N2- and C8-substituted oligodeoxynucleotides with enhanced thrombin inhibitory activity in vitro and in vivo
N2- and C8-substituted oligodeoxynucleotides with enhanced thrombin inhibitory activity in vitro and in vivo
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DOI：
10.1021/jm970434d
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发表时间：
1998-06-18
影响因子：
7.3
通讯作者：
Bischofberger, N
中科院分区：
文献类型：
--
作者：
He, GX;Krawczyk, SH;Bischofberger, N
合成了在N-2和C-8位带有不同疏水取代基的2 ′-脱氧鸟苷（G）类似物，并通过固相合成法将其引入15聚体寡脱氧核苷酸GGTTGGTGTGGTTGG中，形成由两个G-四联体组成的椅状结构，是一种有效的凝血酶抑制剂。G-四聚体形成G残基的N-2和C-8处的取代对凝血酶抑制活性的影响相对较小，表明这些取代对寡脱氧核苷酸形成的椅状结构造成相对较小的扰动。在G（6）和G（11）的N-2上引入苄基和在G（6）的N-2上引入萘甲基可提高凝血酶抑制活性，而在这些位置上的其它取代基几乎没有影响或降低活性。特别地，在G（6）的N-2位携带1-萘基甲基的寡脱氧核苷酸在体外和体内均显示出约60%的活性增加。其他G残基的N-2位上的取代几乎没有影响或降低活性。在G（1）、G（5）、G（10）和G（14）的C-8位引入相对较小的基团，例如甲基和丙炔基，可以增加活性，这可能是由于椅子状结构的稳定性，而引入较大的取代基，苯乙炔基，降低了活性，可能是由于空间位阻。
2'-Deoxyguanosine (G) analogues carrying various hydrophobic substituents in the N-2 and C-8 positions were synthesized and introduced through solid-phase synthesis into 15-mer oligodeoxynucleotide, GGTTGGTGTGGTTGG, which forms a chairlike structure consisting of two G-tetrads and is a potent thrombin inhibitor. The effects of the substitutions at N-2 and C-8 of the G-tetrad-forming G residues on the thrombin inhibitory activity are relatively small, suggesting that these substitutions cause relatively small, perturbations on the chairlike structure formed by the oligodeoxynucleotide. Introduction of a benzyl group into N-2 of G(6) and G(11) and naphthylmethyl groups into N-2 of G(6) increased the thrombin inhibitory activity, whereas other substituents in these positions had almost no effect or decreased the activity. Particularly, the oligodeoxynucleotide carrying a 1-naphthylmethyl group in the N-2 position of G(6) showed an increase in activity by about 60% both in vitro and in vivo. Substitutions on the N-2 position of other G residues had little effect or decreased the activity. Introduction of a relatively small group, such as methyl and propynyl, into the C-8 positions of G(1), G(5), G(10), and G(14) increased the activity, presumably due to the stabilization of a chairlike structure, whereas introduction of a large substituent group, phenylethynyl, decreased the activity, probably due to the steric hindrance.