基于Click反应的5-氟尿嘧啶与4-苯胺喹唑啉骨架的拼接合成及其抗肿瘤活性评价  

Synthesis and Antitumor Activity of 5-Fluorouracil and 4-Anilinoquinazoline Skeleton Based on Click Reaction

作　　者：梁光平 杨杰 梁光焰 王道平[2] 杨俊 LIANG Guang-ping;YANG Jie;LIANG Guang-yan;WANG Dao-ping;YANG Jun(Department of Pharmacy,Zunyi Medical and Pharmaceutical College,Zunyi 563006,China;The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences,Guiyang 550014,China)

机构地区：[1]遵义医药高等专科学校药学系,贵州遵义563006 [2]贵州省中国科学院天然产物化学重点实验室,贵州贵阳550014

出　　处：《化学试剂》2022年第9期1272-1279,共8页Chemical Reagents

基　　金：贵州省科学技术基金资助项目(黔科合基础[2019]1356号);遵义医药高等专科学校博士科研启动项目(遵医专科合BS2018001号)。

摘　　要：以3种羟基喹唑啉-4-酮为原料,经乙酰化、氯化、取代、水解、烷基化反应得到6个末端含有端炔取代的4-苯胺喹唑啉类化合物,同时以5-氟尿嘧啶为原料,经羰基保护、烷基化、叠氮化反应制得1-(3-叠氮丙基)-5-氟尿嘧啶,最后再利用药物拼合原理将其与不同含有端炔取代的4-苯胺喹唑啉类化合物或厄洛替尼通过Click反应合成了7个5-氟尿嘧啶与4-苯胺喹唑啉骨架的新型拼接产物,其结构通过^(1)HNMR和HR-MS确证。以厄洛替尼为阳性对照,采用MTT法初步评价目标化合物对人肝癌细胞HepG2、人非小细胞肺癌细胞A549、人宫颈癌细胞Hela、人乳腺癌细胞MCF-7、人肺腺癌耐顺铂株细胞A549/DDP的抑制作用,同时采用ELISA法检测目标产物对表皮生长因子(EGFR)的抑制能力。结果显示,1-(3-(4-(((4-((4-碘苯基)氨基)-7-甲氧基喹唑啉-6-基)氧)甲基)-1 H-1,2,3-三唑-1-基)丙基)-5-氟尿嘧啶-2,4(1 H,3 H)-二酮对HepG2、A549、A549/DDP细胞的抑制作用分别是阳性对照厄洛替尼的6.5倍、1.8倍、2.8倍,对Hela、MCF-7细胞的IC_(50)也分别达到了(0.95±0.33)、(1.26±0.55)μmol/L。同时,该化合物在0.01、0.1μmol/L对EGFR的抑制作用弱于阳性对照厄洛替尼,提示该化合物并非只通过作用于EGFR产生抗肿瘤作用,可能还存在其他的作用途径,值得进一步研究。Six 4-anilinoquinazolines with terminal alkynes were synthesized by acetylation,chlorination,substitution,hydrolysis and alkylation reaction using 3 kinds of hydroxy substituted quinazoline-4-one as starting materials.Meanwhile,1-(3-azidopropyl)-5-fluorouracil was also prepared from 5-fluorouracil by carbonyl protection,alkylation and azide reaction.Finally,7 novel splicing products were synthesized by the Click reaction of 1-(3-azidopropyl)-5-fluorouracil with 4-anilinoquinazolines containing terminal alkynes or erlotinib,and their structures were confirmed by ^(1)HNMR and HR-MS.With Erlotinib as the positive control,the inhibitory effects of the splicing products on HepG2,A549,Hela,MCF-7 and A549/DDP cells were evaluated by MTT assay,and the inhibition ability of the splicing products to EGFR was also tested by ELISA.The results showed that the inhibitory effects of 1-(3-(4-(((4-((4-iodophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)methyl)-1 H-1,2,3-triazol-1-yl)propyl)-5-fluoropyrimidine-2,4(1H,3H)-dione on HepG2,A549 and A549/DDP were 6.5,1.8 and 2.8 times higher than that from the positive control of Erlotinib,and the inhibitory for the IC_(50)of Hela and MCF-7 cells were(0.95±0.33),(1.26±0.55)μmol/L,respectively.Moreover,the inhibitory effect of this compound on EGFR at 0.01,0.1μmol/L was weaker than that of the positive control Erlotinib,suggesting that this compound cannot produce anti-tumor effect only by acting on EGFR,and that there might be other pathways that deserve to further study.

关 键 词：5-氟尿嘧啶 喹唑啉 CLICK反应 抗肿瘤 表皮生长因子 

分 类 号：R914[医药卫生—药物化学]