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J Med Chem. 2011 Mar 24;54(6):1715-23. doi: 10.1021/jm101354u. Epub 2011 Feb 22.
14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
14-氨基喜树碱通过用 90%发烟硝酸处理喜树碱（1a）和 7-乙基喜树碱（1b），无论是在纯品中还是在乙酸酐中进行，然后还原得到的 14-硝基喜树碱（2），以良好的收率合成。14-氨基喜树碱（3a）和 7-乙基-14-氨基喜树碱（3b）在体外对人肿瘤细胞系表现出优异的细胞毒性，并且它们不是任何主要临床相关外排泵（MDR1、MRP1 和 BCRP）的底物。3a 和 3b 对人和小鼠骨髓祖细胞的细胞毒性相似。这与许多喜树碱类似物形成对比，这些类似物是外排泵的底物，相对于小鼠，对人骨髓细胞的毒性要大得多。3a 和 3b 在口服给予小鼠时表现出显著的脑穿透性。3b 在口服给予三种异位异种移植模型 H460、HT29 和 PC-3 时，与拓扑替康相比，表现出显著更好的疗效。基于其良好的体外和体内特征，3b 值得进一步开发。
