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Dive into the research topics where Robert J. Kempton is active.

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Featured researches published by Robert J. Kempton.


Proteins | 2007

Molecular determinants of sarco/endoplasmic reticulum calcium ATPase inhibition by hydroquinone‐based compounds

Michael Lape; Christopher Elam; Maria Versluis; Robert J. Kempton; Stefan Paula

The ion transport activity of the sarco/endoplasmic reticulum calcium ATPase (SERCA) is specifically and potently inhibited by the small molecule 2,5‐di‐tert‐butylhydroquinone (BHQ). In this study, we investigated the relative importance of the nature and position of BHQs four substituents for enzyme inhibition by employing a combination of experimental and computational techniques. The inhibitory potencies of 21 commercially available or synthesized BHQ derivatives were determined in ATPase activity assays, and 11 compounds were found to be active. Maximum inhibitory potency was observed in compounds with two para hydroxyl groups, whereas BHQ analogues with only one hydroxyl group were still active, albeit with a reduced potency. The results also demonstrated that two alkyl groups were an absolute requirement for activity, with the most potent compounds having 2,5‐substituents with four or five carbon atoms at each position. Using the program GOLD in conjunction with the ChemScore scoring function, the structures of the BHQ analogues were docked into the crystal structure of SERCA mimicking the enzymes E2 conformation. Analysis of the docking results indicated that inhibitor binding to SERCA was primarily mediated by a hydrogen bond between a hydroxyl group and Asp‐59 and by hydrophobic interactions involving the bulky inhibitor alkyl groups. Attempts to dock BHQ into crystal structures corresponding to the E1 conformation of the enzyme failed, because the conformational changes accompanying the E2/E1 transition severely restricted the size of the binding site, suggesting that BHQ stabilizes the enzyme in its E2 form. The potential role of Glu309 in enzyme inhibition is discussed in the context of the computational results. The docking scores correlated reasonably well with the measured inhibitory potencies and allowed the distinction between active and inactive compounds, which is a key requirement for future virtual screening of large compound databases for novel SERCA inhibitors. Proteins 2008.


Analytical Biochemistry | 1983

High-performance liquid chromatography of methotrexate analogs containing terminal lysine or ornithine and their dansyl derivatives

A. Ashok Kumar; Robert J. Kempton; Gregory M. Anstead; Elmer M. Price; James H. Freisheim

A procedure utilizing a reverse-phase semipreparative high-performance liquid chromatography column and a binary solvent system consisting of trifluoroacetic acid and 1-propanol has been developed for the semipreparative scale purification and analytical identification of four newly synthesized analogs of methotrexate. The methotrexate analogs containing a lysine or an ornithine residue in place of a terminal glutamate residue together with their respective dansyl derivatives were purified in milligram quantities by the procedures described.


Bioorganic & Medicinal Chemistry | 2009

Design, synthesis, and biological evaluation of hydroquinone derivatives as novel inhibitors of the sarco/endoplasmic reticulum calcium ATPase.

Stefan Paula; Josh Abell; Joel R. Deye; Christopher Elam; Michael Lape; Justin Purnell; Robert Ratliff; Kelly Sebastian; Jodie Zultowsky; Robert J. Kempton

Analogues of the compound 2,5-di-tert-butylhydroquinone (BHQ) are capable of inhibiting the enzyme sarco/endoplasmic reticulum ATPase (SERCA) in the low micromolar and submicromolar concentration ranges. Not only are SERCA inhibitors valuable research tools, but they also have potential medicinal value as agents against prostate cancer. This study describes the synthesis of 13 compounds representing several classes of BHQ analogues, such as hydroquinones with a single aromatic substituent, symmetrically and unsymmetrically disubstituted hydroquinones, and hydroquinones with omega-amino acid tethers attached to their hydroxyl groups. Structure-activity relationships were established by measuring the inhibitory potencies of all synthesized compounds in bioassays. The assays were complemented by computational ligand docking for an analysis of the relevant ligand/receptor interactions.


Biochemical Pharmacology | 1984

A fluorescent analogue of methotrexate as a probe for folate antagonist molecular receptors

Sandra S. Susten; Robert J. Kempton; Angelique M. Black; James H. Freisheim

A dansyl-L-lysine analogue of methotrexate, N alpha-(4-amino-4-deoxy-10- methylpteroyl )-N epsilon-(5-[N,N-dimethylamino]-1-naphthalenesulfonyl)-L-lysine, is a potent inhibitor of murine L1210 dihydrofolate reductase. The dansyl fluorescence emission was enhanced approximately 3-fold with a 10 nm blue shift upon binding to L1210 dihydrofolate reductase. The fluorescent analogue was only 10-fold less potent than methotrexate in inhibiting the growth of methotrexate-sensitive and -resistant L1210 cells and competes effectively for [3H]methotrexate transport with a Ki of 7.02 microM, a value virtually identical to the Kt for methotrexate in both cell lines. In addition, strong dansyl fluorescence was found to be associated with dihydrofolate reductase from methotrexate-resistant, dihydrofolate reductase-overproducing L1210 cells following incubation of viable cells with the fluorescent methotrexate analogue for 4 hr. The results demonstrate that the dansyl-L-lysine analogue of methotrexate was rapidly transported into L1210 cells where it formed a high-affinity, fluorescent complex with intracellular dihydrofolate reductase.


Journal of Medicinal Chemistry | 1982

Lysine and ornithine analogues of methotrexate as inhibitors of dihydrofolate reductase

Robert J. Kempton; Angelique M. Black; Gregory M. Anstead; A. Ashok Kumar; Dale T. Blankenship; James H. Freisheim


Journal of Medicinal Chemistry | 1981

Chemically reactive estrogens: synthesis and estrogen receptor interactions of hexestrol ether derivatives and 4-substituted deoxyhexestrol derivatives bearing alkylating functions

John A. Katzenellenbogen; Robert J. McGorrin; Tochiro Tatee; Robert J. Kempton; Kathryn E. Carlson; David H. Kinder


Biochemical Pharmacology | 1986

Photoaffinity analogues of methotrexate as probes for dihydrofolate reductase structure and function

Elmer M. Price; Laura Sams; Kathleen M. Harpring; Robert J. Kempton; James H. Freishmein


Journal of Medicinal Chemistry | 1983

Synthesis and characterization of a fluorescent analogue of methotrexate.

A. Ashok Kumar; James H. Freisheim; Robert J. Kempton; Gregory M. Anstead; Angelique M. Black; Larry Judge


Biochemistry | 1977

Estrogen photoaffinity labels. 1. Chemical and radiochemical synthesis of hexestrol diazoketone and azide derivatives; photochemical studies in solution.

John A. Katzenellenbogen; Harvey N. Myers; Howard J. Johnson; Robert J. Kempton; Kathryn E. Carlson


Journal of Organic Chemistry | 1988

Synthesis of a novel tetrahydrothieno[2,3-b]pyrrole

Edward C. Taylor; Stephen Robert Fletcher; Claire McCarthy; Vivian Cody; Robert J. Kempton

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James H. Freisheim

University of Toledo Medical Center

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Gregory M. Anstead

Northern Kentucky University

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Angelique M. Black

Northern Kentucky University

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A. Ashok Kumar

University of Cincinnati

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Christopher Elam

Northern Kentucky University

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Elmer M. Price

University of Cincinnati Academic Health Center

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Larry Judge

Northern Kentucky University

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Michael Lape

Northern Kentucky University

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Stefan Paula

Northern Kentucky University

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Brenda S. Kesler

Northern Kentucky University

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