Tietze Lutz F, Major Felix, Schuberth Ingrid, Spiegl Dirk A, Krewer Birgit, Maksimenka Katja, Bringmann Gerhard, Magull Jörg
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany.
Chemistry. 2007;13(16):4396-409. doi: 10.1002/chem.200700113.
Novel diastereomerically pure beta-D-galactosidic prodrugs (+)-12 a-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 10 a-e. These only slightly toxic compounds can be toxified enzymatically by an antibody-beta-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 (+)-12 a and (+)-12 b, 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.
制备了细胞毒性抗生素CC - 1065和双卡霉素的新型非对映体纯β - D - 半乳糖苷前药(+)-12 a - e，用于抗体导向酶前药疗法（ADEPT），以4为底物，通过自由基环化反应生成rac - 5和rac - 6，然后通过色谱法拆分rac - 5的对映体，进行糖苷化并与DNA结合单元10 a - e连接。这些毒性仅略微的化合物可在恶性细胞表面被抗体 - β - D - 半乳糖苷酶偶联物酶促转化为细胞毒性药物，进而使DNA烷基化。对新前药进行了体外细胞毒性试验，结果显示(+)-12 a和(+)-12 b的QIC(50)值分别为4800和4300，表现优异。通过将实验性圆二色光谱与理论预测的圆二色光谱进行比较以及X射线结构分析，确定了前体(+)-5的绝对构型。
