Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto 606-8502, Japan.
Bioorg Med Chem. 2010 Jan 1;18(1):168-74. doi: 10.1016/j.bmc.2009.11.005. Epub 2009 Nov 11.
We designed and synthesized conjugates between pyrrole-imidazole polyamides and seco-CBI that alkylate within the coding regions of the histone H4 genes. DNA alkylating activity on the histone H4 fragment and cellular effects against K562 chronic myelogenous leukemia cells were investigated. One of the conjugates, 5-CBI, showed strong DNA alkylation activity and good sequence specificity on a histone H4 gene fragment. K562 cells treated with 5-CBI down-regulated the histone H4 gene and induced apoptosis efficiently. Global gene expression data revealed that a number of histone H4 genes were down-regulated by 5-CBI treatment. These results suggest that sequence-specific DNA alkylating agents may have the potential of targeting specific genes for cancer chemotherapy.
我们设计并合成了吡咯并咪唑聚酰胺与 sec o-CBI 的缀合物，这些缀合物能够在组蛋白 H4 基因的编码区内进行烷基化。我们研究了这些缀合物对组蛋白 H4 片段的 DNA 烷基化活性和对 K562 慢性髓性白血病细胞的细胞效应。其中一种缀合物 5-CBI 在组蛋白 H4 基因片段上表现出很强的 DNA 烷基化活性和良好的序列特异性。用 5-CBI 处理的 K562 细胞能够有效地下调组蛋白 H4 基因并诱导细胞凋亡。全基因表达数据显示，5-CBI 处理后许多组蛋白 H4 基因的表达下调。这些结果表明，序列特异性 DNA 烷化剂可能具有针对特定基因进行癌症化疗的潜力。
