5-(Acridin-9-ylamino)uracil — A hydrolytically labile nucleobase modification in peptide nucleic acid

Abstract

5-Aminouracil (5-AU) is a readily available yet underutilized starting material for the synthesis of labelled nucleobase analogues. We have prepared the derivative of 5-AU with the amine-reactive chromophore 9-chloroacridine for the purpose of investigating its potential as a base-discriminating fluorophore. 9-Chloroacridine readily undergoes substitution by reaction with 5-AU to yield a fluorescent nucleobase that after standard manipulations produced a monomer suitable for incorporation into peptide nucleic acid (PNA) by fluorenylmethyloxycarbonyl (Fmoc)-based oligomerization chemistry. Although the monomer was stable in organic solvents, once incorporated into an oligomer the 5-substitution was found to be thermally labile and hydrolyzed to a small degree in neutral aqueous solution during study of its hybridization to cDNA. We have determined that 5-(acridin-9-ylamino)uracil and related derivatives produce the highly fluorescent acridone and 5-AU by hydrolysis in water.

Antibacterial Peptide Nucleic Acids—Facts and Perspectives

“…The most common non-coding pyrimidine bases introduced in PNA include 2-thiouracil 18, used for the development of pseudo-complementary PNA [76,77], pseudoisocytosine 19 [78], thio-pseudoisocytosine 20 [49], and 2-aminopyrimidine 21 [79] for stable triplex formation with RNA duplexes. N 4 -benzoylcytosine 22 was introduced by the Nielsen group [80,81] as a candidate for a pseudo-complementary G-C base pair, and 5-(acridin-9-ylamino)uracil 23 was applied as fluorescent, hydrolytically labile nucleobase modification [82]. Manicardi et al studied the pyrene-labeled, fluorescent PNA monomer 24 [83] and used it to investigate stacking interactions and selective excimer emission in PNA 2 /DNA triplexes.…”

Peptide nucleic acids: Advanced tools for biomedical applications

“…Recently, Rozners and coworkers (Li et al, 2010;Rozners, 2012) reported that P and E nucleobases modified PNA monomers were able to isolate pyrimidine interruptions in polypurine tracts of double helical RNA. Another hydrolytically labile nucleobase 5-(acridin-9-ylamino) uracil was prepared by Matarazzoo et al (Matarazzo et al, 2013) which on hydrolysis produced highly fluorescent acridone and 5-aminouracil. Other modified nucleobases reported are thio-pseudo isocytosine (Devi et al, 2014) for targeting RNA duplex region; 2-amino pyridine (Annoni et al, 2016) as a tool for detecting RNA editing and mono-m-(guanidinoethoxy)phenyl] pyrrolocytosine (Wojciechowski and Hudson, 2009) with enhanced and selective affinity for RNA (Table 2).…”

“…E-base In polypurine tracts of double helical RNA, able to isolate pyrimidine interruptions (Li et al, 2010;Rozners, 2012) 12. 5(acridin-9-ylamino)uracil Hydrolytically labile modification (Matarazzo et al, 2013) 13. Thio-pseudo isocytosine Enhanced RNA duplexes recognition (Devi et al, 2014) 13.…”

Synthesis and Structural Studies of Three Uracil Derivatives, Methyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanate, Methyl 3-(5-Nitro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate and Ethyl 3-(5-Nitro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)propanoate

“…The vibrational studies on uracil and 5-substituted uracils have also been made by several researchers, which regarded be helpful in understanding their scientific vibrational results with the view of biological process and in the analysis of relatively complex systems [5][6][7][8][9][10][11][12]. Moreover, the biological activity of uracil and its derivatives has stimulated exceptional interest in biochemistry and pharmacology [13][14][15][16][17][18]. In particular, substitution at the C5 site of uracil yields derivatives with outstanding properties.…”