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
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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 Gly~6 with Cys and substitution of C-terminal Gly~(10)-NH_2 by ethylamide andα-azaGly~(10)-NH_2,respectively.The GnRH analogs were conjugated with doxorubicin(Dox)through a linker containing thioether bond to afford two GnRH-Dox conjugates,named[Cys~6-desGly~(10)-Pro~9-NHEt]-GnRH-Dox(conjugate 1)and[Cys~6-α-azaGly~(10)-NH_2]-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[Cys~6-α-azaGly~(10)-NH_2]-GnRH to GnRH receptors.
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 Gly~6 with Cys and substitution of C-terminal Gly~(10)-NH_2 by ethylamide andα-azaGly~(10)-NH_2,respectively.The GnRH analogs were conjugated with doxorubicin(Dox)through a linker containing thioether bond to afford two GnRH-Dox conjugates,named[Cys~6-desGly~(10)-Pro~9-NHEt]-GnRH-Dox(conjugate 1)and[Cys~6-α-azaGly~(10)-NH_2]-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[Cys~6-α-azaGly~(10)-NH_2]-GnRH to GnRH receptors.
引文
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[12]田玲,路学智.瑞林类人工合成肽类药物的研究进展[J].中国新药杂志,2006,15(20):1723-1726.
[13]孙立春,COY DH.受体靶向多肽载体抗肿瘤药物[J].上海医药,2015,36(1):69-74.
[14]代涛,尹志峰,赵红玲,等.布舍瑞林的合成[J].中国新药杂志,2014,23(15):1806-1810.
[15]SHI NQ,GAO W,XIANG B,et al.Enhancing cellular uptake of activable cell-penetrating peptide-doxorubicin conjugate by enzymatic cleavage[J].Int J Nanomedicine,2012,7:1613-1621.
[16]PRIBYLOVA M,DVORAKOVA M,HANUSOVA V,et al.Paclitaxel conjugation with the analog of the gonadotropin-releasing hormone as a targeting moiety[J].Int J Pharm,2011,415(1-2):175-180.
[17]WANG C,MA Y,FENG S,et al.Gonadotropin-releasing hormone receptor-targeted paclitaxel-degarelix conjugate:synthesis and in vitro evaluation[J].J Pept Sci,2015,21(7):569-576.
[2]REUTTER M,EMONS G,GRUNDKER C.Starving tumors:inhibition of glycolysis reduces viability of human endometrial and ovarian cancer cells and enhances antitumor efficacy of GnRH receptor-targeted therapies[J].Int J Gynecol Cancer,2013,23(1):34-40.
[3]SEITZ S,BUCHHOLZ S,SCHALLY AV,et al.Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs,AEZS 108 and AEZS125[J].BMC Cancer,2014,14(1):847-859.
[4]KWOK CK,TREECK O,BUCHHOLZ S,et al.Receptors for luteinizing hormone-releasing hormone(GnRH)as therapeutic targets in triple negative breast cancers(TNBC)[J].Targ Oncol,2015,10(3):365-373.
[5]MOREAU JP,DELAVAULT P,BLUMBERG J.Luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer:a review of their discovery,development,and place in therapy[J].Clin Ther,2006,28(10):1485-1508.
[6]RICK FG,BLOCK NL,SCHALLY AV.Agonists of luteinizing hormone-releasing hormone in prostate cancer[J].Expert Opin Pharma,2013,14(16):2237-2247.
[7]KARTEN MJ,RIVIER JE.Gonadotropin-releasing hormone analog design.structure-function studies toward the development of agonists and antagonists:rationale and perspective[J].Endocr Rev,1986,7(1):44-66.
[8]FLANAGAN CA,MILLAR RP,ILLING N.Advances in understanding gonadotrophin-releasing hormone receptor structure and ligand interactions[J].Rev Reprod,1997,2(2):113-120.
[9]SCHNEIDER F,TOMEK W,GRUNDKER C.Gonadotropin-releasing hormone(GnRH)and its natural analogues:a review[J].Theriogenol,2006,66(4):691-709.
[10]宋芸,魏绍川,王永峰,等.瑞林类寡肽抗癌药物的合成研究进展[J].合成化学,2010,18(2):141-147.
[11]潘芹芹,崔毓桂,王兴海.促性腺激素释放激素及其类似物的研究进展[J].生殖医学杂志,2004,13(4):244-247.
[12]田玲,路学智.瑞林类人工合成肽类药物的研究进展[J].中国新药杂志,2006,15(20):1723-1726.
[13]孙立春,COY DH.受体靶向多肽载体抗肿瘤药物[J].上海医药,2015,36(1):69-74.
[14]代涛,尹志峰,赵红玲,等.布舍瑞林的合成[J].中国新药杂志,2014,23(15):1806-1810.
[15]SHI NQ,GAO W,XIANG B,et al.Enhancing cellular uptake of activable cell-penetrating peptide-doxorubicin conjugate by enzymatic cleavage[J].Int J Nanomedicine,2012,7:1613-1621.
[16]PRIBYLOVA M,DVORAKOVA M,HANUSOVA V,et al.Paclitaxel conjugation with the analog of the gonadotropin-releasing hormone as a targeting moiety[J].Int J Pharm,2011,415(1-2):175-180.
[17]WANG C,MA Y,FENG S,et al.Gonadotropin-releasing hormone receptor-targeted paclitaxel-degarelix conjugate:synthesis and in vitro evaluation[J].J Pept Sci,2015,21(7):569-576.
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