以二肽为连接臂的新型聚乙二醇修饰阿霉素的合成
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摘要
采用Fmoc固相合成策略,以Wang树脂为载体,Fmoc保护的L-氨基酸为原料,EDC/HOBt为缩合剂,合成了8种聚乙二醇修饰的二肽。以HATU/DIPEA为缩合剂,通过酰化反应将修饰后的多肽连接到阿霉素上,合成了一系列新型阿霉素前药,纯度高于90%,收率高于52%,其结构经~1H NMR和MS(ESI)表征。
Eight glycol modified dipeptides were synthesized by Fmoc solid-phase synthetic strategy using Wang resin as carrier, Fmoc-protected L-amino acids as raw materials, and EDC/HOBt as the condensing agent. Then eight novel PEG-modified doxorubicin were synthesized by linking the modified polypeptides to doxorubicin via acylation, using HATU/DIPEA as the condensing agent. The purities were higher than 90%, and the yields were higher than 52%. The structures were characterized by ~1H NMR and MS(ESI).
Eight glycol modified dipeptides were synthesized by Fmoc solid-phase synthetic strategy using Wang resin as carrier, Fmoc-protected L-amino acids as raw materials, and EDC/HOBt as the condensing agent. Then eight novel PEG-modified doxorubicin were synthesized by linking the modified polypeptides to doxorubicin via acylation, using HATU/DIPEA as the condensing agent. The purities were higher than 90%, and the yields were higher than 52%. The structures were characterized by ~1H NMR and MS(ESI).
引文
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[2] ZORDOKY B N M,ANWAR M A,ABOUTABL M E,et al.Acute doxorubicin toxicity differentially alters cytochrome P450 expression and arachidonic acid metabolism in rat kidney and liver[J].Drug Metab Dispos,2011,39(8):1440-1450.
[3] PAWAR S K,BADHWAR A J,KHARAS F,et al.Design,synthesis and evaluation of N-acetyl glucosamine (NAG)-PEG-doxorubicin targeted conjugates for anticancer delivery[J].Int J Pharm,2012,436(1-2):183-193.
[4] 田浤,金宇灏,陈阳建,等.聚乙二醇氨基酸衍生物的合成及其对紫杉醇的修饰[J].中国药科大学学报,2011,42(1):78-82.
[5] LI W,ZHAN P,DE CLERCQ E,et al.Current drug research on PEGylation with small molecular agents[J].Prog Polym Sci,2013,38(3-4):421-444.
[6] 赵瑾,袁泉,蔡伟惠,等.PEG修饰小分子抗肿瘤药的研究进展[J].中国医药工业杂志,2015,46(9):1027-1033.
[7] PARANIPE P V,CHEN Y,KHOLODOVYCH V,et al.Tumor-targeted bioconjugate based delivery of camptothecin:Design,synthesis and in vitro evaluation[J].J Controlled Release,2004,100(2):275-292.
[8] CONOVER C D,GREENWALD R B,PENDRI A,et al.Camptothecin delivery systems:Enhanced efficacy and tumor accumulation of camptothecin following its conjugation to polyethylene glycol via a glycine linker[J].Cancer Chemother Pharmacol,1998,42(5):407-414.
[9] PAN Z,WANG H,ZHANG M,et al.Nuclear-targeting TAT-PEG-Asp8-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer[J].Acta Pharmacol Sin,2016,37(8):1110-1120.
[10] ULBRICH K,SUBR V,STROHALM J,et al.Polymeric drugs based on conjugates of synthetic and natural macromolecules.I.Synthesis and physico-chemical characterisation[J].J Controlled Release,2000,64(3):63-79.
[11] ZHAO Y J,WEI W,SU Z G,et al.Poly (ethylene glycol) prodrug for anthracyclines via N-Mannich base linker:Design,synthesis and biological evaluation[J].Int J Pharm,2009,379(1):90-99.
[12] 王延龙,宁波,沈鸿雁.单分散聚乙二醇单甲醚的合成[J].精细化工中间体,2015,45(3):17-19.
[13] 廖晓雨,宁喜波,王延龙,等.甲基六聚乙二醇衍生物修饰胸腺五肽的合成及其体外稳定性[J].沈阳药科大学学报,2017,34(12):1044-1048.