Florent J C, Dong X, Gaudel G, Mitaku S, Monneret C, Gesson J P, Jacquesy J C, Mondon M, Renoux B, Andrianomenjanahary S, Michel S, Koch M, Tillequin F, Gerken M, Czech J, Straub R, Bosslet K
UMR 176 CNRS/Institut Curie, Section Recherche, 26 rue d'Ulm, F-75248 Paris Cedex 05, France.
J Med Chem. 1998 Sep 10;41(19):3572-81. doi: 10.1021/jm970589l.
A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibody-directed enzyme prodrug therapy (ADEPT) is reported. These compounds (25a,b,c and 32a,b,c) have been designed to generate cytotoxic drugs after activation with beta-glucuronidase. As expected, recovery of the active drug was observed after enzymatic cleavage by Escherichia coli beta-glucuronidase as well as by a fusion protein which has been obtained from human beta-glucuronidase and humanized CEA-specific binding region. The six prodrugs are highly stable and are more than 100-fold less cytotoxic than doxorubicin against murine L1210 cell lines. The ortho-substituted phenyl carbamates 25a,b,c are better substrates for beta-glucuronidase than the corresponding para-substituted analogues. After taking into account additional factors such as stability in plasma and kinetics of enzymatic cleavage, we selected the o-nitro prodrug 25c for clinical trials.
报道了一系列柔红霉素和阿霉素的新型前药，它们是抗体导向酶前药疗法（ADEPT）的候选药物。这些化合物（25a、b、c和32a、b、c）经设计可在β-葡萄糖醛酸酶激活后产生细胞毒性药物。正如预期的那样，在用大肠杆菌β-葡萄糖醛酸酶以及从人β-葡萄糖醛酸酶和人源化癌胚抗原（CEA）特异性结合区获得的融合蛋白进行酶切后，观察到了活性药物的释放。这六种前药高度稳定，对鼠L1210细胞系的细胞毒性比阿霉素低100倍以上。邻位取代的苯基氨基甲酸酯25a、b、c比相应的对位取代类似物更易被β-葡萄糖醛酸酶作用。在考虑了诸如血浆稳定性和酶切动力学等其他因素后，我们选择了邻硝基前药25c进行临床试验。
