Designed DNA probes from the neocarzinostatin family: impact of glycosyl linkage stereochemistry on bulge base binding.
Bulged sites in DNA and RNA have become targets for rational drug design due to their suspected involvement in a number of key biomolecular processes. A lead compound, derived from the enediyne natural product NCS-chrom has been used to inform chemical synthesis of a family of designed probes of DNA bulges, one of which shows 80 nM affinity for a two base bulged target. Key contributors to binding of these spirocyclic compounds have been studied in order to correlate affinity and specificity with structural features. Herein, we demonstrate that the glycosyl linkage stereochemistry of the pendant aminofucosyl group plays a pivotal role in binding, and coupled with insight obtained with various bulged targets, will allow rational design of second generation ligands.
Ma
Dong
D
Bioorganic and Medicinal Chemistry Laboratories, Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave, 101HT, Boston, MA 02115, USA.
Lin
Yiqing
Y
Xiao
Ziwei
Z
Kappen
Lizzy
L
Goldberg
Irving H
IH
Kallmerten
Amy E
AE
Jones
Graham B
GB
D001483:Base Sequence; D015342:DNA Probes; D005453:Fluorescence; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D009353:Zinostatin / Q000737:chemistry*
D015342:DNA Probes; D009353:Zinostatin