Thomas C. Bruice Group

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PAST ACCOMPLISHMENTS of the laboratory are described in over 530 research papers. For historical reasons and convenience these papers are listed both by the dates of publication and by the research topic (see papers). Through the years, studies have been carried out in thirty two discernable areas related to biochemical problems. Professor Bruice invented the term BIOORGANIC CHEMISTRY and defined the field. Significant advances have been made in this laboratory in the elucidation of the catalytic processes in acyl and phosphate transfer reactions, the mechanisms of cofactor reactions (pyridoxal, flavins, lipoic acid, dihydronicotinimides) and metalloporphyrin chemistry.

RECENT AREAS of investigation include the design, synthesis and study of putative antisense and antigene agents as well as the use of computational methods in the study of reaction mechanisms and in particular enzyme catalysis and drug design.

DNA and RNA Binding Agents


CATIONIC ANALOGS OF DNA. An area of research under study in this lab is the creation of oligonucleoside analogues. Oligonucleoside analogues capable of arresting cellular processes at the translational and transcriptional levels via recognition and binding to complementary RNA or DNA are known, as antisense and antigene agents, respectively. Solid-Phase synthesis of cationic analogues of DNA and RNA have been pioneered in this lab. Oligmers with the phosphate linkages replaced with guanidine (DNG/RNG) or S-methylthiourea (DNmt) have been created. The guanidium linkage is resistant to nucleases and the positive charges of the backbone may give rise to cell membrane permeability through electrostatic attraction of the oligonucleoside to the negatively charged phosphate groups of the cell surface. Both DNG and DNmt are able to discriminate between their complementary strands and noncomplementary base-pairs.

Representative Publications:

479. Linkletter, B. A.; Szabo, I. E.; Bruice, T. C.. Solid-phase synthesis of deoxynucleic guanidine (DNG) oligomers and melting point and circular dichroism analysis of binding fidelity of octameric thymidyl oligomers with DNA oligomers. J. Am. Chem. Soc. 1999, 121, 3888–3896. PDF

499. Barakar, D. A.; Kwok; Y.; Bruice, T. W. and Bruice, T. C.. Deoxynucleic Guanidine/Peptide Nucleic Acid Chimeras: Synthesis, Binding and Invasion Studies with DNA. J. Am. Chem Soc. 2000, 122, 5244. PDF

512. Challa, H. & Bruice, T. C.. Incorporation of positively charged deoxynucleic S-methylthiourea linkages into oligonucleotides: Synthesis and characterization of DNmt/DNA chimera. Bioorg. Med. Chem. Lett. 2001, 11, 2423-2427. PDF

517. Kojima, N.; Szabo, I. E. & Bruice, T. C.. Synthesis of ribonucleic guanidine: Replacement of the negative phosphodiester linkages of RNA with positive guanidinium linkages. Tetrahedron 2002, 58, 867-879. PDF

Microgonotropens (MGTs) are a novel class of minor groove binding ligands that consists of an A+T selective DNA minor groove binding tripyrrole peptide and polyamine chains attached to the central pyrrole that extend drug contact into the DNA major groove. Interaction of the MGTs polyamine moiety with the phosphate backbone leads to extremely tight binding and results in bending of DNA. MGTs are extraordinary effective inhibitors of the associtation of the transcription factors E2 factor 1 to its DNA promotor element. Our goal is to design a new class of MGTs to further investigate the structure-activity relationship between DNA binding strengths, transcription factor inhibition, and phophate backbone interaction. We have designed a minor groove binding vehicle that can readily functionalized and is based upon the widely used DNA fluorophore Hoeshst 33258, which is known to bind A+T rich sequences of dsDNA.

Representative Publications:

489. Satz, A. L.; Bruice, T. C.. Synthesis of fluorescent microgonotropen (FMGT–1) and its interactions with the dodecamer d(CCGGAATTCCGG). Bioorg. Med. Chem. Lett. 1999, 9, 3261–3266. PDF

502. Satz, A. L. & Bruice, T. C.. Synthesis of Fluorescent Microgonotropens (FMGTs) and Their Interactions with dsDNA. Bioorg. Med. Chem. 2000, 8, 1871-1880. PDF

507. Satz, A.. L. & Bruice, T. C.. Recognition of nine base pairs in the minor groove of dsDNA by a Tripyrrole Peptide-Hoechst Conjugate. J. Am. Chem. Soc. 2001, 123, 2469-2477. PDF

518. Satz, L. S. & Bruice, T. C.. Recognition in the Minor Groove of double-stranded DNA by microgonotropens. Acc. Chem. Res. 2002, 35, 86-95. PDF

Computational Studies


Enzyme Mechanisms. Transition state stabilization is commonly invoked to explain the amazing ability of enzymes to lower the activation barrier of reactions. Recent investigations in this lab and elsewhere, however, have brought into focus the contributions of thermal motions and ground state conformers associated with the Michaelis complex to the rate of enzymatic reactions. Computational studies in this lab utilizing quantum mechanical, molecular dynamics, and hybrid quantum mechanics/molecular mechanics calculations on Catechol O-Methyltransferase, Formate Dehydrogenase, Haloalkane Dehalogenase, and Alcohol Dehydrogenase have shown the importance of positioning the reactants into Near Attack Conformers (NACs). NACs are ground state conformers which are geometrically similar to the transition state. Calculations on model compounds show a significant decrease in the activation barrier when the reaction proceeds from a NAC to the transition state. A direct correlation between the mole fraction of NACs accessible to strain free dicarboxylic acid monoesters and the relative rate enhancement in the intramolecular reaction of these molecules to form cyclic anhydrides has been shown.

Representitive Publications:

478. T. C. Bruice & F. C. Lightstone. Ground State and Transition State Contributions to Intramolecular and Enzymatic Reactions. Acc. Chem Res. 1999, 32, 127. PDF

497. Bruice, T. C.; Benkovic, S. J.. Chemical basis for enzyme catalysis. Biochemistry 2000, 39, 6267–74. PDF

519. Hur, S.; Bruice, T, C.. The mechanism of catalysis of the chorismate to prephenate reaction by the Escherichia coli mutase enzyme. Proc. Natl. Acad. Sci. (USA) 2002, 99, 1176-1181. PDF

520. Bruice, T. C.. A view at the millennium: the efficiency of enzymatic catalysis. Acc. Chem. Res. 2002, 35, 139-146. PDF

523. Hur, S.; Bruice, T. C.. The mechanism of cis-trans isomerization of prolyl peptides by cyclophilin. J. Am. Chem. Soc. 2002, 124, 7303-7313. PDF

Drug Design. The immunosuppressive drugs FK506 and Rapamycin form complexes with the immunophilin FKBP12. The FKBP12-FK506 complex subsequently binds to the protein calcinerin. The binding of calcinerin to the FKBP12-drug complexes is responsible for the immunosuppressive activities of the drugs. Modifications to FK506 or Rapamycin that preclude binding of calcineurin lead to loss of immunosuppressive activity. Both drugs have been reported to promote neurite outgrowth. The immunosuppressive and neurite outgrowth activities of these drugs can be separated into the effector and binding domains, respectively. Virtual point mutations to the ketide units in the effector domains of these drugs have been made to create combinatorial libraries of compounds that may able to promate neurite outgrowth but are non-immunosuppressive.

Representative Publications:

500. Kahn, K.; Bruice, T. C.. alpha-Ketoamides and alpha-ketocarbonyls: Conformational analysis and development of all-atom OPLS force field. Bioorg. Med. Chem. 2000, 8, 1881-1891. PDF

492. Adalsteinsson, H.; Bruice, T. C.. Generation of putative neuroregenerative drugs. 1. Virtual point mutations to the polyketide rapamycin. Bioorg. Med. Chem. 2000, 8, 617–624. PDF

493. Adalsteinsson, H.; Bruice, T. C.. Generation of putative neuroregenerative drugs. 2. Screening virtual libraries of novel polyketides which possess the binding domain of rapamycin. Bioorg. Med. Chem. 2000, 8, 625–635. PDF

522. Kahn, K.; Bruice, T. C.. Parameterization of OPLS–AA force field for the conformational analysis of macrocyclic polyketides. J. Comput. Chem. 2002, 23, 977-996. PDF