Haritha Reddy, Alison Duffy, Noa G Holtzman, Ashkan Emadi
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The net outcome is entrapment of the DNMT by 5-aza-cytosine analogues and its eventual degradation, leading to DNA hypomethylation. Second, we analyze the critical role of β-elimination reaction in the activation of cyclophosphamide and ifosfamide. The incapability of undergoing β-elimination results in reduction of the cytotoxic activity of these agents. It appears that the conversion of aldehyde group, in aldophosphamide metabolites of cyclophosphamide and ifosfamide, to carboxyl group by aldehyde dehydrogenase makes the protons on the carbon atom attached to carboxyl group not acidic enough that can be removed under physiologic conditions via initiation of the critical β-elimination reaction. 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引用次数: 0
摘要
β-消除反应一般是指在β(β)位将σ(σ)键裂解为一对电子,这对电子通过亲核离去基团离开分子,随后形成新的π(π)键。我们描述了β-消除反应在两类化疗药物作用机制中的重要性。首先,我们评估了通过 β-消除反应形成 5-甲基胞嘧啶并使其与 DNA 甲基转移酶(DNMT)脱离的化学步骤。当 5-氮杂胞嘧啶类似物中胞嘧啶的碳 5(C5)被氮原子(N)取代时,关键的β-消除反应就无法进行,从而导致 5-氮杂胞嘧啶永久性地附着在 DNMT 上。最终的结果是 DNMT 被 5-氮杂胞嘧啶类似物困住并最终降解,导致 DNA 低甲基化。其次,我们分析了β-消除反应在环磷酰胺和伊福酰胺活化过程中的关键作用。不能进行β-消除反应会导致这些药物的细胞毒性活性降低。环磷酰胺和伊福酰胺的醛磷酰胺代谢物中的醛基被醛脱氢酶转化为羧基后,与羧基相连的碳原子上的质子似乎不够酸性,无法在生理条件下通过启动关键的β-消除反应将其去除。这最终导致这些制剂对淋巴细胞产生选择性细胞毒性作用,而对造血细胞和其他醛脱氢酶含量高的干细胞则无效。
The role of β-elimination for the clinical activity of hypomethylating agents and cyclophosphamide analogues.
A beta-elimination reaction generally involves the cleavage of a sigma (σ) bond at the position beta (β) to a pair of electrons that departs a molecule via a nucleophilic leaving group, subsequently leading to the formation of a new pi (π) bond. We describe the importance of β-elimination reactions in the mechanisms of action of two classes of chemotherapeutic agents. First, we evaluate the chemical steps resulting in formation of 5-methyl-cytosine and its disassociation from DNA methytransferase (DNMT) by β-elimination reaction. When carbon 5 (C5) of cytosine is substituted with a nitrogen atom (N) in 5-aza-cytosine analogues, the critical β-elimination reaction cannot proceed, which results in the permanent attachment of 5-aza-cytosine to DNMT. The net outcome is entrapment of the DNMT by 5-aza-cytosine analogues and its eventual degradation, leading to DNA hypomethylation. Second, we analyze the critical role of β-elimination reaction in the activation of cyclophosphamide and ifosfamide. The incapability of undergoing β-elimination results in reduction of the cytotoxic activity of these agents. It appears that the conversion of aldehyde group, in aldophosphamide metabolites of cyclophosphamide and ifosfamide, to carboxyl group by aldehyde dehydrogenase makes the protons on the carbon atom attached to carboxyl group not acidic enough that can be removed under physiologic conditions via initiation of the critical β-elimination reaction. This ultimately culminates in selective cytotoxic effect of these agents against lymphocytes but not hematopoietic and other stem cells with high aldehyde dehydrogenase content.