhBMP2 microspheres.” J Biomed Mater Res A 2010, 92, 1256-1264.

U. Tehler, C. H. Nelson, L. W. Peterson, C. J. Provoda, J. M. Hilfinger, K. D. Lee, C. E. McKenna, G. L. Amidona. “Puromycin-sensitive aminopeptidase: An antiviral prodrug activating enzyme.” Antivir Res 2010, 85, 482-489.

A. J. Roelofs, F. P. Coxon, F. H. Ebetino, M. W. Lundy, Z. J. Henneman, G. H. Nancollas, S. Sun, K. M. Blazewska, J. L. Bala, B. A. Kashemirov, A. B. Khalid, C. E. McKenna, M. J. Rogers. “Fluorescent risedronate analogues reveal bisphosphonate uptake by bone marrow monocytes and localization around osteocytes in vivo.” J. Bone Miner. Res. 2010, 25, 606-616.

M. Serpi, I. S. Krylov, V. M. Zakharova, C. E. McKenna. “Synthesis of peptidomimetic conjugates of cyclic nucleoside phosphonates.” Curr Protoc Nucleic Acid Chem 2010, Chapter 15, Unit15.4.

2009

T. G. Upton, B. A. Kashemirov, C. E. McKenna, M. F. Goodman, G. K. Prakash, R. Kultyshev, V. K. Batra, D. D. Shock, L. C. Pedersen, W. A. Beard, S. H. Wilson. “α,β-difluoromethylene deoxynucleoside 5’-triphosphates: a convenient synthesis of useful probes for DNA polymerase β structure and function.” Org. Lett. 2009, 11, 1883-1886.

I. S. Krylov, L. W. Peterson, B. A. Kashemirov, J. Breitenbach, K. Borysco, J. C. Drach, J. S. Kim, J. M. Hilfinger, C. E. McKenna. “In vitro transport, activation and antiviral evaluation of new HPMPA prodrugs synthesized on a solid support.” Antivir Res 2009, 82, A75-A75.

A. Boyde, M. W. Lundy, F. P. Coxon, C. E. McKenna, A. Roelofs, J. Bala, M. J. Rogers, K. Blazewska, R. G.G. Russelle, F. H. Ebetino. “The differential distribution in vivo of fluorescently-labeled bisphosphonate analogues with different mineral affinity to bone surfaces.” Bone 2009, 44, S57-S57.

C. E. McKenna, B. A. Kashemirov, K. M. Blazewska. “Product Class Phosphoric Acid [PO(OH)³] and Derivatives.” Science of Synthesis, Houben-Weyl Methods of Molecular Transformations 2009, 42, 779-921.

C. E. McKenna, L. W. Peterson, B. A. Kashemirov, M. Serpi, S. Mitchell, J. S. Kim, J. M. Hilfinger, J. C. Drach. “New peptidomimetic prodrugs of acyclic and cyclic cidofovir: sat studies of chemical and enzymatic activation mechanisms.” Antivir Res 2009, 82, A75-A75.

R. A. Baron, R. Tavare, A. C. Figueiredo, K. M. Blazewska, B. A. Kashemirov, C. E. McKenna, F. H. Ebetino, A. Taylor, M. J. Rogers, F. P. Coxon, M. C. Seabra. “Phosphonocarboxylates inhibit the second geranylgeranyl addition by Rab geranylgeranyl transferase.” J. Biol. Chem. 2009, 284, 6861-6868.

K. E. Metlushka, B. A. Kashemirov, V. F. Zheltukhin, D. N. Sadkova, B. Buchner, C. Hess, O. N. Kataeva, C. E. McKenna, V. A. Alfonsov. “1-(α-aminobenzyl)-2-naphthol: a new chiral auxiliary for the synthesis of enantiopure α-aminophosphonic acids.” Chemistry 2009, 15, 6718-6722.

L. W. Peterson, C. E. McKenna. “Prodrug approaches to improving the oral absorption of antiviral nucleotide analogues.” Expert Opin Drug Deliv 2009, 6, 405-420.

E. Gaidamauskas, H. Parker, B. A. Kashemirov, A. A. Holder, K. Saejueng, C. E. McKenna, D. C. Crans. “Complexation of bisphosphonates with ytterbium(III): application of phosphate and ATP detection assay based on Yb(3+)-pyrocatechol violet.” J. Inorg. Biochem. 2009, 103, 1652-1657.

A. J. Roelofs, A. Boyde, M. W. Lundy, C. E. McKenna, K. Blazewska, S. T. Sun, B. A. Kashemirov, R. G. G. Russell, F. H. Ebetino, M. J. Rogers, F. P. Coxon. “Bone mineral affinity influences the distribution of a bisphosphonate and a lower affinity analogue in vivo.” Bone 2009, 44, S430-S431.

S. C. Kamerlin, C. E. McKenna, M. F. Goodman, A. Warshel. “A computational study of the hydrolysis of dGTP analogues with halomethylene-modified leaving groups in solution: implications for the mechanism of DNA polymerases.” Biochemistry 2009, 48, 5963-5971.

M. Sala-Rabanal, L. W. Peterson, M. Serpi, I. S. Krylov, B. A. Kashemirov, J. S. Kim, S. Mitchell, J. M. Hilfinger, C. E. McKenna. “Interactions Between the Human Oligopeptide Transporter, hPepT1 and Serine Side-chain-linked Cidofovir Prodrugs.” Antivir Res 2009, 82, A53-A54.

2008

E. Metlushka, V. A. Alfonsov, C. E. McKenna, B. A. Kashemirov, O. N. Kataeva, V. F. Zheltukhin, D. N. Sadkova, A. B. Dobrynin. “Phosphonylation of 1,3-Diaryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine by Dialkyl and Diaryl Phosphonates.” Phosphorus Sulfur Silicon Relat Elem 2008, 183, 2645-2646.

F. P. Coxon, J. L. Bala, B. A. Kashemirov, M. W. Lundy, X. L. Chen, Z. Xia, J. E. Dunford, G. G. Russell, A. J. Roelofs, M. J. Rogers, C. E. McKenna, F. H. Ebetino. “Fluorescently labeled risedronate and related analogs: Design and evaluation as imaging probes.” Bone 2008, 42, S36-S36.

F. P. Coxon, C. A. Stewart, R. Tavare, R. Baron, A. Taylor, M. S. Marma, K. M. Blazewska, B. A. Kashemirov, F. H. Ebetino, M. C. Seabra, M. J. Rogers, C. E. McKenna. “Inhibition of Rab geranylgeranyl transferase and Rab prenylation by phosphonocarboxylate drugs.” Calcified Tissue Int 2008, 82, S127-S127.

F. P. Coxon, J. L. Bala, B. A. Kashemirov, A. J. Roelofs, M. Lundy, X. Chen, Z. Xia, J. E. Dunford, R. G. Russell, M. J. Rogers, C. E. McKenna, F. Ebetino. “Fluorescently labeled risedronate and related analocs: Design and evaluation as imaging probes.” Calcified Tissue Int 2008, 82, S127-S128.

C. A. Sucato, T. G. Upton, B. A. Kashemirov, J. Osuna, K. Oertell, W. A. Beard, S. H. Wilson, J. Florian, A. Warshel, C. E. McKenna, M. F. Goodman. “DNA polymerase β fidelity: halomethylene-modified leaving groups in pre-steady-state kinetic analysis reveal differences at the chemical transition state.” Biochemistry 2008, 47, 870-879.

R. Tavare, R. Baron, A. Taylor, M. C. Seabra, K. M. Blazewska, C. E. McKenna, B. A. Kashemirov, F. H. Ebetino, M. J. Rogers, F. P. Coxon. “Characterisation of the inhibition of rab prenylation by phosphonocarboxylates.” Bone 2008, 42, S88-S89.

T. G. Upton, J. Osuna, B. A. Kashemirov, C. E. McKenna, M. F. Goodman, C. A. Sucato, S. H. Wilson, V. K. Batra, L. C. Pedersen, W. A. Beard. “ORGN 278-Synthesis and pKa values of stereoelectronically diverse methylenebisphosphonic acids: A nucleotide analog toolkit to probe nucleic acid polymerase structure and function.” J Chem Soc Chem Commun 2008, 235.

T. Kotti, D. D. Head, C. E. McKenna, D. W. Russell. “Biphasic requirement for geranylgeraniol in hippocampal long-term potentiation.” Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 11394-11399.

S. Deprele, B. A. Kashemirov, J. M. Hogan, F. H. Ebetino, B. L. Barnett, A. Evdokimov, C. E. McKenna. “Farnesyl pyrophosphate synthase enantiospecificity with a chiral risedronate analog, [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid) (NE-10501): Synthetic, structural, and modeling studies.” Bioorg. Med. Chem. Lett. 2008, 18, 2878-2882.

L. W. Peterson, B. A. Kashemirov, U. Eriksson, J. S. Kim, S. Mitchell, P. Kijek, K. D. Lee, J. M. Hilfinger, C. E. McKenna. “Serine side-chain-linked peptidomimetic prodrugs of cidofovir and cyclic cidofovir: C-ester effects on transport and activation.” Antivir Res 2008, 78, A46-A46.

L. W. Peterson, B. A. Kashemirov, M. Sala-Rabanal, J. S. Kim, S. Mitchell, P. Kijek, J. Hilfinger, C. E. McKenna. “MEDI 183-Synthesis and transport studies on serine side-chain-linked peptidomimetic prodrugs of cyclic cidofovir.” J Chem Soc Chem Commun 2008, 235.

C. V. Pham, B. A. Kashemirov, J. Osuna, K. Saejueng, J. M. Hilfinger, C. E. McKenna. “Synthesis of P-O-C-linked foscarnet-peptide conjugates and sensitive methods to detect the released drug in biological samples.” Antivir Res 2008, 78, A62-A62.

F. H. Ebetino, J. E. Dunford, M. W. Lundy, M. Pozzi, Z. Xia, R. Dobson, M. Quijano, R. Christian, B. A. Kashemirov, C. E. McKenna, G. G. Russell, B. L. Barnett. “A mirror image pair of bisphosphonate analogs further demonstrates the mode of binding of the bisphosphonates in farnesyl pyrophosphate synthase.” Bone 2008, 42, S36-S37.

A. J. Roelofs, F. P. Coxon, F. H. Ebetino, J. F. Bala, B. A. Kashemirov, C. E. McKenna, M. J. Rogers. “Use of a fluorescent analogue of risedronate to study localisation and cellular uptake of bisphosphonates in vivo.” Bone 2008, 42, S85.

U. Eriksson, L. W. Peterson, B. A. Kashemirov, J. M. Hilfinger, J. C. Drach, K. Z. Borysko, J. M. Breitenbach, J. S. Kim, S. Mitchell, P. Kijek, C. E. McKenna. “Serine peptide phosphoester prodrugs of cyclic cidofovir: synthesis, transport, and antiviral activity.” Mol Pharm 2008, 5, 598-609.

A. J. Roelofs, F. P. Coxon, F. H. Ebetino, J. F. Bala, B. A. Kashemirov, C. E. McKenna, M. J. Rogers. “Visualisation of cellular uptake and localisation of bisphosphonate in vivo using a fluorescent analogue of risedronate.” Calcified Tissue Int 2008, 82, S59-S59.

E. Gaidamauskas, K. Saejueng, A. A. Holder, S. Bharuah, B. A. Kashemirov, D. C. Crans, C. E. McKenna. “Metal complexation chemistry used for phosphate and nucleotide determination: an investigation of the Yb3+-pyrocatechol violet sensor.” J Biol Inorg Chem 2008, 13, 1291-1299.

A. J. Roelofs, F. P. Coxon, M. W. Lundy, F. H. Ebetino, J. F. Bala, B. A. Kashemirov, C. E. McKenna, M. J. Rogers. “Studying Cellular Uptake and Distribution of Bisphosphonate in vivo Using Fluorescently-labelled Analogues of Risedronate.” J. Bone Miner. Res. 2008, 23, S20-S20.

B. A. Kashemirov, J. L. Bala, X. Chen, F. H. Ebetino, Z. Xia, R. G. Russell, F. P. Coxon, A. J. Roelofs, M. J. Rogers, C. E. McKenna. “Fluorescently labeled risedronate and related analogues: “magic linker” synthesis.” Bioconjug Chem 2008, 19, 2308-2310.

V. A. Alfonsov, C. E. McKenna, E. V. Bayandina, B. A. Kashemirov, L. N. Yarmieva, L. N. Punegova, O. N. Kataeva. “Stereoselective synthesis of enantiopure cyclic α-aminophosphonic acids: Direct observation of inversion at phosphorus in phosphonate ester silyldealkylation by bromotrimethylsilane.” Heteroatom Chem 2008, 19, 575-582.

V. A. Alfonsov, C. E. McKenna, E. V. Bayandina, B. Kashemirov, L. N. Yarmieva, O. N. Kataeva, L. N. Punegova. “Diastereoselective Synthesis of Enantiopure Cyclic α-Aminophosphonic Acids.” Phosphorus Sulfur 2008, 183, 2647-2648.

C. Stewart, J. E. Dunford, Z. Xia, R. Baron, M. S. Marma, B. A. Kashemirov, C. E. McKenna, F. H. Ebetino, F. P. Coxon. “The effects of substitution of the geminal hydroxyl group of bisphosphonates and phosphonocarboxylates on their target enzyme inhibition.” Scot Med J 2008, 53, 53-53.

C. A. Stewart, R. Baron, K. M. Blazewska, B. A. Kashemirov, F. H. Ebetino, J. R. Navea, C. E. McKenna, M. J. Rogers, F. P. Coxon. “Differential inhibition of rab geranylgeranyl transferase by stereoisomers of phosphonocarboxylates.” Bone 2008, 42, S87-S87.

C. A. Stewart, R. Baron, M. S. Marma, K. M. Blazewska, B. A. Kashemirov, F. H. Ebetino, C. E. McKenna, M. J. Rogers, F. P. Coxon. “Structure activity relationships of phosphonocarboxylate inhibitors of rab geranylgeranyl transferase.” Bone 2008, 42, S86-S87.

 

Chemistry Dept., USC College of Letters, Arts & Sciences