Minoshima Masafumi, Sasaki Shunta, Fujimoto Jun, Shinohara Ken-Ichi, Bando Toshikazu, Sugiyama Hiroshi
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-oiwakecho, Sakyo, Kyoto 606-8502, Japan.
Nucleic Acids Symp Ser (Oxf). 2007(51):35-6. doi: 10.1093/nass/nrm018.
We have developed a series of conjugates between pyrrole (Py)-imidazole (Im) polyamides and 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H benz[e]indole (seco-CBI) with an indole linker. High resolution polyacrylamide gel electrophoresis revealed that these conjugates alkylated DNA at predetermined sequences. Then, we demonstrated that conjugates 1 and 2 have DNA alkylation activities at double stranded human telomere sequence and potent cytotoxicities in cancer cell lines. In addition, we showed that conjugate 3 alkylates DNA with ten-base-pair recognition sequence in the presence of partner polyamide 4, which suggested alkylation through 3-4 heterodimer formation.
我们已研发出一系列带有吲哚连接体的吡咯（Py）-咪唑（Im）聚酰胺与1-(氯甲基)-5-羟基-1,2-二氢-3H-苯并[e]吲哚（开环-CBI）之间的缀合物。高分辨率聚丙烯酰胺凝胶电泳显示，这些缀合物在预定序列处使DNA烷基化。随后，我们证明缀合物1和2对双链人类端粒序列具有DNA烷基化活性，并对癌细胞系具有强大的细胞毒性。此外，我们表明，在配对聚酰胺4存在的情况下，缀合物3能使具有十个碱基对识别序列的DNA烷基化，这表明通过3-4异二聚体形成实现烷基化。
