Bando Toshikazu, Narita Akihiko, Iwai Aki, Kihara Kazunori, Sugiyama Hiroshi
School of Biomedical Science, Tokyo Medical and Dental University, 2-3-10 Surugadai, Kanda, Chiyoda, Tokyo 101-0062, Japan.
J Am Chem Soc. 2004 Mar 24;126(11):3406-7. doi: 10.1021/ja0387103.
We designed and synthesized sequence-specific alkylating conjugates 1 and 2, which selectively alkylate matched sequences at nanomolar concentrations. Conjugates 1 and 2 differ only in that the C-H is substituted by an N in the second ring, which precisely recognizes and effectively alkylates DNA according to the recognition rule of Py-Im polyamides. We investigated sequence-specific DNA alkylation, cytotoxicity in 39 human cancer cell lines, and the effect on expression levels in cancer cell lines by Py-Im conjugates 1 and 2. The COMPARE analysis of the mean graphs showed that conjugates 1 and 2 did not correlate well with each other (r = 0.65) despite having a common DNA alkylating mechanism (purine N3 alkylation). Array-based gene expression analysis demonstrated that there are several oppositely regulated genes. The results suggest the intriguing possibility that DNA alkylating agents recognizing longer base-pair sequences may provide a promising approach for developing new types of antigene agents.
我们设计并合成了序列特异性烷基化缀合物1和2，它们在纳摩尔浓度下能选择性地使匹配序列烷基化。缀合物1和2的区别仅在于第二个环中的C-H被N取代，根据嘧啶-咪唑聚酰胺的识别规则，其能精确识别并有效使DNA烷基化。我们研究了Py-Im缀合物1和2的序列特异性DNA烷基化、对39种人类癌细胞系的细胞毒性以及对癌细胞系表达水平的影响。对平均图谱的COMPARE分析表明，尽管缀合物1和2具有共同的DNA烷基化机制（嘌呤N3烷基化），但它们之间的相关性并不好（r = 0.65）。基于阵列的基因表达分析表明存在几个调控相反的基因。结果表明，识别更长碱基对序列的DNA烷基化剂可能为开发新型反基因药物提供一种有前景的方法，这一可能性引人关注。
