Design of Small Molecules That Recognize RNA: Development of Aminoglycosides as Potential Antitumor Agents That Target Oncogenic RNA Sequences

✍ Scribed by Steven J. Sucheck; William A. Greenberg; Thomas J. Tolbert; Chi-Huey Wong

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: English
• Weight: 129 KB
• Volume: 112
• Category: Article
• ISSN: 0044-8249
• DOI: 10.1002/(sici)1521-3757(20000317)112:6<1122::aid-ange1122>3.0.co;2-v

✦ Synopsis

Aminoglycosides are a structurally diverse family of aminosugar and aminocyclitol derivatives that are currently the only well-characterized class of small molecules that selectively bind RNA, [1] including sites on prokaryotic 16S rRNA which is believed to be the locus of aminogylcoside antibiotic activity. [2] Of particular relevance to our own studies were the recent observations that aminoglycoside ± RNA interactions could be designed and could potentially be used to modify gene expression. [3] These results suggest that methods for synthesizing libraries of aminoglycosides or aminoglycoside mimetics may have wide application for inhibiting oncogenic RNA transcripts. We have chosen the breakpoints of the Bcr ± Abl and PAX3 ± FKHR translocations as model mRNA sequences for studying aminoglycoside ± mRNA interactions (Figure ). 5' GGAUUUAAGCAGAGUUCAA-AAGCCCUUCAGCGGCCAGUAG 3' O O P S O O P 5' GGCUGACCAUCAAUAAGGAAG-AAGCCCUUCAGCGGCCAGUA 3' A) S PAX3-FKHR Bcr-Abl B) biotin biotin Figure 1. Biotinylated 5'-monophosphorotioates mimicking the break points of the Bcr ± Abl (A) and PAX3 ± FKHR gene translocations (B).