Design, synthesis, and biochemical evaluation of ribitylaminopyrimidine substrate analogs of lumazine synthase as potential enzyme inhibitors and mechanistic probes

MEDI 161

Arindam Talukdar, atalukda@purdue.edu1, Adelbert Bacher2, Markus Fisher2, Boris Illarionov2, and Mark Cushman3. (1) Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, IN 47907, (2) Lehrstühl für Organische Chemie und Biochemie, Technische Universität München, Garching, Germany, (3) Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, School of Pharmacy and Pharmacacuetical Sciences, Purdue University, West Lafayette, IN 47907
Lumazine synthase and riboflavin synthase catalyze the last two steps in the biosynthesis of riboflavin (Scheme 1), a vitamin that is involved in many critical biochemical reactions that are essential for maintenance of life. The inhibition of these enzymes represents a very specific strategy for antibiotic drug design, because the targets are not present in human or animal hosts. The detailed mechanisms of lumazine synthase and riboflavin synthase catalysis are not completely known. In order to elucidate these mechanisms, metabolically stable structural probes have been designed based on hypothetical reaction mechanisms and molecular modeling. Replacement of nitrogen of the ribitylamine side chain with oxygen (O-nucleoside), sulfur (S-nucleoside) or an alkene linkage would not be expected to produce gross changes in the orientation of ribityl chain, and the resulting compounds could possibly bind to lumazine synthase. They obviously could not complete the catalytic cycle. The interactions could be studied by enzyme kinetics, X-ray diffraction and NMR.

 

General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006