Dr. Derek Horton Ph.D., Sc.D, FRIC
Isbell Professor - E-mail - Curriculum vitae
Research of the Horton group is primarily concerned with the organic and biological chemistry of carbohydrates, both simple sugars and glycoconjugates, from the standpoints of structure, synthesis, and reactivity.
Synthetic Interests
Development of reactions of high specificity for use in polyfunctional biological
molecules - Specific deoxygenation reactions. Amination at predetermined positions.
Specific oxidation; enols in stereochemically controlled synthesis. Use of
acetylenes in synthesis. Preparative photochemical reactions. Specifically
labelled sugars as biochemical probes. Reactions of dithioacetals.
Structural modification of antibiotics - Application of reactions
for pinpointing structural alteration of carbohydrate antibiotics
(especially aminocyclitols)
to modify biological activity. Also, modifications of nucleoside structure.
Antitumor compounds - Synthesis of compounds showing in vivo antitumor activity,
especially anthracycline antibiotics. Synthesis of daunosamine analogs, glycosidic
coupling to natural and synthetic anthracyclinones, evaluation in tumor screens,
cardiotoxity determination, design of pro-drugs. Coupling of nucleic acid bases
and analogues to sugars of modified functionality (aminated, acyclic-chain,
deoxy, aminoacylated) and stereochemistry. Structural characterization of products
and
biological evaluation against tumor lines and viruses.
Polysaccharides of biological importance - Specific structural modification of natural polysaccharides to provide synthetic anticoagulants, antilipemic agents, and polymers of interest in technology, and modified substrates for studies on mode of enzyme action. Application of synthetic transformations to such molecules as amylose, cellulose, chitin, and cycloamyloses, to introduce specific repeating functionality such as amino groups, oxidized or reduced groups, deoxy functions, or stereochemical variants.
Structural Work
Conformational analysis of polysubstituted tetrahydropyran and tetrahydrofuran
rings - The effect of multiple substitution (OH and OR, systematically as
a function of configuration) on the static and dynamic conformational properties
of the molecule in solution. Influence of cations and anions; relation to
enzyme-catalyzed reactions of sugars. Techniques: 1H NMR and 13C NMR spectroscopy;
correlation with X-ray crystallography. The role of acyclic sugars in chemical
and biochemical reactions. Development of quantitative treatments of steric
and electronic interactions in multi-substituted systems. Correlations with
optical rotatory behavior.
Lipopolysaccharide antigens of gram-negative bacteria - Structural characterization
of antigenic lipopolysaccharides. Determination of structural units and linkage-sequence
in polysaccharide moiety, to establish nature of antigenic site at the molecular
level. Chemical synthesis of the antigenic-determinant groups and their conjugation
to carrier proteins (for synthesis of artificial antigens) and to solid-support
media to furnish affinity adsorbents used in isolating and studying homologous
antibodies. Development of monoclonal antibody-based therapeutic vaccines.
Major tools: GLC-mass spectrometry, high-field NMR.
Heparin, the natural blood anticoagulant - Details of the fine structure
of this complex sulfated glycosaminoglycan: its component units,
position of sulfation,
structure of the heparin-protein linkage in the biological source. Nature
of the thrombin- and antithrombin-binding sites. Chemical synthesis
of orally
active agents of high antithrombotic and low hemorrhagic activity. Techniques
of macromolecular chemistry and biochemistry; chromatography.
Physical methodology for structural analysis of complex carbohydrates - Structures
of oligosaccharides (including antibiotics), extension to polysaccharides,
by 1H NMR and 13C NMR and mass spectrometry.
Reactivity Studies
Ring-closure reactions of carbohydrates under kinetic and thermodynamic conditions
- Competition between hydroxl groups in ring closure of sugars; influence
of stereochemical and conformational factors. Rationale for design of synthesis.
Understanding of steric control in biological reactions of carbohydrates.
Enzymology of modified polysaccharides - Evaluation of the action of hydrolase enzymes (amylases, cellulases) and transglycosylases on synthetic products to provide: (a) information on the specificity and mode of action of the enzymes, (b) fragment molecules useful in synthesis, structural work, and biochemistry, and (c) technological leads such as protection of wood from rotting, promotion of biodegradability.
Relative reactivity of hydroxyl groups in sugars and polysaccharides
- Determination of the site and extent of competitive substitution
reactions, such as acylation
and alkylation, in simple sugar derivatives and in polysaccharides. Implications
in synthesis, in technology (textiles, foods), and in biochemistry.