Targeting E2F1-DNA complexes with microgonotropen DNA binding agents.
Targeting E2F1-DNA complexes with microgonotropen DNA binding agents.
复制标题
DOI：
10.1073/pnas.94.7.2811
复制
发表时间：
1997-04
影响因子：
11.1
通讯作者：
S. Chiang;T. C. Bruice;Jane Clifford Azizkhan;L. Gawron;T. Beerman
中科院分区：
文献类型：
--
作者：
S. Chiang;T. C. Bruice;Jane Clifford Azizkhan;L. Gawron;T. Beerman
Microgonotropen (MGT) DNA结合药物由A+ t选择性DNA小槽结合三吡咯肽和多胺链连接到中心吡咯，将药物接触延伸到DNA主槽，被发现是E2因子1 （E2F1）与其DNA启动子元件（5'-TTTCGCGCCAAA）结合的非常有效的抑制剂。这些药物中最活跃的MGT-6a比distamycin有效三个数量级，并在0.00085微米时抑制E2F1和二氢叶酸还原酶启动子之间的复合物50%。mgt与A+T区结合的平衡常数d(GGCGA3T3GGC)/d（CCGCT3A3CCG）与它们抑制E2F1与DNA启动子元件之间复合物形成的关系。一种有效的MGT抑制剂的代表在抑制E2F1-DNA复合体形成方面明显比破坏预先存在的复合体更活跃。
Microgonotropen (MGT) DNA binding drugs, which consist of an A+T-selective DNA minor groove binding tripyrrole peptide and polyamine chains attached to a central pyrrole that extend drug contact into the DNA major groove, were found to be extraordinarily effective inhibitors of E2 factor 1 (E2F1) association with its DNA promoter element (5'-TTTCGCGCCAAA). The most active of these drugs, MGT-6a, was three orders of magnitude more effective than distamycin and inhibited complexes between E2F1 and the dihydrofolate reductase promoter by 50% at 0.00085 microM. A relationship was found between the measured equilibrium constants for binding of MGTs to the A+T region of d(GGCGA3T3GGC)/d(CCGCT3A3CCG) and their inhibition of complex formation between E2F1 and the DNA promoter element. A representative of the potent MGT inhibitors was significantly more active on inhibition of E2F1-DNA complex formation compared with disruption of a preexisting complex.