A strategy for tumor-selective chemotherapy by enzymatic liberation of seco-duocarmycin SA-derivatives from nontoxic prodrugs.
A strategy for tumor-selective chemotherapy by enzymatic liberation of seco-duocarmycin SA-derivatives from nontoxic prodrugs.
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通过从无毒前药中酶促释放司科多卡霉素 SA 衍生物来进行肿瘤选择性化疗的策略。
DOI：
10.1016/s0968-0896(01)00098-0
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发表时间：
2001
影响因子：
3.5
通讯作者：
I. Schuberth
中科院分区：
文献类型：
--
作者：
L. Tietze;M. Lieb;T. Herzig;F. Haunert;I. Schuberth
通过将酶与结合肿瘤相关抗原的适当单克隆抗体连接而获得的免疫缀合物可用于肿瘤选择性抗体导向的酶前药疗法（ADEPT）。对于该策略，将糖苷17 a-c制备为CI-TMI 14的前药，CI-TMI 14是高效抗肿瘤剂倍癌霉素SA 2的结构简化的类似物。将17 a-c暴露于培养的A549系癌细胞显示出非常低的毒性;然而，在加入相应的酶并在前药浓度<0.1 μM下暴露24 h后，在存在和不存在酶的情况下，当ED 50前药/ED 50药物高达270时，癌细胞的增殖几乎完全被抑制。17 a-c的合成是通过将硝基茴香胺6转化为12来实现的，12被糖苷化以得到16 a-c。除去甲硅烷基，引入氯原子和缩醛基团的溶剂分解导致17 a-c，其中17 a和17 c是有希望的候选者，用于进一步加工。
Immuno-conjugates obtained by linking enzymes with appropriate monoclonal antibodies, which bind to tumor-associated antigens, can be employed in a tumor-selective antibody directed enzyme prodrug therapy (ADEPT). For this strategy the glycosides 17a–c were prepared as prodrugs of CI-TMI 14 which is a structurally simplified analogue of the highly potent antitumor agent duocarmycin SA 2. Exposure of 17a–c to cultured carcinoma cells of line A549 displayed a very low toxicity; however, after addition of the corresponding enzymes and exposure for 24 h at prodrug concentrations of <0.1 μM the proliferation of the carcinoma cells was inhibited almost completely with ED50prodrug/ED50drugof up to 270 in the presence and in the absence of the enzyme. The synthesis of 17a–c was achieved by transformation of nitroanisidine 6 into 12 which was glycosidated to give 16a–c. Removal of the silyl groups, introduction of a chlorine atom and solvolysis of the acetal groups led to 17a–c, of which 17a and 17c are promising candidates for further elaboration.