SEQUENCE SPECIFIC ALKYLATION OF DNA

含有咪唑和吡咯氨基酸的聚酰胺具有结合双链体DNA的预定序列的能力。 该研究方案试图利用这一现象，并创造出不仅能够识别双链DNA的任何预定序列，而且能够在预定位置引入DNA损伤的合成分子。为了实现这一点，提出了将抗肿瘤、抗生素类天然产物吡咯并（1，4）苯并二氮杂卓的衍生物与各种聚酰胺共价连接的合成杂合物。吡咯并（1，4）苯并二氮杂卓具有排他地结合双链体DNA的小沟和烷基化鸟嘌呤残基的能力。因此，预计将聚酰胺偶联到各种吡咯并（1，4）苯并二氮杂卓将产生能够识别双链体DNA的任何预定序列的合成缀合物，如由分子的聚酰胺部分所决定的，并在相邻的鸟嘌呤残基处引入DNA烷基化。

Polyamides containing imidazole and pyrrole amino acids have the ability to bind an predetermined sequence of duplex DNA. This research proposal seeks to exploit this phenomenon and create synthetic molecules capable of not only recognizing any predetermine sequence of duplex DNA but also capable of introducing DNA damage in a predetermine location. To accomplish this, synthetic hybrids are proposed which covalently link derivatives of the antitumor, antibiotic class of natural products the pyrrolo(l,4)benzodiazepines with various polyamides. The pyrrolo(l,4)benzodiazepines have the ability to bind exclusively to the minor groove of duplex DNA and alkylate guanine residues. Therefore, it is predicted that coupling polyamides to various pyrrolo(l,4)benzodiazepines will create a synthetic conjugate capable of recognizing any predetermined sequence of duplex DNA, as dictated by the polyamide portion of the molecule, and introduce DNA alklation at neighboring guanine residues.