Department of Medicinal & Biological Chemistry : Richard A. Hudson

Institutions/Degrees

New concepts in drug design based on molecular recognition of bioactive molecules at protein catalytic and regulatory sites; design of site-directed agents.

Research Interests

Our general interest is in the development of a molecular-level understanding of how proteins recognize and interact with other molecules. Such interactions regulate nearly all interesting biological functions. We hope to be able to translate this knowledge from the synthesis and study of useful molecular probes. Such studies would reveal interesting details of protein function, and also provide a useful starting point for drug design.

Currently, there are several major interrelated problems in which we are interested. First, we have been studying the underlying mechanisms of catalysis in pyrroloquinoline quinone (PQQ) isomeric analogues.

PQQ

These agents represent cofactors for a variety of enzymes that catalyze oxidation-reduction processes. While widespread in prokaryotes, PQQ-requiring enzymes appear also to be important in eukaryotes. The cofactor, indeed, appears to be a micro-nutrient in vertebrates, equivalent in importance to biotin and vitamin K. Our interest has been in the synthesis and examination of isosteric, isomeric analogues of PQQ because they provide us with a unique series of mechanistic probes for studying the underlying enzymatic reactions catalyzed by PQQ. Studies with the enzyme flavin reductase, which utilizes PQQ in preference to riboflavin, are a focus at present. As such enzymes mediate the continuous reduction of oxidized hemoglobin in erythrocytes and further protect against reoxygenation injury in both the heart and brain, structural analogues of PQQ may possess the potential for use as therapeutic agents in heart attack and stroke.

A second class of agents on which our lab is focusing consists of affinity-dependent redox-sensitive agents. These molecules are activated through oxidation reactions, which occur at protein binding sites. Possessing the structures of choline analogues, their interaction with choline- or acetyl-choline-containing macromolecules facilitates their use in studying the underlying processes of acetylcholine-mediated neurotransmission. Thus, they have been useful in dissecting selective cholinergic neuronal contributions in complex neuronal systems in culture and in vivo. These novel choline analogues may be useful in the search for agents that enhance cognition.
There are several classes of agents we have been developing. These agents are of interest in studying the underlying basis for neoplastic transformation or in providing novel therapeutic approaches in cancer. First, we are developing the synthesis of some novel conformationally rigid analogues of the epothilones. These agents are known to stabilize microtubule formation and ultimately induce cancer cells to enter apoptosis. A second class of agents are the stryllactones for which we have developed stereospecific synthesis. These agents also may function by reintroducing apoptosis into cancer cells, but may do this in a mechanistically significant way.

Representative Publications

1. Patel, P., S. Stahl, K. McLaughlin and R.A. Hudson. Redox reactive reagents inhibiting and inactivating choline acetyltransferase. Biochem. Biophys. Res. Comm. 175, 407-413, 1991.
   
   
2. Wohlfeil, E. and R.A. Hudson. Characterization of a mercurialated curarimimetic neurotoxin which reacts with the reduced nicotinic acetylcholine receptor. Biochemistry 30, 7231-7241, 1991.
   
   
3. Patel, P.J., W.S. Messer and R.A. Hudson. Inhibition and inactivation of presynaptic cholinergic markers using redox-inactivated choline analogues. J. Med. Chem. 36, 1893-1901, 1993.
   
   
4. Gu, Y., H. Lee, J.R. Kirchoff, L. Manzey and R.A. Hudson. Mechanism of action of the redox affinity reagent trimethylammoniomethyl catechol. Biochemistry 33, 8486-8494, 1994.
   
   
5. Gu, Y., H. Lee and R.A. Hudson. Bis-catechol substituted redox-reactive analogues of hexamethonium and decamethonium: stimulated affinity-dependent reactivity through iron peroxide catalysis. J. Med. Chem. 37, 4417-4420, 1994.
   
   
6. Zhang, Z., L.V.M. Tillekeratne, J.R. Kirchhoff and R.A. Hudson. High performance liquid chromatographic separation and pH-dependent electrochemical properties of pyrroloquinoline quinone and three closely related isomeric analogues. Biochem. Biophys. Res. Comm. 212, 41-47, 1995.
   
   
7. Hudson, R. A. Paul Dawson Award: Some reflections on research, instruction, the new biotechnology and on pharmacy into the next century. Am. J. Pharm. Ed. 59, 417-424, 1995.
   
   
8. Zhang, Z.P., L.M.V. Tillekeratne and R.A. Hudson. Isomeric analogues of coenzyme pyrroloquinoline quinone. Synthesis 3, 377-382, 1996.
   
   
9. Shen, R., L.M.V. Tillekeratne, J.R. Kirchhoff and R.A. Hudson. 6-Hydroxycatecholine, a choline-mimicking analogue of the selective neurotoxin 6-hydroxydopamine. Biochem. Biophys. Res. Comm. 228, 187-192, 1996.
   
   
10. McInerney, M.F., M.J. Seidel, J.M.D. Nguyen, J.C. Flynn, N. Sturm, H. Lee, Z. Zhang, L.M.V. Tillekeratne and R.A. Hudson. Effects of a 33 residue interleukin-1-beta peptide and the antioxidant PQQ on interleukin-1-beta-mediated inhibition of glucose-stimulated insulin release from cultured mouse pancreatic islets. Res. Commun. Mol. Pathol. and Pharmacol. 94, 115-128, 1996.
    
    
11. Hudson, R.A., Tillekeratne, L.M.V. Reactive quinones: from chemical defense mechanisms in plants to drug design, in Natural Products: Agrochemicals and Pharmaceuticals, ed. by Horace and Stephen Cutler, CRC Press, 1999.
    
    
12. Zhang, Z.P., Tillekeratne, L.M.V and Hudson, R.A. An unusual product in a Doebner-von Miller quinoline synthesis Tetrahedron Lett. 39: 5133-5134, 1998.
    
    
13. Hinman, C.L., R. Stevens-Truss, C. Swarz and R.A. Hudson. Sequence determinants of modified cobra venom neurotoxin which induce immune resistance to experimental allergic encephalomyelitis: molecular mechanisms for immunologic action. Imuno. Pharmacol. & Immunpotoxicol., in press, 1999.
    
    
14. Smith, A. R., Kirchhoff, J. R., Tillekeratne, L. V. M., and Hudson, R. A. (1999) Separation of negatively charged isomeric quinones in acidic solution by capillary electrophoresis with reductive electrochemical detection. Anal Commun 36, 371-374.
    
    
15. Biotechnology Part 1: The Tools of Genetic Engineering: New product Development Through Gene Manipulation. Hudson, R. A., and Black, C.D. 2nd Edition, Amgen Cont. Ed. Series-A 1999, 1-17.
    
    
16. Biotechnology Part 2: Monoclonal Antibodies: The Keys to Disease Detection and Treatment. Hudson, R. A., Black, C. D. 2nd Edition, Amgen Cont. Ed. Series-B 1999, 1-15.
    
    
17. Biotechnology Part 3: New Directions in Drug Design from Gene Sequences to Genomics, Part 3. Hudson, R. A., Black, C. D. 2nd Edition, Amgen Cont. Ed. Series-C 1999, 1-13.
    
    
18. Hudson, R. A., and Tillekeratne, L. M. V. (2000) Reactive Quinones: From Chemical Defense Mechanisms in Plants to Drug Design, Biologically Active Natural Products: Pharmaceuticals, CRC Press, Boca Raton, FL, pp.109-119.
    
    
19. Smith, A. R., Kirchhoff, J. R., Zhang, Z.P., Tillekerantne, and Hudson, R. A (2000) separation of enzyme cofactor pyrroloquinoline quinone and three isomeric analogues by capillary electrophoresis with ion-pairing media. J . Chromatogr. A, 876, 193-199.
    
    
20. Suleman, A., Tillekeratne, L. M. V., Hudson, R. A. (2001) Desilylation of TBDMS ethers of phenols susceptible to polymerization. Syn Comm. 31(21), 3308-3311.
    
    
21. Suleman, A., Tillekeratne, L. M. V., Hudson, R. A., (2001) Novel inhibitors of HIV-reverse transcriptase DNA strand transfer: Can we alter the infidelity of the enzyme? Biochem. Biophys. Res Comm 283, 896-899.
    
    
22. Tillekeratne, L. M. V., Sherette, A., Grossman, P. Hupe, L., Hupe D., and Hudson, R. A. (2001) Simplified Catechin-Gallate Inhibitors of HIV-Reverse Transcriptase, Bioorg & Med Chem Lett 11, 2763-2767.
    
    
23. Tillekeratne, L. M. V., Sherrette, A., Grossman, P., Hupe, D., Gabbara, S., Peliska, J. and Hudson, R. A. (2002) Differential inhibitors of polymerase and DNA-strand transfer activities of HIV-1 reverse transcriptase. Bioorg & Med Chem Lett 12, 525-528.
    
    
24. Wise, D.D., Barkhimer, T.V., Brault, P.-A., Kirchhoff, J.R. Messer, Jr, W.S., Hudson, R.A. (2002) An internal standard method for the measurement of choline and acetylcholine by capillary electrophoresis with electrochemical detection., J. Chromatogr., B 775, 49-56.
    
    
25. Inoue, T., Kirchhoff, J. R., Hudson, R. A. (2002) Enhanced measurement stability and selectivity for choline and acetylcholine by capillary electrophoresis with electrochemical detection at a covalently linked enzyme modified electrode, Anal. Chem. 74, 5321-5326.
    
    
26. Barkhimer, T. V., Kirchhoff, J. R., Hudson, R. A., Messer, W. S. Jr. (2002) Evaluation of the inhibition of choline uptake in synaptosomes by capillary electrophoresis with electrochemical detection. Electrophoresis 23, 3699-3704.
    
    
27. Acey, R., Unger, T.F., Healy, P. and Hudson, R.A. (2002) A Butrylcholinesterase in the early development of the brine shrimp (artemia salina) larvae: A target for phthalate ester embryotoxicity, Biochem Biophys Res Comm. 299, 659-662.
    
    
28. Chiral separation of highly negatively charged enantiomers by capillary electrophoresis. (2003) Liu, Q., Inoue, T., Kirchhoff, J. R., Huang, C. L. Tillekeratne, L. M. V. Olmstead, K. and Hudson, R. A. J. Chromatog A 1033, 349-356
    
    
29. Fouchard, D., Tillekeratne, L.M.V., Hudson, R. A. (2004) Synthesis of Imidazolo analogues of the Oxidation-reduction cofactor pyrroloquinoline quinone J. Org. Chem. 69, 2626-2629.
    
    
30. Khobzaui, M., Tillekeratne, L. M. V., Hudson, R. A. (2004) Potential Irreversible Inhibitors of Carbonic Anhydrase: Synthesis and Evaluation Biochem. Biophys. Res Comm 318, 1-3
    
    
31. Hudson, R. A., Tillekeratne, L. M. V., Tobey, N. A., Orlando, R. C. (2004) Methods for Protection of Stratified Squamous Epithelium Against injury by Noxious Substances and Novel Agents for use Therefor, Patent US 6,743,829 B2, June 1, 2004.