HSP90抑制剂前药设计及合成

Design and synthesis of HSP90 inhibitor prodrugs

为解决热休克蛋白90(Heat shock protein 90,HSP90)抑制剂的周身毒性问题,自主设计并合成了两个HSP90抑制剂的三肽前药P1和P2。以4-(2-羟乙基)哌啶-1-甲酸叔丁酯和1-(溴甲基)-4-硝基苯为起始原料,经羟胺缩合、硝基还原、关环等反应合成HSP90抑制剂HSP90i-1和HSP90i-2;以L-脯氨酸和L-缬氨酸衍生物为原料,经缩合、脱保护、酰化等反应合成多肽连接子M1。将HSP90i-1、HSP90i-2分别和M1缩合,得到两个三肽前药P1和P2。1H NMR、LCMS、13C NMR分析表征结果表明两个前药分子被成功合成。该研究具有使用的原料廉价易得、反应都在常温下进行、条件温和可控、总产率较高等特点,为多肽前药的设计及合成提供了新的思路和方法。

To solve the peripheral toxicity problem of heat shock protein 90(HSP90)inhibitors,we designed and synthesized two HSP90 inhibitors,P1 and P2,as tripeptide prodrugs.The HSP90 inhibitors HSP90i-1 and HSP90i-2 were synthesized from tert-Butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate and 1-Bromo-4-nitrobenzene by the reactions of hydroxylamine condensation,nitroreduction,ring closure,etc.The peptide linker M1 was synthesized from L-proline and L-valine derivatives by the reactions of condensation,deprotection,acylation,etc.HSP90i-1 and HSP90i-2 were condensed with M1 to obtain the two tripeptide prodrugs of P1 and P2.~1H NMR,LCMS,~(13)C NMR analysis and characterization results indicated that the two prodrugs were successfully synthesized.The study is characterized by the availability of inexpensive raw materials,the mild and controlled conditions of the reactions at room temperature,and the high overall yields,which provides new ideas and methods for the design and synthesis of polypeptide prodrugs.