Albumin-binding高活性的喜树碱和阿霉素Ala-Leu-Ala-Leu-linker裂解的组织蛋白酶B:合成和抗肿瘤功效。
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施密德B,钟DE, Warnecke Fichtner我Kratz F
Albumin-binding高活性的喜树碱和阿霉素Ala-Leu-Ala-Leu-linker裂解的组织蛋白酶B:合成和抗肿瘤功效。
Bioconjug May-Jun化学2007;18 (3):702 - 16。Epub 2007年3月23日。
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17378599 (在PubMed]
- 文摘
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我们最近验证大分子前药策略改进癌症化疗基于两个特点:(a)的快速和选择性绑定thiol-reactive高活性cysteine-34内生白蛋白的位置和(b) acid-sensitive提升或酶释放的药物在肿瘤部位(Kratz F。Warnecke,。Scheuemann, K。Stockmar C。施瓦布,J。麻风病患者,P。德鲁克,P。艾瑟,N。Drevs, J。Rognan D。Bissantz C。Hinderling C。Folkers, G。Fichtner,我。昂格尔,c (2002) j .地中海,化学。45 5523 - 33)。在目前的工作,我们开发了水溶性喜树碱(CPT)和阿霉素(DOXO)高活性化合物,包含肽连接器Ala-Leu-Ala-Leu作为基质的肿瘤相关蛋白酶、组织蛋白酶B,这是在几个实体肿瘤中。因此,两个albumin-binding高活性化合物合成[EMC-Arg-Arg-Ala-Leu-Ala-Leu-Ala-CPT(1)和EMC-Arg-Arg-Ala-Leu-Ala-Leu-DOXO (2) (EMC = 6-maleimidocaproic酸)]。 Both prodrugs exhibited excellent water-solubility and bound rapidly and selectively to the cysteine-34 position of endogenous albumin. Further in vitro studies showed that the albumin-bound form of the prodrugs was cleaved specifically by cathepsin B as well as in human tumor homogenates. Major cleavage products were CPT-peptide derivatives and CPT for the CPT prodrug and H-Leu-Ala-Leu-DOXO, H-Leu-DOXO, and DOXO for the doxorubicin prodrug. In vivo, 1 was superior to free camptothecin in an HT-29 human colon xenograft model; the antitumor efficacy of prodrug 2 was comparable to that of free doxorubicin in the M-3366 mamma carcinoma xenograft model at equimolar doses.