Optimization of Triple-Helix-Directed DNA Cleavage by Benzoquinoquinoxaline–Ethylenediaminetetraacetic Acid Conjugates

✍ Scribed by Rula Zain; David Polverari; Chi-Hung Nguyen; Yves Blouquit; Emile Bisagni; Thérèse Garestier; David S. Grierson; Jian-Sheng Sun

• Publisher: John Wiley and Sons
• Year: 2003
• Tongue: English
• Weight: 172 KB
• Volume: 4
• Category: Article
• ISSN: 1439-4227
• DOI: 10.1002/cbic.200300621

✦ Synopsis

Abstract

The formation of triple‐helical structures of DNA is based on sequence‐specific recognition of oligopyrimidine⋅oligopurine stretches of double‐helical DNA. Triple‐helical structures can be stabilized by DNA‐binding ligands. Benzoquinoquinoxaline (BQQ) derivatives are among the most potent intercalating‐type agents known to stabilize DNA triple‐helical structures. We previously reported the conversion of BQQ into a triplex‐directed DNA cleaving agent, namely BQQ–ethylenediaminetetraacetic acid (EDTA), by coupling of 6‐(3‐aminopropylamino)BQQ to a suitable ethylenediaminetetraacetic acid derivative, and we demonstrated the ability of this conjugate to cause double‐stranded cleavage of DNA at the triplex site. However, this prototype derivative BQQ–EDTA conjugate showed lower affinity towards triplex DNA than BQQ itself. In the light of this observation, and guided by molecular modeling studies, we synthesized a second generation of BQQ–EDTA conjugates based on 6‐[bis(2‐aminoethyl)amino]‐ and 6‐(3,3′‐diamino‐N‐methyldipropylamino)–BQQ derivatives. We confirmed by DNA melting experiments that the new conjugates displayed an increased specific affinity towards triple helices when compared to the previously synthesized BQQ–EDTA. In addition, the efficiency of these new agents in triplex‐specific binding and cleavage was demonstrated by triplex‐directed double‐stranded cleavage of plasmid DNA.