Vrudhula V M, Svensson H P, Senter P D
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.
J Med Chem. 1995 Apr 14;38(8):1380-5. doi: 10.1021/jm00008a016.
The synthesis of a series of cephalosporin doxorubicin derivatives that differ with respect to the substituent at position 7 of the cephem nucleus is described. These compounds are designed as prodrugs of doxorubicin for activation by monoclonal antibody-beta-lactamase conjugates. The key step in the synthesis of this series of compounds involves the use of the phenylacetamido group as an enzymatically removable protecting group for the 7-amino group on the cephem. In vitro cytotoxicity assays with H2981 lung adenocarcinoma cells revealed that cephalosporin doxorubicin derivatives were all less toxic than the released drug. Prodrugs containing negatively charged groups in the side chain, such as the delta-carboxybutanamido derivative 4 and the alpha-sulfophenylacetyl derivative 5, displayed the least cytotoxic activity and were 46- and 26-fold less toxic than doxorubicin, respectively. The efficiency of activation of all the prodrugs was evaluated in cytotoxicity assays on H2981 cells with the beta-lactamases from Enterobacter cloacae P99, Escherichia coli TEM-1, and Bacillus cereus (type II). In general, the E. cloacae enzyme was found to most rapidly activate the majority of these prodrugs. Phenylacetamido prodrug 2 and delta-carboxybutanamido prodrug 4 were both activated in an immunospecific manner by L6-E. cloacae beta-lactamase, a monoclonal antibody conjugate that binds to receptors on H2981 lung adenocarcinoma cells.
描述了一系列在头孢烯核7位取代基上有所不同的头孢菌素阿霉素衍生物的合成。这些化合物被设计为阿霉素的前药，可通过单克隆抗体-β-内酰胺酶缀合物激活。该系列化合物合成中的关键步骤涉及使用苯乙酰胺基作为头孢烯上7-氨基的酶促可去除保护基。用H2981肺腺癌细胞进行的体外细胞毒性试验表明，头孢菌素阿霉素衍生物的毒性均低于释放出的药物。侧链中含有带负电荷基团的前药，如δ-羧基丁酰胺衍生物4和α-磺基苯乙酰衍生物5，显示出最低的细胞毒性活性，其毒性分别比阿霉素低46倍和26倍。在对H2981细胞进行的细胞毒性试验中，使用来自阴沟肠杆菌P99、大肠杆菌TEM-1和蜡样芽孢杆菌（II型）的β-内酰胺酶评估了所有前药的激活效率。一般来说，发现阴沟肠杆菌的酶能最迅速地激活这些前药中的大多数。苯乙酰胺基前药2和δ-羧基丁酰胺基前药4都能被L6-阴沟肠杆菌β-内酰胺酶以免疫特异性方式激活，L6-阴沟肠杆菌β-内酰胺酶是一种与H2981肺腺癌细胞上的受体结合的单克隆抗体缀合物。
