CARBORANYL OLIGONUCLEOTIDES .2. SYNTHESIS AND PHYSICOCHEMICAL PROPERTIES OF DODECATHYMIDYLATE CONTAINING 5-(O-CARBORAN-1-YL)-2'-DEOXYURIDINE
CARBORANYL OLIGONUCLEOTIDES .2. SYNTHESIS AND PHYSICOCHEMICAL PROPERTIES OF DODECATHYMIDYLATE CONTAINING 5-(O-CARBORAN-1-YL)-2'-DEOXYURIDINE
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DOI：
10.1021/ja00096a004
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发表时间：
1994-08-24
影响因子：
15
通讯作者：
SCHINAZI, RF
中科院分区：
文献类型：
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作者：
FULCRANDELKATTAN, G;LESNIKOWSKI, ZJ;SCHINAZI, RF
用自动化的β-氰乙基亚磷酰胺方法合成了含有一个或多个5-(o-Carboran-1-yl)-2‘-脱氧尿苷(CDU)而不是胸苷的碱基修饰的寡硫酰胺类化合物d(T)(12)。这些新的寡核苷酸与天然互补链d(A)(12)和聚(Ra)形成的双链的热稳定性受到链中Carboranyl核苷酸位置的影响。5‘端修饰的CDUd(T)(11)寡聚体的熔融温度(T-m=28℃)与天然的d(T)(12)((T)m=29℃)相近，而3’-末端修饰的d(T)(10)CDUd(T)(T)和中心修饰的d(T)(6)CDUd(T)(5)寡核苷酸的T-m值较低(Tm分别为20.5和15.3℃)。T-m研究得到了含有d(T)(6)CDUd(T)(5)的双链的分子模拟的支持，该分子模拟表明了硼笼与5‘-相邻碱基之间的空间相互作用。另一个好处是，寡聚体3‘端的CDU修饰显著增加了它们对半衰期(t(1/2))测定的5’-核酸外切酶活性的抵抗力。T(1/2)按d(T)(12)和lt；d(T)(10)cDUd(T)的顺序增加。
Base modified oligothymidylates d(T)(12) containing one or more 5-(o-carboran-1-yl)-2'-deoxyuridine (CDU) instead of thymidine were synthesized using an automated beta-cyanoethyl phosphoramidite approach. The thermostability of duplexes formed by these new oligonucleotides with natural complementary strand d(A)(12) and poly(rA) was affected by the location of the carboranyl nucleotide within the chain. CDUd(T)(11) oligomer modified at the 5'-terminus displayed a melting temperature (T-m = 28 degrees C) similar to natural d(T)(12) ((T)m = 29 degrees C), whereas 3'-modified d(T)(10)CDUd(T) and centrally modified d(T)(6)CDUd(T)(5) oligonucleotide had lower T-m values (Tm = 20.5 and 15.3 degrees C, respectively). The T-m studies were supported by molecular modeling of a duplex containing d(T)(6)CDUd(T)(5), which showed steric interactions between the boron cage and 5'-adjacent base. As an added benefit, CDU modification at the 3'-terminus of the oligomers markedly increased their resistance toward 5'-exonuclease activity, as determined by half-life (t(1/2)) measurements. The t(1/2) increased in the order d(T)(12) < d(T)(10)CDUd(T)