Solid-phase-based synthesis and biological evaluation of quinoxaline antibiotics and structural analogs

ORGN 96

Simon J. Dawson, simon.dawson@pharmacy.ac.uk1, John P. Malkinson, john.malkinson@pharmacy.ac.uk1, Mark Searcey2, and Simon Gibbons1. (1) Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, 29-39 Brunswick Square, London, WC1N 1AX, United Kingdom, (2) School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, NR4 7TJ, United Kingdom
Triostin A N-Demethylated (TANDEM, 1) is a synthetic analogue of triostin A (2) a naturally occurring octadepsipeptide originally isolated from Streptomyces aureus S-2-210. This class of compounds interacts with duplex DNA by a mechanism of bis-intercalation, thus conferring antibacterial and anti-tumour activity on these agents. This work details the synthesis of four novel chromophore analogues of TANDEM by a solid phase methodology. The flexibility of this approach has allowed access to compounds where the natural symmetry has been removed, by the installation of two different chromophores. Biological evaluation of these compounds by footprinting assay demonstrates how minor alterations of the chromophore, or a removal of symmetry, can lead to dramatic changes in binding strength and specificity.

 

Physical Organic Chemistry, Combinatorial and Process Chemistry, New Reactions and Methodology, Peptides, Proteins and Amino Acids
8:00 PM-10:00 PM, Sunday, April 6, 2008 Morial Convention Center -- Hall A, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, April 7, 2008 Morial Convention Center -- Hall A, Sci-Mix

Division of Organic Chemistry

The 235th ACS National Meeting, New Orleans, LA, April 6-10, 2008