SEQUENCE SPECIFIC ALKYLATION OF DNA

含有咪唑和吡咯氨基酸的聚酰胺具有结合预定序列的双链DNA的能力。这项研究计划试图利用这一现象，创造出不仅能够识别任何预定的双链DNA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，人们提出了合成杂化化合物，将抗肿瘤、抗生素类天然产物吡咯(L，4)苯并二氮杂氮类化合物与各种聚酰胺共价连接。吡咯(L，4)苯并二氮杂氮类化合物能够与双链DNA的小沟槽和烷化鸟嘌呤残基结合。因此，可以预测，将聚酰胺与不同的吡咯(L，4)苯并二氮杂氮类化合物偶联，将产生一种合成的偶联物，能够识别分子中聚酰胺部分所决定的任何预定的双链DNA序列，并在相邻的鸟嘌呤残基上引入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.