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首页> 外文期刊>Chemistry: A European journal >Selective treatment of cancer: Synthesis, biological evaluation and structural elucidation of novel analogues of the antibiotic CC-1065 and the duocarmycins
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Selective treatment of cancer: Synthesis, biological evaluation and structural elucidation of novel analogues of the antibiotic CC-1065 and the duocarmycins

机译：癌症的选择性治疗：抗生素CC-1065和Duocarmycins的新类似物的合成，生物学评估和结构解析

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摘要

Novel diastereomerically pure beta-D-galactosidic prodrugs (+)-12a-e of the cytotoxic antibiotics CC-1065 and the duocarmycins were prepared for an antibody directed enzyme prodrug therapy (ADEPT) using 4 as a substrate via a radical cyclization to give rac-5 and rac-6 followed by a chromatographic resolution of the enantiomers of rac-5, glycosidation and linkage to the DNA-binding units 10a-e. These only slightly toxic compounds can be toxified enzymatically by an antibody-p-D-galactosidase conjugate at the surface of malignant cells to give the cytotoxic drugs, which then alkylate DNA. The new prodrugs were tested in in vitro cytotoxicity assays showing excellent QIC(50) values of 4800 and 4300 for (+)-12a and (+)-12b, respectively. The absolute configuration of precursor (+)-5 was determined by comparison of the experimental CD spectrum with the theoretically predicted CD spectra and by X-ray structure analysis.
机译：制备了新的非对映体纯的细胞毒性抗生素CC-1065和duocarcin的β-D-半乳糖苷前药（+）-12a-e，用于抗体导向的酶前药治疗（ADEPT），使用4作为底物，通过自由基环化得到rac -5和rac-6，然后进行rac-5对映体的色谱分离，糖基化和与DNA结合单元10a-e的连接。这些只有轻微毒性的化合物可以通过在恶性细胞表面被抗体-p-D-半乳糖苷酶偶联物酶解，产生细胞毒性药物，然后将其烷基化。新的前药在体外细胞毒性试验中进行了测试，分别显示（+）-12a和（+）-12b的QIC（50）值分别为4800和4300。前体（+）-5的绝对构型是通过将实验CD光谱与理论上预测的CD光谱进行比较并通过X射线结构分析确定的。

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