SELF-IMMOLATIVE PRODRUGS - CANDIDATES FOR ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY IN CONJUNCTION WITH A NITROREDUCTASE ENZYME
SELF-IMMOLATIVE PRODRUGS - CANDIDATES FOR ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY IN CONJUNCTION WITH A NITROREDUCTASE ENZYME
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DOI：
10.1021/jm00047a002
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发表时间：
1994-10-14
影响因子：
7.3
通讯作者：
KNOX, RJ
中科院分区：
文献类型：
--
作者：
MAUGER, AB;BURKE, PJ;KNOX, RJ
介绍了一些抗体导向酶前药治疗（ADEPT）候选前药的合成和性质。这些化合物被设计成在与细菌硝基还原酶相互作用后产生相应的活性药物，该硝基还原酶可以结合到识别肿瘤选择性抗原的抗体上。研究中包括的活性药物有放线菌素D、丝裂霉素C、阿霉素、4-[双（2-氯乙基）氨基]苯胺和4-双（2-氯乙基）氨基]苯酚。前药均为这些药物的4-硝基苯氧羰基衍生物，经酶还原后，通过4-（羟氨基）苯氧羰基自焚生成药物。在放线菌素D的情况下，产生相同细胞毒性所需的药物与前药剂量之比大于100。前药对小鼠的体内毒性也远低于放线菌素D（20-100倍）。因此，这种自焚前药具有潜在的应用前景，可用于治疗癌症。
The synthesis and properties of some prodrug candidates for antibody-directed enzyme prodrug therapy (ADEPT) are described. These compounds have been designed to generate the corresponding active drug upon interaction with a bacterial nitroreductase that can be conjugated to antibodies that recognize tumor-selective antigens. The active drugs included in the study are actinomycin D, mitomycin C, doxorubicin, 4-[bis(2-chloroethyl)amino]aniline and 4-Lbis(2-chloroethyl)amino]phenol. The prodrugs were all 4-nitrobenzyloxycarbonyl derivatives of these drugs, which upon enzymatic reduction, generated the drug through self-immolation of the 4-(hydroxyamino)benzyloxycarbonyl group. In the case of actinomycin D, the ratio of the dose required between drug and prodrug to give the same cytotoxicity was greater than 100. The prodrug was also much less toxic (20-100x) than actinomycin D to mice in vivo. Therefore this self-immolative prodrug has a potential application in the treatment of cancer using an ADEPT-type approach.