含手性纯R(P)甲基膦酸酯键的寡核苷酸的合成与热力学
Synthesis and thermodynamics of oligonucleotides containing chirally pure R(P) methylphosphonate linkages.
作者信息
Reynolds M A, Hogrefe R I, Jaeger J A, Schwartz D A, Riley T A, Marvin W B, Daily W J, Vaghefi M M, Beck T A, Knowles S K, Klem R E, Arnold L J
机构信息
Genta Inc., San Diego, CA 92121, USA.
出版信息
Nucleic Acids Res. 1996 Nov 15;24(22):4584-91. doi: 10.1093/nar/24.22.4584.
Abstract
Methylphosphonate (MP) oligodeoxynucleotides (MPOs) are metabolically stable analogs of conventional DNA containing a methyl group in place of one of the non-bonding phosphoryl oxygens. All 16 possible chiral R(P) MP dinucleotides were synthesized and derivatized for automated oligonucleotide synthesis. These dimer synthons can be used to prepare (i) all-MP linked oligonucleotides having defined R(P) chirality at every other position (R(P) chirally enriched MPOs) or (ii) alternating R(P) MP/phosphodiester backbone oligonucleotides, depending on the composition of the 3'-coupling group. Chirally pure dimer synthons were also prepared with 2'-O-methyl sugar modifications. Oligonucleotides prepared with these R(P) chiral methylphosphonate linkage synthons bind RNA with significantly higher affinity than racemic MPOs.
摘要
甲基膦酸酯（MP）寡脱氧核苷酸（MPO）是传统DNA的代谢稳定类似物，其中一个非键合磷酰氧被甲基取代。合成了所有16种可能的手性R(P) MP二核苷酸，并进行衍生化以用于自动化寡核苷酸合成。这些二聚体合成子可用于制备（i）在每隔一个位置具有确定R(P) 手性的全MP连接寡核苷酸（R(P) 手性富集MPO）或（ii）交替的R(P) MP/磷酸二酯主链寡核苷酸，具体取决于3'-偶联基团的组成。还制备了具有2'-O-甲基糖修饰的手性纯二聚体合成子。用这些R(P) 手性甲基膦酸酯连接合成子制备的寡核苷酸与RNA的结合亲和力明显高于外消旋MPO。
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本文引用的文献
1
Stereospecific Grignard-Activated Solid Phase Synthesis of DNA Methylphosphonate Dimers.
J Org Chem. 1996 Jan 26;61(2):510-513. doi: 10.1021/jo9517499.
2
Deprotection of methylphosphonate oligonucleotides using a novel one-pot procedure.使用一种新型一锅法对甲基膦酸酯寡核苷酸进行脱保护。
Nucleic Acids Res. 1993 May 11;21(9):2031-8. doi: 10.1093/nar/21.9.2031.
3
Antisense DNA oligonucleotides. I: The use of ionspray tandem mass spectrometry for the sequence verification of methylphosphonate oligodeoxyribonucleotides.
Rapid Commun Mass Spectrom. 1993 Mar;7(3):190-4. doi: 10.1002/rcm.1290070305.
4
Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides.反义寡核苷酸恢复地中海贫血前体mRNA中的正确剪接
Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8673-7. doi: 10.1073/pnas.90.18.8673.
5
An improved method for the synthesis and deprotection of methylphosphonate oligonucleotides.一种用于合成和脱保护甲基膦酸酯寡核苷酸的改进方法。
Methods Mol Biol. 1993;20:143-64. doi: 10.1385/0-89603-281-7:143.
6
Effect of excess water on the desilylation of oligoribonucleotides using tetrabutylammonium fluoride.过量水对使用四丁基氟化铵进行寡核糖核苷酸脱硅反应的影响。
Nucleic Acids Res. 1993 Oct 11;21(20):4739-41. doi: 10.1093/nar/21.20.4739.
7
(Aminomethyl)phosphonate derivatives of oligonucleotides.寡核苷酸的（氨甲基）膦酸酯衍生物。
Bioconjug Chem. 1994 Jan-Feb;5(1):47-57. doi: 10.1021/bc00025a007.
8
Synthesis of specific diastereomers of a DNA methylphosphonate heptamer, d(CpCpApApApCpA), and stability of base pairing with the normal DNA octamer d(TPGPTPTPTPGPGPC).一种DNA甲基膦酸七聚体d（CpCpApApApCpA）特定非对映异构体的合成以及与正常DNA八聚体d（TPGPTPTPTPGPGPC）碱基配对的稳定性
Nucleic Acids Res. 1994 Jun 25;22(12):2404-9. doi: 10.1093/nar/22.12.2404.
9
Modulation of in vitro splicing of the upstream intron by modifying an intra-exon sequence which is deleted from the dystrophin gene in dystrophin Kobe.通过修饰肌营养不良蛋白神户型中从肌营养不良蛋白基因中缺失的外显子内序列来调节上游内含子的体外剪接。
J Clin Invest. 1995 Feb;95(2):515-20. doi: 10.1172/JCI117693.
10
PNA hybridizes to complementary oligonucleotides obeying the Watson-Crick hydrogen-bonding rules.肽核酸（PNA）根据沃森-克里克氢键规则与互补寡核苷酸杂交。
Nature. 1993 Oct 7;365(6446):566-8. doi: 10.1038/365566a0.
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