Quinone Methides Tethered to Naphthalene Diimides as Selective G-Quadruplex Alkylating Agents
Quinone Methides Tethered to Naphthalene Diimides as Selective G-Quadruplex Alkylating Agents
复制标题
DOI：
10.1021/ja904876q
复制
发表时间：
2009-09-16
影响因子：
15
通讯作者：
Freccero, Mauro
中科院分区：
文献类型：
--
作者：
Di Antonio, Marco;Doria, Filippo;Freccero, Mauro
我们开发了新的g -四联体（G-4）配体/烷基化杂化结构，将萘二亚胺部分系在曼尼希碱的季铵盐上，作为醌-甲基前体，可通过温和的热消化（40℃）激活。摘要高效合成了二取代萘二亚胺，并研究了其在硫醇和苯胺存在下作为可活化双烷基化剂的反应性。缓冲溶液中的胺。在乙基乙烯醚的存在下，参与烷基化过程的亲电中间体醌-甲基被困在杂Diels-Alder[4 + 2]环加成反应中，生成取代的2-乙氧基铬。通过凝胶电泳、圆二色性和酶分析研究了这些新衍生物的DNA识别和烷基化性质。与其他DNA构象相比，烷基化过程优先发生在G-4结构。通过剖析可逆识别和烷基化事件，我们发现可逆过程是DNA烷基化的先决条件，而烷基化反过来又加强了g -四重体结构重排。
We have developed novel G-quadruplex (G-4) ligand/alkylating hybrid structures, tethering the naphthalene diimide moiety to quaternary ammonium salts of Mannich bases, as quinone-methide precursors, activatable by mild thermal digestion (40 degrees C). The bis-substituted naphthalene diimides were efficiently synthesized, and their reactivity as activatable bis-alkylating agents was investigated in the presence of thiols and. amines in aqueous buffered solutions. The electrophilic intermediate, quinone-methide, involved in the alkylation process was trapped, in the presence of ethyl vinyl ether, in a hetero Diels-Alder [4 + 2] cycloaddition reaction, yielding a substituted 2-ethoxychroman. The DNA recognition and alkylation properties of these new derivatives were investigated by gel electrophoresis, circular dichroism, and enzymatic assays. The alkylation process occurred preferentially on the G-4 structure in comparison to other DNA conformations. By dissecting reversible recognition and alkylation events, we found that the reversible process is a prerequisite to DNA alkylation, which in turn reinforces the G-quadruplex structural rearrangement.