OLIGODEOXYNUCLEOTIDES CONTAINING 2'-O-MODIFIED ADENOSINE - SYNTHESIS AND EFFECTS ON STABILITY OF DNA-RNA DUPLEXES

被引:205
作者
LESNIK, EA
GUINOSSO, CJ
KAWASAKI, AM
SASMOR, H
ZOUNES, M
CUMMINS, LL
ECKER, DJ
COOK, PD
FREIER, SM
机构
[1] ISIS PHARMACEUT, DEPT MED CHEM, 2292 FARADAY AVE, CARLSBAD, CA 92008 USA
[2] ISIS PHARMACEUT, DEPT MOLEC CELLULAR & STRUCT BIOL, CARLSBAD, CA 92008 USA
关键词
D O I
10.1021/bi00081a031
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hybridization thermodynamics were compared for oligonucleotide sequences containing 2'-fluoro dA, 2'-O-methyl A, 2'-O-ethyl A, 2'-O-propyl A, 2'-O-butyl A, 2'-O-pentyl A, 2'-O-nonyl A, 2'-O-allyl A, and 2'-O-benzyl A in place of deoxyadenosine. Although the effect of 2'-modified adenosine on duplex stability is sequence dependent, a clear trend is apparent. For six sequences containing a few 2'-modified adenosines in a background of unmodified deoxynucleotides, the average DELTAT(M) per substitution ranged from +1.3-degrees-C for 2'-fluoro dA to -2.0-degrees-C for 2'-O-nonyl A. For the 2'-O-alkyl series, the average DELTAT(M) per substitution correlates well with size of the substituent; the order of stability is 2'-O-methyl A > 2'-O-ethyl A > 2'-O-propyl A > 2'-O-butyl A > 2'-O-pentyl A > 2'-O-nonyl A. This correlation also extends to 2'-fluoro dA, 2'-O-allyl A, and 2'-O-benzyl A if chain length is measured by number of carbon atoms. When examined in the background of 2'-O-methyl ribonucleotides, all 2'-modified adenosines with a substituent no larger than 2'-O-pentyl stabilized the duplex nearly 2-degrees-C per substitution compared to unmodified dA. These thermodynamic results and CD spectra of modified and unmodified hybrids support a model of DNA:RNA hybrids in which the geometry is between that of B-form and A-form.
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页码:7832 / 7838
页数:7
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