促性腺激素释放激素类似物-阿霉素偶联物的合成与抗肿瘤活性  

Synthesis and antitumor activity of GnRH-doxorubicin conjugates

作　　者：李松涛[1] 赵红玲[1] 常晓敏 王建平 尹志峰[1] 邓淑华[1] 杨雅琪 王慧娜 LI Song-tao;ZHAO Hong-ling;CHANG Xiao-min;WANG Jian-ping;YIN Zhi-feng;DENG Shu-hua;YANG Ya-qi;WANG Hui-na(Hebei Province Key Laboratory of Research and Development of Traditional Chinese Medicine,Chengde Medical University,Hebei 067000,China;Department of Immunology,Chengde Medical University,Hebei 067000,China)

机构地区：[1]承德医学院河北省中药研究与开发重点实验室,承德067000 [2]承德医学院免疫学教研室,承德067000

出　　处：《中国新药杂志》2019年第10期1248-1252,共5页Chinese Journal of New Drugs

基　　金：河北省教育厅高等学校青年拔尖人才计划项目(BJ2017055);河北省自然科学基金资助项目(H2017406022);承德医学院大学生创新创业训练计划项目(201721);河北省高校重点学科建设项目(冀教高[2013]4)

摘　　要：目的:制备靶向肿瘤细胞促性腺激素释放激素(GnRH)受体的多肽-药物偶联物。方法:将GnRH的6位甘氨酸(Gly^6)用半胱氨酸(Cys)替代,10位的甘氨酰胺(Gly^(10)-NH_2)分别用乙胺和氨基脲取代,合成了2个GnRH类似物。以硫醚键将上述GnRH类似物与阿霉素(Dox)偶联,得到了2个多肽-药物偶联物[Cys^6-desGly^(10)-Pro^9-NHEt]-GnRH-Dox(偶联物1)和[Cys^6-α-azaGly^(10)-NH_2]-GnRH-Dox(偶联物2)。MTT实验考察2个偶联物对GnRH受体过表达的MCF-7人乳腺癌细胞的体外增殖抑制活性,GnRH受体抑制实验评价偶联物2的靶向性。结果:2个偶联物对MCF-7细胞的增殖抑制活性均低于阿霉素,偶联物2对MCF-7细胞的增殖抑制活性高于偶联物1。结论:偶联物2的抗肿瘤活性可能是由[Cys^6-α-azaGly^(10)-NH_2]-GnRH与GnRH受体的靶向结合而介导的细胞内吞摄取作用而实现。Objective:To prepare peptide-drug conjugates targeting gonadotropin-releasing hormone(GnRH)receptor on tumor cells.Methods:Two new GnRH analogs were synthesized by replacing the Gly6 with Cys and substitution of C-terminal Gly10-NH2 by ethylamide andα-azaGly10-NH2,respectively.The GnRH analogs were conjugated with doxorubicin(Dox)through a linker containing thioether bond to afford two GnRH-Dox conjugates,named[Cys6-desGly10-Pro9-NHEt]-GnRH-Dox(conjugate 1)and[Cys6-α-azaGly10-NH2]-GnRH-Dox(conjugate2),respectively.The direct in vitro growth inhibitory effect of these two conjugates on MCF-7 human breast cancer cells which overexpress GnRH recepter was examined by MTT assay,and the targeting effect of conjugate 2 was evaluated by GnRH receptor inhibition test.Results:Both of the two conjugates exhibited lower antiproliferative activity against MCF-7 cell line in comparison with Dox,and the antiproliferative activity of conjugate 2 was higher than that of conjugate 1.Conclusion:The antiproliferative effect of conjugate 2 on MCF-7 cells might be due to the cellular uptake mediated by the target binding of[Cys6-α-azaGly10-NH2]-GnRH to GnRH receptors.

关 键 词：促性腺激素释放激素 多肽偶联药物 阿霉素 抗肿瘤活性 

分 类 号：R914.5[医药卫生—药物化学]