Stereoelectronic effect on one-electron reductive release of 5-fluorouracil from 5-fluoro-1-(2′-oxocycloalkyl)uracils as a new class of radiation-activated antitumor prodrugs
Stereoelectronic effect on one-electron reductive release of 5-fluorouracil from 5-fluoro-1-(2′-oxocycloalkyl)uracils as a new class of radiation-activated antitumor prodrugs
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DOI：
10.1021/jo000245u
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发表时间：
2000-07-28
影响因子：
3.6
通讯作者：
Nishimoto, S
中科院分区：
文献类型：
--
作者：
Mori, M;Hatta, H;Nishimoto, S
合成了一系列5-氟-1-（2 ′-氧代环烷基）尿嘧啶（3-11），它们是用于缺氧肿瘤细胞放射治疗的潜在的新型辐射活化前药，以评价分子结构与抗肿瘤5-氟尿嘧啶（1）在缺氧水溶液中的单电子还原释放反应性之间的关系。所有带有2 ′-氧代基团的化合物3-11都被水合电子（e（aq）（-））还原一个电子，从而经历C（1 ′）-N（1）键解离，在缺氧水溶液辐解时以47-96%的产率释放5-氟尿嘧啶1，而对照化合物（12，13）没有2 ′-ore取代基，对这种还原性C（1 ′）-N（1）键解离没有反应性。2-氧代化合物在辐解单电子还原中的分解更增强，因为在N，N-二甲基甲酰胺中通过循环伏安法测量的单电子还原电位变得更正。5-氟尿嘧啶的释放效率强烈依赖于2-ore化合物的结构灵活性。代表性化合物的X射线晶体学研究表明，C（1 '）-N（I）键在基态具有正常的几何构型和键长。用AM 1方法计算的分子轨道表明，LUMO主要位于5-氟尿嘧啶C（5）-（C6）双键的π * 轨道上，LUMO + 1在2 ′-氧代取代基的π * 轨道和相邻的C（1 ′）-N（1）键的σ * 轨道之间离域. 5-氟尿嘧啶1在缺氧水溶液中的单电子还原释放被认为是由自由基阴离子中间体的LUMO + 1发生的，该自由基阴离子中间体具有反键C（2 '）= O pi* 和C（1'）-N（1）sigma* MO的部分混合，这可能是由动态构象变化促进的，以实现更高程度的（x* + a*）MO混合。
series of 5-fluoro-1-(2'-oxocycloalkyl)uracils (3-11) that are potentially novel radiation-activated prodrugs for the radiotherapy of hypoxic tumor cells have been synthesized to evaluate a relationship between the molecular structure and the reactivity of one-electron reductive release of antitumor 5-fluorouracil (1) in anoxic aqueous solution. All the compounds 3-11 bearing the 2'-oxo group were one-electron reduced by hydrated electrons (e(aq)(-)) and thereby underwent C(1')-N(1) bond dissociation to release 5-fluorouracil 1 in 47-96% yields upon radiolysis of anoxic aqueous solution, while control compounds (12, 13) without the 2'-ore substituent had no reactivity toward such a reductive C(1')-N(1) bond dissociation. The decomposition of 2-oxo compounds in the radiolytic one-electron reduction was more enhanced, as the one-electron reduction potential measured by cyclic voltammetry in N,N-dimethylformamide became more positive. The efficiency of 5-fluorouracil release was strongly dependent on the structural flexibility of 2-ore compounds. X-ray crystallographic studies of representative compounds revealed that the C(1')-N(I) bond possesses normal geometry and bond length in the ground state. MO calculations by the AM1 method demonstrated that the LUMO is primarily localized at the pi* orbital of C(5)-(C6) double bond of the 5-fluorouracil moiety, and that the LUMO + 1 is delocalized between the pi* orbital of 2'-oxo substituent and the sigma* orbital of adjacent C(1')-N(1) bond. The one-electron reductive release of 5-fluorouracil 1 in anoxic aqueous solution was presumed to occur from the LUMO + 1 of radical anion intermediates possessing a partial mixing of the antibonding C(2') = O pi* and C(1')-N(1) sigma* MO's, that may be facilitated by a dynamic conformational change to achieve higher degree of (x* + a*) MO mixing.