Design and Synthesis of DNA-Cleaving Molecules

人们对设计以所需序列选择性地与DNA双链结合的试剂非常感兴趣。这类分子配备了化学或光化学标签，能够在结合部位修饰或切割DNA，应该有很大的应用前景，作为“人工合成限制酶”，尤其是作为基因选择性药物。我们的重点是使用天然的DNA结合剂，如抗肿瘤抗生素、DNA结合蛋白或序列定义的寡核苷酸与光活化的DNA裂解分子相结合。我们成功地设计了一种新的序列特异性的“光化学DNA切割器”，它能与-5‘-GG-3’序列特异结合。这种被称为光芬顿试剂的分子作为一种方便的羟基自由基源被广泛使用。我们还成功地设计了一种不同类型的DNA裂解分子，基于对烯-二炔类抗肿瘤抗生素作用机理的研究，如新卡环抑素或埃司帕米星。

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.