具更佳成药性的新型三氮烯化合物的设计、合成及抗癌活性研究  

Design,Syntheses of Novel Triazenes with Better Druggability and the Investigation on Their Anti-tumor Activities

作　　者：许芹芳 胡健灵 刘园林 张超 李明月 彭姝羚 刘志军[1,2] 陈河如 Xu Qinfang;Hu Jianling;Liu Yuanlin;Zhang Chao;Li Mingyue;Peng Shuling;Liu Zhijun;Chen Heru(International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education,Institute of Traditional Chinese Medicine and Natural Products,College of Pharmacy,Jinan University,Guangzhou 510632;Guangzhou PharmCherub Medical Sci.&Tech.Incorporated Corporation,Guangzhou 510663;Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research,Jinan University,Guangzhou 510632;State Key Laboratory of Bioactive Molecules and Druggability Assessment,Jinan University,Guangzhou 510632)

机构地区：[1]暨南大学药学院中药及天然药物研究所中药现代化与创新药物研究国际合作联合实验室,广州510632 [2]广州药本君安医药科技股份有限公司,广州510663 [3]广东省中药药效物质基础及创新药物研究重点实验室,广州510632 [4]暨南大学生物活性分子与成药性优化全国重点实验室,广州510632

出　　处：《有机化学》2024年第5期1606-1619,共14页Chinese Journal of Organic Chemistry

基　　金：广东省自然科学基金(No.2021A1515011238)资助项目。

摘　　要：以4-氨基苯甲酸为原料,经重氮化反应后与甲基烷基胺反应构建三氮烯骨架,随后将羧基与2-二乙基氨基乙氨缩合,合成了11个1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)苯基-3-甲基-3-烷基(R2)三氮烯化合物1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-环己基三氮烯(6a)~1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-(4-硝基)苄基三氮烯(6k),3步反应的总收率为46.5%~68.3%.噻唑蓝(MTT)比色法检测发现,6a、1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-苯基三氮烯(6e)~1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-(4-甲氧基)苄基三氮烯(6j)对人肝癌细胞(Hep G-2)、大鼠胶质瘤细胞(C6)、人结肠癌细胞(SW620)、人前列腺癌细胞(PC-3)、小鼠黑色素瘤细胞(B16)和人非小细胞肺癌细胞(A549)共六株肿瘤细胞都有良好的抗肿瘤活性,显示出广谱的抗癌特性;其中,1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-(4-氯)苯基三氮烯(6g)的抗癌活性最为突出,对C6、SW620、PC-3和B16的IC50值均小于10μmol/L,抗癌活性远优于阳性对照药达卡巴嗪.研究发现,当R^(2)为具有适当吸电子效应的芳基时,化合物的抗癌活性较高.药物安全性评价发现,6e、6g、1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-(4-氯)苄基三氮烯(6h)对C6、SW620、PC-3,6g~1-(4-(N-(2-二乙氨基)乙基)氨甲酰基)-3-甲基-3-(4-甲氧基)苯基三氮烯(6i)对B16,6e、6h、6i对Hep G-2,6i对C6、SW620,其安全指数(SI)均大于2.0,其安全性高于达卡巴嗪.化合物6e、6g~6i的油水分布系数(lg P)为3.0~4.0,具有较高的膜渗透性.所有数据证实,新型三氮烯化合物6e、6g~6i具有更佳的成药性.Eleven novel 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-alkyl(R2)triazenes have been designed and synthesized.Firstly,4-aminobenzoic acid,as starting material,underwent diazo reaction following the reaction with methyl alkylamine to build the triazene scaffold.Condensation of carboxylic group with 2-diethylaminoethylamine re-sulted in all the title compounds.The overall yield of these 3-step reactions was between 46.5%and 68.3%.By using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay,1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-cyclohexyltriazene(6a),1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-phenyltriazene(6e)~1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-methoxyl)benzyltriazene(6j)were confirmed as good broad-spectrum anti-cancer agents again/st human liver cancer cells(HepG-2),rat glioma cells(C6),human colon cancer cells(SW620),human prostate cancer cells(PC-3),murine melanoma cells(B16),and human non-small-cell lung cancer cells(A549).Among them,1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-chloro)phenyltriazene(6g)showed as the most active agent,where IC50 values of 6g against C6,SW620,PC-3,and B16 cell lines are less than 10μmol/L,which is far better than the positive dacarbazine.It was found that when R2 is aryl group with propriate electron-withdrawal intensity,the triazene will have good even excellent anti-cancer activity.Through drug safety evaluation,the safety indexes(SI)of 6e,6g,and 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-chloro)benzyltriazene(6h)against C6,SW620,and PC-3 cell lines,respectively;6g,6h,and 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-methoxyl)phenyltriazene(6i)against B16 cell line respectively;6e,6h,and 6i against HepG-2 cell line respectively;6i against C6,and SW620 cell lines,respectively;were identified more than 2.0,implied better drug safety than dacarbazine.The partition coefficient(lg P)of 6e,6g~6i lied between 3.0

关 键 词：三氮烯 抗肿瘤 药物安全性评价 成药性 药物设计合成 

分 类 号：O622.6[理学—有机化学] TQ460.1[理学—化学]