C-H to N substitution dramatically alters the sequence-specific DNA alkylation, cytotoxicity, and expression of human cancer cell lines

被引:19
作者
Bando, T
Narita, A
Iwai, A
Kihara, K
Sugiyama, H
机构
[1] Tokyo Med & Dent Univ, Sch Biomed Sci, Tokyo 1010062, Japan
[2] Tokyo Med & Dent Univ, Grad Sch, Dept Urol & Reprod Med, Tokyo 1138519, Japan
[3] Kyoto Univ, Grad Sch Sci, Dept Chem, Kyoto 6068502, Japan
关键词
D O I
10.1021/ja0387103
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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. Copyright © 2004 American Chemical Society.
引用
收藏
页码:3406 / 3407
页数:2
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