Model Studies Directed toward a General Triplex DNA Recognition Scheme: A Novel DNA Base That Binds a CG Base-Pair in an Organic Solvent
Model Studies Directed toward a General Triplex DNA Recognition Scheme: A Novel DNA Base That Binds a CG Base-Pair in an Organic Solvent
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针对通用三重 DNA 识别方案的模型研究：一种在有机溶剂中结合 CG 碱基对的新型 DNA 碱基
DOI：
10.1021/ja00148a030
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发表时间：
1995
影响因子：
15
通讯作者：
P. Schmitt
中科院分区：
文献类型：
--
作者：
S. Zimmerman;P. Schmitt
Oligonucleotides are capable of binding to regions of double helical DNA throughthe formation of localized triple helical (triplex) structures. 1 Recently, this recognition process has attracted considerable interest because of its potential use in regulating gene expression, lcselectively cleaving DNA, 2 and affecting a range of other biological processes. 3 However, for these applications to be realized, triplex formation must occur selectively at any chosen sequence, and yet to date, the DNA target sites are mostly limited to homopurine tracts. This limitation arises from the mechanism of recognition which involves specific Hoogsteen-type hydrogen bonds between the bases of the third strand and purine bases in the major groove of the DNA duplex. 4 In the best-studied case, the third strand contains pyrimidines which bind the duplex by forming the base triplets shown in Figure la, b. Within this pyr—pur—pyr motif, G will selectively recognize the TA base-pair with intermediate affinity, but none of the four naturally occurring bases shows selectivity for the CG base-pair. 5 Thus, there is a need for nonnatural bases that selectively bind the CG base-pair with high affinity in the pyr—pur—pyr motif. The difficulty in designing a base to selectively and tightly bind the CG base-pair is apparent from Figure lc, where a single hydrogen bond donor group is presented by the cytosine base. One logical wayto achieve affinity and selectivity is to use an extended base that can simultaneously contact the cytosine 4-NH group and the Hoogsteen hydrogen bonding site on the guanine base (Figure lc). 6 The novel DNA nucleoside 3-(2-deoxy-/3-D-ribofuranosyl)-2-methyl-8-(iV-n-butylureido) naphth [l, 2-if| imi-dazole (1) was designed to contain a complementary acceptor-donor—donor hydrogen bonding array to theCG base-pair and to form the base-triplet shown in Figure Id. An important design criterion was that 1 contain a glycosidic bond compatible with the geometrical constraints imposedby the phosphodiester backbone within the pyr—pur—pyr motif. Herein we describe the synthesis of 1 and show that its alkyl analog 5 binds a CG base-pair in chloroform through the formation of simultaneous hydrogenbonds to both bases. To our knowledge, this is the first study to examine an isolated, nonnatural base-triplet in an organic solvent. 7 This type of model study allows the quality of the hydrogen bonding (1)(a) Moser,. E.; Dervan, P. B. Science 1987, 238, 645-650.(b) LeDoan, T.; Perrouault, L.; Praseuth, D.; Habhoub, N.; Decout, J.-L.; Thoung, NT; Lhomme, J.; Héléne, C. Nucleic Acids Res. 1987, 15, 7749-7760.(c) Cooney, M.; Czemuszewicz, G.; Postel, E. H.; Flint, S. J.; Hogan,. E. Science 1988, 241, 456-459.
