Designed DNA probes from the neocarzinostatin family: Impact of glycosyl linkage stereochemistry on bulge base binding

Abstract

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.

Recognition of DNA/RNA bulges by antimicrobial and antitumor metallohelices

“…The binding of [Fe 2 L 1a 3 ]Cl 4 flexicates first quenched the fluorescence of 2AP incorporated in the loop of the T-A3-T (14) bulge and at an approximately 1 : 1 flexicate : bulge ratio it started to increase upon further addition of the flexicates (Fig. 5B, C).…”

“…In these experiments we used 14 bp long duplexes with the central sequence which was identical to the sequence of the 12 bp duplexes used for the melting experiments (Fig. The autoradiograms of the DNA cleavage-inhibition patterns for the T-A2-T (14) are shown in Fig. These duplexes were designed by the addition of the C·G pair on both ends of these 12 bp duplexes (see Fig.…”

“…[6][7][8] In view of the importance of bulges in biological systems, compounds capable of targeting bulged sequences could be used as valuable probes for studying their role in nucleic acid function or could even have significant therapeutic potential. [10][11][12][13][14][15] Recently, we have demonstrated that DNA duplexes containing bulges are specifically recognized by [Fe 2 (I) 3 ]Cl 4 (I = C 25 H 20 N 4 ) metallosupramolecular helicates (Fig. The most promising bulge binding agents discovered to date are: those based on NCS-chrom, a wedge-shaped enediyne antitumor antibiotic neocarzinostatin chromophore, 2-acylamino-1,8-naphthyridine, rhodium intercalators or the zinc(II) complex of 1-(4-quinoylyl)methyl-1,4,7,10-tetraazacyclododecane, and dinuclear ruthenium complexes.…”

“…The most promising bulge binding agents discovered to date are: those based on NCS-chrom, a wedge-shaped enediyne antitumor antibiotic neocarzinostatin chromophore, 2-acylamino-1,8-naphthyridine, rhodium intercalators or the zinc(II) complex of 1-(4-quinoylyl)methyl-1,4,7,10-tetraazacyclododecane, and dinuclear ruthenium complexes. [10][11][12][13][14][15] Recently, we have demonstrated that DNA duplexes containing bulges are specifically recognized by [Fe 2 (I) 3 ]Cl 4 (I = C 25 H 20 N 4 ) metallosupramolecular helicates (Fig. S1 †).…”

Recognition of DNA bulges by dinuclear iron(II) metallosupramolecular helicates

“…Many attempts have been made to prepare such compounds. Examples of promising bulge-binding agents discovered to date are: those based on NCSchrom, a wedge-shaped enediyne antitumor antibiotic neocarzinostatin chromophore, 2-acylamino-1,8-naphthyridine, rhodium intercalators, the zinc(II) complex of 1-(4-quinoylyl)methyl-1,4,7,10-tetraazacyclododecane, and dinuclear ruthenium complexes [8][9][10][11][12][13].…”