Design of phosphoramidite monomer for optimal incorporation of functional intercalator to main chain of oligonucleotide.
Chirally pure phosphoramidite monomers bearing 9-amino-6-chloro-2-methoxyacridine were synthesized from D- or L-threoninol and omega-aminocarboxylic acid, and incorporated into oligonucleotides. These acridine-DNA conjugates formed stable duplexes with complementary RNA because of intercalation of the acridine to DNA/RNA heteroduplexes. The stability of duplexes was not very dependent on either the chirality of the central carbon bearing the acridine or the length of the side chain. However, the ability for site-selective activation of the phosphodiester linkage in front of the acridine, which induced Lu(III)-promoted RNA scission, was strongly dependent on these two factors. The largest activation was achieved when the monomer unit was prepared from L-threoninol and 4-aminobutyric acid and the acridine was bound to the amino group. By attaching the more acidic 9-amino-2-methoxy-6-nitroacridine to this optimized scaffold, a quite effective acridine-DNA conjugate for site-selective RNA scission was obtained.
Shi
Yun
Y
Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
Machida
Kenzo
K
Kuzuya
Akinori
A
Komiyama
Makoto
M
D000609:Aminoacridines / Q000737:chemistry; D001665:Binding Sites; D015195:Drug Design; D006868:Hydrolysis / Q000187:drug effects; D007364:Intercalating Agents / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D009693:Nucleic Acid Hybridization; D009841:Oligonucleotides / Q000737:chemistry* / Q000494:pharmacology; D009943:Organophosphorus Compounds; D012313:RNA / Q000187:drug effects* / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D013329:Structure-Activity Relationship
D000609:Aminoacridines; D007364:Intercalating Agents; D009841:Oligonucleotides; D009943:Organophosphorus Compounds; C434331:phosphoramidite; C010847:9-amino-6-chloro-2-methoxyacridine; D012313:RNA