Unexpected Reactivity of the 9-Aminoacridine Chromophore in Guanidylation Reactions

The 9-aminoacridine chromophore is an important building
block of DNA-targeted chemotherapeutic agents. The success
of 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea as a
carrier group in cytotoxic platinum−intercalator conjugates
prompted us to explore the synthesis of an analogous
guanidine-functionalized acridine. In a successful effort to
generate such a derivative, various methods of guanidylation
were employed, which demonstrate that the acridine C9−N9 linkage is highly susceptible to electrophilic and nucleophilic attack. The newly established reactivities provide
efficient pathways to novel cyclic and spirocyclic acridine
derivatives.

9-氨基吖啶发色团（9-aminoacridine chromophore）是靶向DNA的化疗药物的关键构建模块。1-[2-(吖啶-9-基氨基)乙基]-1,3-二甲基硫脲作为细胞毒性铂-嵌入剂偶联物（cytotoxic platinum−intercalator conjugates）中的载体基团所取得的成功，促使我们探索类似胍基修饰吖啶的合成工作。为成功获得此类衍生物，我们采用了多种胍基化（guanidylation）方法，实验结果证实，吖啶的C9−N9键极易受到亲电与亲核进攻。本次新发现的反应活性为新型环状和螺环吖啶衍生物的合成提供了高效路径。