Lau A, Bérubé G, Ford C H, Gallant M
School of Pharmacy, Memorial University of Newfoundland, St. John's, Canada.
Bioorg Med Chem. 1995 Oct;3(10):1305-12. doi: 10.1016/0968-0896(95)00126-2.
Doxorubicin was modified with five different heterobifunctional reagents to produce drug analogs containing 3'-N-amide or C-13 hydrazone linkage with maleimide. Synthesis and characterization of two new reagents, 4-maleimidobenzohydrazide trifluoroacetate salt (13) and N-(4-maleimidobenzoyl)-6-aminocaprohydrazide trifluoroacetate salt (14) are described here. All Dox maleimido derivatives were conjugated to thiolated anti-carcinoembryonic antigen monoclonal antibody, 11-285-14, via a Michael addition reaction. Antibody-directed cytotoxicity was demonstrated with the MTT assay using combinations of antigen-positive and antigen-negative cell lines. The immunoconjugates prepared from Dox 3'-N-amide analogs are not active in vitro, however, Dox(hydrazone-linked) immunoconjugates are selectively toxic to the CEA positive cell line.
用五种不同的异双功能试剂对阿霉素进行修饰，以制备含有与马来酰亚胺的3'-N-酰胺或C-13腙键的药物类似物。本文描述了两种新试剂4-马来酰亚胺基苯甲酰肼三氟乙酸盐（13）和N-（4-马来酰亚胺基苯甲酰基）-6-氨基己酰肼三氟乙酸盐（14）的合成与表征。所有阿霉素马来酰亚胺衍生物均通过迈克尔加成反应与硫醇化抗癌胚抗原单克隆抗体11-285-14偶联。使用抗原阳性和抗原阴性细胞系的组合，通过MTT试验证明了抗体导向的细胞毒性。由阿霉素3'-N-酰胺类似物制备的免疫缀合物在体外无活性，然而，阿霉素（腙连接）免疫缀合物对CEA阳性细胞系具有选择性毒性。
