Design and Synthesis of DNA-Cleaving Molecules

人们对设计在所需序列选择性结合 DNA 双链体的试剂产生了极大的兴趣。这种配备有能够在结合位点修饰或切割DNA的化学或光化学标签的分子作为“合成的人工限制性酶”，尤其是作为基因选择性药物，应该具有广阔的前景。我们专注于使用天然 DNA 结合剂，例如抗肿瘤抗生素、DNA 结合蛋白或序列定义的寡核苷酸与光激活 DNA 切割分子的组合。我们成功地设计了一种新的序列特异性“光化学DNA切割器”，可以特异性结合-5'-GG-3'序列。这种被称为“光芬顿试剂”的分子被广泛用作羟基自由基的便捷来源。我们还基于对新制癌菌素或埃斯帕霉素等烯二炔型抗肿瘤抗生素的作用机制的研究而成功地设计了不同类型的DNA切割分子。

There has been great interest in designing reagents that bind to DNA duplex selectively at desired sequences. Such molecules equipped with a chemical or photochemical tag capable of modifying or cleaving DNA at the site of binding should have great prospects as "synthetic artificial restriction enzymes" and not least as gene-selective drugs. We have focused on the use of natural DNA-binders such as antitumor antibiotics, DNA-binding proteins or sequence-defined oligonucleotides in combination with photoactivated DNA-cleaving molecules. We have succeeded in designing a new sequence specific "photochemical DNA cleaver" that binds specifically to-5'-GG-3'sequence. This molecule named as "photo-Fenton-reagent" is widely used as a convenient source of hydroxyl radical. We also succeeded in designing a different type of DNA-cleaving molecules based on the conceit obtained from the work on the action mechanism of ene-diyne type antitumor antibiotics such as neocarzinostatin or esperamicin.