Conjugation of a hairpin pyrrole-imidazole polyamide to a quinone methide for control of DNA cross-linking
Conjugation of a hairpin pyrrole-imidazole polyamide to a quinone methide for control of DNA cross-linking
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DOI：
10.1021/bc049941h
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发表时间：
2004-07-01
影响因子：
4.7
通讯作者：
Rokita, SE
中科院分区：
文献类型：
--
作者：
Kumar, D;Veldhuyzen, WF;Rokita, SE
制备了一系列用于DNA交联的醌甲基化物前体，并将其与吡咯-咪唑聚酰胺缀合以选择性地与小沟缔合。虽然反应只观察到含有预测的识别序列的DNA，链烷基化的产率低。链间交联比烷基化更有效，但仍然相当温和，与含有N-芥末苯丁酸氮芥的可比缀合物产生的交联相当。改变连接聚酰胺和醌甲基化物衍生物的接头的长度不会极大地影响DNA交联的产率。相反，分子内捕获的醌甲基化物中间体的亲核试剂连接的聚酰胺似乎是主要的决定因素，限制其与DNA的反应。通过色谱和质谱的组合检测，醌甲基化物缀合物的自加合物容易且不可逆地形成。这一结果不同于对于寡核苷酸缀合物观察到的相当的自加合物，其形成更慢并且保持可逆。在类似条件下，未观察到聚酰胺通过其连接的苯丁酸氮芥的等效分子内烷基化。然而，DNA的存在确实促进了这种芥末缀合物的水解。
A series of quinone methide precursors designed for DNA cross-linking were prepared and conjugated to a pyrrole-imidazole polyamide for selective association to the minor groove. Although reaction was only observed for DNA containing the predicted recognition sequence, yields of strand alkylation were low. Interstrand cross-linking was more efficient than alkylation but still quite modest and equivalent to that generated by a comparable conjugate containing the N-mustard chlorambucil. Varying the length of the linker connecting the polyamide and quinone methide derivative did not greatly affect the yield of DNA cross-linking. Instead, intramolecular trapping of the quinone methide intermediate by nucleophiles of the attached polyamide appears to be the major determinant that limits its reaction with DNA. Self-adducts of the quinone methide conjugate form readily and irreversibly as detected by a combination of chromatography and mass spectroscopy. This result is unlike comparable self-adducts observed for oligonucleotide conjugates that form more slowly and remain reversible. Equivalent intramolecular alkylation of a polyamide by its attached chlorambucil mustard was not observed under similar condition. The presence of DNA, however, did facilitate hydrolysis of this mustard conjugate.