Selective treatment of cancer: Synthesis, biological evaluation and structural elucidation of novel analogues of the antibiotic CC-1065 and the duocarmycins
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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DOI：
10.1002/chem.200700113
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发表时间：
2007-01-01
影响因子：
4.3
通讯作者：
Magull, Joerg
中科院分区：
文献类型：
--
作者：
Tietze, Lutz F.;Major, Felix;Magull, Joerg
以4为底物，通过自由基环化反应得到rac-5和rac-6，然后色谱拆分rac-5的对映体，糖苷化并连接到DNA结合单元10a-e，制备了用于抗体导向酶前药治疗（ADEPT）的新型非对映体纯的细胞毒性抗生素CC-1065和倍癌霉素的β-D-半乳糖苷前药（+）-12 a-e。这些只有轻微毒性的化合物可以通过抗体-β-D-半乳糖苷酶缀合物在恶性细胞表面酶促降解，得到细胞毒性药物，然后使DNA烷基化。在体外细胞毒性测定中测试了新的前药，显示出对于（+）-12a和（+）-12b分别为4800和4300的优异QIC（50）值。通过比较实验CD谱和理论预测CD谱以及X射线结构分析确定了前体（+）-5的绝对构型。
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.