Synthesis and DNA Cleavage Activity of Bis-3-chloropiperidines as Alkylating Agents
Synthesis and DNA Cleavage Activity of Bis-3-chloropiperidines as Alkylating Agents
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DOI：
10.1002/cmdc.201400034
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发表时间：
2014-09-01
期刊：
影响因子：
3.4
通讯作者：
Goettlich, Richard
中科院分区：
文献类型：
--
作者：
Zuravka, Ivonne;Roesmann, Rolf;Goettlich, Richard
氮芥是一类重要的双功能烷化剂，常用于化疗。它们作为亲电试剂通过形成高度反应性的氮丙啶鎓离子中间体与DNA反应。具有潜在抗肿瘤活性的抗生素593 A可以被认为是含有独特的3-氯哌啶环的天然存在的哌啶芥末。然而，这种抗生素的全合成被证明是相当具有挑战性的。为了设计这种天然产物的简化类似物，我们开发了一种有效的双向合成路线，通过灵活的，构象限制的，或刚性的二胺接头连接到双-3-氯哌啶。关键步骤包括碘化物催化的不饱和双-N-氯胺的双环化，以同时生成两个哌啶环。在这里，我们描述了一系列新的氮桥连的双-3-氯哌啶的合成和随后的评估，使研究的连接结构对DNA烷基化性能的影响。我们的研究表明，合成的化合物具有DNA烷基化能力，并诱导链断裂，具有强烈的偏好鸟嘌呤残基。
Nitrogen mustards are an important class of bifunctional alkylating agents routinely used in chemotherapy. They react with DNA as electrophiles through the formation of highly reactive aziridinium ion intermediates. The antibiotic 593A, with potential antitumor activity, can be considered a naturally occurring piperidine mustard containing a unique 3-chloropiperidine ring. However, the total synthesis of this antibiotic proved to be rather challenging. With the aim of designing simplified analogues of this natural product, we developed an efficient bidirectional synthetic route to bis-3-chloropiperidines joined by flexible, conformationally restricted, or rigid diamine linkers. The key step involves an iodide-catalyzed double cyclization of unsaturated bis-N-chloroamines to simultaneously generate both piperidine rings. Herein we describe the synthesis and subsequent evaluation of a series of novel nitrogen-bridged bis-3-chloropiperidines, enabling the study of the impact of the linker structure on DNA alkylation properties. Our studies reveal that the synthesized compounds possess DNA alkylating abilities and induce strand cleavage, with a strong preference for guanine residues.