Vekhoff Pierre, Halby Ludovic, Oussedik Kahina, Dallavalle Sabrina, Merlini Lucio, Mahieu Christine, Lansiaux Amélie, Bailly Christian, Boutorine Alexandre, Pisano Claudio, Giannini Giuseppe, Alloatti Domenico, Arimondo Paola B
CNRS UMR, Museum National d'Histoire Naturelle USM, INSERM, Paris, France.
Bioconjug Chem. 2009 Apr;20(4):666-72. doi: 10.1021/bc800494y.
Sequence-specific camptothecins are useful tools to inhibit specifically gene expression. The camptothecins are attached to the 3' end of triplex-forming oligonucleotides (TFO), sequence-specific DNA ligands that position the camptothecin moiety exclusively in proximity to their binding site. We studied here different gimatecan derivatives or analogues, a potent lipophilic camptothecin compound in clinical trials. We optimized the synthesis procedure in order to increase the yields and the purity and obtain the conjugates on a large scale. The greatly improved synthesis is now based on the conjugation of a bromoalkyl analogue of gimatecan to the 3' phosphorothioate of the TFO. We showed that the most efficient conjugate, both in vitro and in HeLa cells, bears the TFO on position 7 of the gimatecan analogue, and it is more efficient than the previous camptothecin conjugates. In addition, the gimatecan-like moiety at the 3' end of the TFO protects from nuclease degradation.
序列特异性喜树碱是特异性抑制基因表达的有用工具。喜树碱连接在三链形成寡核苷酸（TFO）的3'末端，TFO是序列特异性DNA配体，可将喜树碱部分专门定位在其结合位点附近。我们在此研究了不同的吉马替康衍生物或类似物，这是一种在临床试验中有效的亲脂性喜树碱化合物。我们优化了合成程序以提高产率和纯度，并大规模获得缀合物。现在大大改进的合成方法是基于吉马替康的溴代烷基类似物与TFO的3'硫代磷酸酯的缀合。我们表明，在体外和HeLa细胞中最有效的缀合物，其TFO位于吉马替康类似物的7位，并且比先前的喜树碱缀合物更有效。此外，TFO 3'末端的吉马替康样部分可防止核酸酶降解。
