Synthesis and antitumor activity evaluation of a novel combi-nitrosourea prodrug: Designed to release a DNA cross-linking agent and an inhibitor of O6-alkylguanine-DNA alkyltransferase
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- 作者：Guohui Sun ; Na Zhang ; Lijiao Zhao ; zhaolijiao@bjut.edu.cn" class="auth_mail" title="E-mail the corresponding author ; Tengjiao Fan ; Shufen Zhang ; Rugang Zhong
- 关键词：CENUs ; chloroethylnitrosoureas ; ACNU ; 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosourea ; BCNU ; 1 ; 3-bis(2-chloroethyl)-1-nitrosourea ; CCNU ; 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea ; me-CCNU ; 1-(2-chloroethyl)-3-(4-methyl-cyclohexyl)-1-nitrosourea ; ICLs ; interstrand cross-links ; O6-ClEtdGuo ; O6-(2-chloroethyl)deoxyguanosine ; N1 ; O6-EtdGuo ; N1 ; O6-ethanodeoxyguanosine ; dGuo ; deoxyguanosine ; dCyd ; deoxycytidine ; AGT ; O6-alkylguanine-DNA alkyltransferase ; Cys145 ; cysteine14
- 刊名：Bioorganic & Medicinal Chemistry
- 出版年：2016
- 出版时间：1 May 2016
- 年：2016
- 卷：24
- 期：9
- 页码：2097-2107
- 全文大小：2397 K
文摘
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A combi-nitrosourea prodrug releasing DNA cross-linking agent and AGT inhibitor was synthesized.
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The combi-nitrosourea exhibits higher cytotoxicity against mer+ glioma cells than ACNU.
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The prodrug induces higher levels of dG–dC crosslink than traditional CENU chemotherapies.
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AGT activity is efficiently inhibited by the O6-benzylguanine analog released from the prodrug.