Fenick D J, Taatjes D J, Koch T H
Department of Chemistry and Biochemistry, University of Colorado, Boulder 80309-0215, USA.
J Med Chem. 1997 Aug 1;40(16):2452-61. doi: 10.1021/jm970237e.
The recent discovery that the clinically important antitumor drugs doxorubicin and daunorubicin alkylate DNA via catalytic production of formaldehyde prompted the synthesis of derivatives bearing formaldehyde. Reaction of the parent drugs with aqueous formaldehyde at pH 6 produced in 40-50% yield conjugates consisting of two molecules of the parent drug as oxazolidine derivatives bound together at their 3'-nitrogens by a methylene group. The structures were established as bis(3'-N-(3'-N,4'-O-methylenedoxorubicinyl)) methane (Doxoform) and bis(3'-N-(3'-N,4'-O-methylenedaunorubicinyl))methane (Daunoform) from spectroscopic data. Both derivatives are labile with respect to hydrolysis to the parent drugs. 3'-N,4'-O-Methylenedoxorubicin and 3'-N,4'-O-methylenedaunorubicin are intermediates in the hydrolysis. Daunoform reacts with the self-complementary deoxyoligonucleotide (GC)4 faster than the combination of daunorubicin and formaldehyde at an equivalent concentration to given drug-DNA adducts. In spite of hydrolytic instability, Doxoform is 150-fold more toxic to MCF-7 human breast cancer cells and 10000-fold more toxic to MCF-7/ADR resistant cells. Toxicity to resistant cancer cells is interpreted in terms of higher lipophilicity of the derivatives and circumvention of catalytic formaldehyde production.
最近发现临床上重要的抗肿瘤药物阿霉素和柔红霉素通过催化产生甲醛使DNA烷基化，这促使了含甲醛衍生物的合成。在pH 6条件下，母体药物与甲醛水溶液反应，以40 - 50%的产率生成共轭物，该共轭物由两分子母体药物作为恶唑烷衍生物组成，它们在3'-氮原子处通过亚甲基连接在一起。根据光谱数据确定其结构为双(3'-N-(3'-N,4'-O-亚甲基阿霉素基))甲烷（多柔比星甲醛）和双(3'-N-(3'-N,4'-O-亚甲基柔红霉素基))甲烷（柔红霉素甲醛）。两种衍生物对水解为母体药物都不稳定。3'-N,4'-O-亚甲基阿霉素和3'-N,4'-O-亚甲基柔红霉素是水解的中间体。柔红霉素甲醛与自互补脱氧寡核苷酸(GC)4反应的速度比相同浓度下柔红霉素和甲醛组合生成药物-DNA加合物的速度快。尽管存在水解不稳定性，多柔比星甲醛对MCF-7人乳腺癌细胞的毒性高150倍，对MCF-7/ADR耐药细胞的毒性高10000倍。对耐药癌细胞毒性的解释是衍生物具有更高的亲脂性以及避免了催化甲醛的产生。
