肿瘤靶向性多功能亚硝基脲的合成及抗肿瘤活性评价  

Synthesis and Antitumor Activity Evaluation of Tumor-targeting Multifunctional Nitrosourea

作　　者：刘琪 王娇娇 赵丽娇[1] 孙国辉[1] 任婷[1] 张娜[1] 钟儒刚[1] LIU Qi;WANG Jiao-jiao;ZHAO Li-jiao;SUN Guo-hui;REN Ting;ZHANG Na;ZHONG Ru-gang(Beijing Key Laboratory of Environmental&Viral Oncology,Faculty of Environment&Life,Beijing University of Technology,Beijing 100124,China)

机构地区：[1]北京工业大学环境与生命学部环境与病毒肿瘤学北京市重点实验室,北京100124

出　　处：《化学试剂》2021年第6期775-782,共8页Chemical Reagents

基　　金：国家自然科学基金资助项目(21778011);北京市长城学者计划项目(CIT&TCD20180308);北京市百千万人才计划项目(2019A16);北京市自然科学基金资助项目(7192015);北京市教委北京市重点实验室建设项目(PXM2015014204500175)。

摘　　要：氯乙基亚硝基脲(CENUs)是临床上重要的抗肿瘤药物,该类药物通过诱导形成DNA股间交联(dG-dC交联)发挥抗肿瘤作用。但O^(6)-烷基鸟嘌呤-DNA烷基转移酶(O^(6)-alkylguanine-DNA alkyltransferase,AGT)介导的细胞耐药性及明显的毒副作用降低了其抗癌效果。合成了一种肿瘤靶向性多功能亚硝基脲,该化合物由具有低氧选择活性的偶氮苯衍生物、能够抑制AGT活性的O^(6)-苄基鸟嘌呤衍生物和氯乙基亚硝基脲3部分组成。该化合物能够特异性地在低氧肿瘤区域被还原,释放AGT抑制剂和氯乙基亚硝基脲,从而发挥靶向抗肿瘤作用。多功能亚硝基脲及其各中间产物的化学结构经高分辨质谱、^(1)HNMR、^(13)CNMR及IR数据确证。通过CCK-8法评价了上述化合物对人脑神经胶质瘤SF763细胞的增殖抑制活性;并用荧光成像法评价了该化合物对SF763细胞的促凋亡活性。结果表明,与临床一线亚硝基脲类抗肿瘤药物尼莫司汀相比,多功能亚硝基脲能够更有效地抑制肿瘤细胞增殖、促进肿瘤细胞凋亡,并具有明显的低氧靶向性。CENUs are important antitumor drugs in clinic and exert anti-tumor activity by inducing the formation of DNA interstrand crosslinks(dG-dC crosslinks).However,the drug resistance mediated by O^(6)-alkylguanine-DNA alkyltransferase(AGT)and the obvious side effect decrease its anti-tumor activity.In this study,a tumor-targeted multifunctional nitrosourea was synthesized,which consisted of three parts including an azobenzene derivative with hypoxic selective activity,an O^(6)-benzyl guanine derivative with AGT inhibitory activity,and a chloroethyl nitrosourea moiety.Target compound can be specifically reduced in hypoxic tumor region and release AGT inhibitors and chloroethylating intermediate,which renders the compound tumor-targeting property.While in normoxic conditions of normal tissues,target compound cannot be reduced to AGT inhibitor,which protects the normal tissue DNA from being damaged.The chemical structures of target compound and its intermediates were confirmed by high-resolution mass spectrometry,^(1)HNMR,^(13)CNMR and IR.The inhibitory activity of target compound on human brain glioma SF763 cells was evaluated by CCK-8 assay.The pro-apoptotic activity of the target compound on SF763 cells was evaluated by fluorescence imaging assay.The results indicated that target compound exhibited higher efficacy of inhibiting proliferation and promoted the apoptosis of tumor cells compared with the clinically used chemotherapy nimustine.Moreover,target compound exhibits obvious hypoxia targeting ability.

关 键 词：氯乙基亚硝基脲 肿瘤靶向性 肿瘤低氧 耐药 化疗药物 

分 类 号：R914[医药卫生—药物化学]