Doxoform and daunoform: Anthracycline-formaldehyde conjugates toxic to resistant tumor cells
Doxoform and daunoform: Anthracycline-formaldehyde conjugates toxic to resistant tumor cells
复制标题
DOI：
10.1021/jm970237e
复制
发表时间：
1997-08-01
影响因子：
7.3
通讯作者：
Koch, TH
中科院分区：
文献类型：
--
作者：
Fenick, DJ;Taatjes, DJ;Koch, TH
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而烷基化DNA，这促使了含甲醛衍生物的合成。母体药物与甲醛水溶液在pH 6下反应，产生40-50%的偶联物，该偶联物由两个母体药物分子组成，作为恶唑烷衍生物，通过亚甲基在其3 ′-氮上结合在一起。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（Doxoform）和双（3'-N-（3 '-N，4'-O-亚甲基道诺红基））甲烷（Daunoform）。这两种衍生物在水解成母体药物方面都是不稳定的。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过程中的中间体。柔红霉素与自身互补脱氧寡核苷酸（GC）（4）的反应速度比柔红霉素和甲醛在同等浓度下的反应速度更快，从而产生药物-DNA加合物。尽管具有水解不稳定性，但Doxoform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。对耐药癌细胞的毒性被解释为衍生物的亲脂性更高，并避免了催化甲醛的产生。
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 give 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.