Synthesis and DNA cleavage reaction characteristics of enediyne prodrugs activated via an allylic rearrangement by base or UV irradiation.
Synthesis and DNA cleavage reaction characteristics of enediyne prodrugs activated via an allylic rearrangement by base or UV irradiation.
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DOI：
10.1016/j.bmc.2005.12.040
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发表时间：
2006-05
影响因子：
3.5
通讯作者：
Y. Tachi;W. Dai;K. Tanabe;S. Nishimoto
中科院分区：
文献类型：
--
作者：
Y. Tachi;W. Dai;K. Tanabe;S. Nishimoto
以Sonogashira偶联和分子内Nozaki-Hiyama-Kishi反应为关键步骤，合成了一系列具有（E）-3-羟基-4-（2′-羟基-1 ′-苯亚乙基）环癸-1，5-二炔骨架的烯二炔前药1-5。在与在环外双键上具有游离羟甲基的烯二炔前药4和5孵育后，环状超螺旋DNA（形式I）在pH 8.5的缓冲溶液中经历单链切割成环状松弛DNA（形式II），而甲硅烷基化的类似物1-3显示出非常弱的DNA切割活性。或者，甲硅烷基化的类似物1-3可以通过UV照射经由光化学烯烃异构化，随后烯丙基重排而活化，以形成推定的环氧烯二炔，导致与前药4和5所观察到的水平类似的有效DNA切割。
A number of enediyne prodrugs 1–5 possessing an (E)-3-hydroxy-4-(2′-hydroxy-1′-phenylethylidene)cyclodeca-1,5-diyne scaffold have been synthesized via the Sonogashira coupling and an intramolecular Nozaki–Hiyama–Kishi reaction as the key steps. Upon incubation with enediyne prodrugs 4 and 5 possessing a free hydroxymethyl group on the exocyclic double bond, circular supercoiled DNA (Form I) underwent single strand cleavage into circular relaxed DNA (Form II) in buffer solution at pH 8.5, while the silylated analogs 1–3 showed very weak DNA cleavage activity. Alternatively, the silylated analogs 1–3 could be activated by UV irradiation via a photochemical alkene isomerization followed by an allylic rearrangement to form the putative epoxy enediyne, resulting in efficient DNA cleavage similar to the level observed with the prodrugs 4 and 5.