Gottikh M B, Ivanovskaia M G, Skripkin E A, Shabarova Z A
Bioorg Khim. 1990 Apr;16(4):514-23.
A new type of modified antisense oligodeoxyribonucleotides is suggested, containing an intercalating drug (e.g., daunomycin (Dnm-NH2)) at one end of the oligonuleotide, and a compound, improving the oligonucleotide transport into the cell, e.g., polymyxin B1 (PmH) at its other end. Schemes for joining these antibiotics to the terminal groups of oligonucleotides have been developed. From undecanucleotide pTGTAAAACGACp (I); the corresponding derivative (Pm)pTGTAAAACGACp (NH-Dnm) (II) was obtained with 20% yield. It was found that joining of daunomycin significantly lowers the rate of the oligonucleotide's exonuclease degradation, whereas joining of polymyxin blocks the degradation completely. Derivative (II) is much more stable to hydrolysis by cell enzymes that the unmodified oligonucleotide (I): upon incubation with E. coli cells (I) is quantitatively hydrolyzed with in 40 minutes while (II) is hydrolyzed by 30% with in 24 h. Derivative (II) is also better adsorbed by E. coli cells. This sort of derivative of antisense oligonucleotides may prove to be efficient inhibitors of the gene expression.
有人提出了一种新型的修饰反义寡脱氧核糖核苷酸，它在寡核苷酸的一端含有一种嵌入药物（例如柔红霉素（Dnm-NH2）），在另一端含有一种可改善寡核苷酸向细胞内转运的化合物，例如多粘菌素B1（PmH）。已经开发出将这些抗生素连接到寡核苷酸末端基团的方案。从十一核苷酸pTGTAAAACGACp（I）；以20%的产率获得了相应的衍生物（Pm）pTGTAAAACGACp（NH-Dnm）（II）。发现柔红霉素的连接显著降低了寡核苷酸的核酸外切酶降解速率，而多粘菌素的连接则完全阻断了降解。衍生物（II）对细胞酶水解的稳定性比未修饰的寡核苷酸（I）高得多：与大肠杆菌细胞一起孵育时，（I）在40分钟内被定量水解，而（II）在24小时内被水解30%。衍生物（II）也更容易被大肠杆菌细胞吸附。这种反义寡核苷酸衍生物可能被证明是有效的基因表达抑制剂。
