Taatjes D J, Fenick D J, Koch T H
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215, USA.
J Med Chem. 1998 Apr 9;41(8):1306-14. doi: 10.1021/jm970739s.
The recent discovery that the formaldehyde conjugates of doxorubicin and daunorubicin, Doxoform and Daunoform, are cytotoxic to resistant human breast cancer cells prompted the search for hydrolytically more stable anthracycline-formaldehyde conjugates. Doxoform and Daunoform consist of two molecules of the parent drug bound together with three methylene groups, two forming oxazolidine rings and one binding the oxazolidines together at their 3'-amino nitrogens. The 4'-epimer of doxorubicin, epidoxorubicin, reacts with formaldehyde at its amino alcohol functionality to produce a conjugate, Epidoxoform, in 59% yield whose structure consists of two molecules of epidoxorubicin bound together with three methylene groups in a 1, 6-diaza-4,9-dioxabicyclo[4.4.1]undecane ring system. The structure was established from spectroscopic data and is consistent with products from reaction of simpler vicinal trans-amino alcohols with formaldehyde. Epidoxoform hydrolyzes at pH 7.3 to an equilibrium mixture with dimeric and monomeric epidoxorubicin-formaldehyde conjugates without release of formaldehyde or epidoxorubicin. The hydrolysis follows the rate law (A if B) if C + D where A (Epidoxoform) is in rapid equilibrium with B, and B is in slow equilibrium with C and D. The forward rate constant for A/B going to C+D gives a half-life of approximately 2 h at 37 degrees C. At equilibrium the mixture is stable for at least 2 days. At pH 6.0, hydrolysis proceeds with first-order kinetics to epidoxorubicin and formaldehyde with a half-life of 15 min at 37 degrees C. Epidoxoform and epidoxorubicin plus formaldehyde react with the self-complementary DNA octamer (GC)4 to yield five drug-DNA adducts which have structures analogous to the doxorubicin-DNA adducts from reaction of Doxoform with (GC)4. Epidoxoform is 3-fold more toxic to MCF-7 human breast cancer cells and greater than 120-fold more toxic to MCF-7/ADR resistant cells than epidoxorubicin. Epidoxoform in equilibrium with its hydrolysis products is greater than 25-fold more toxic to resistant cells with respect to epidoxorubicin.
最近发现阿霉素和柔红霉素的甲醛共轭物多柔比星甲醛（Doxoform）和柔红霉素甲醛（Daunoform）对耐药性人乳腺癌细胞具有细胞毒性，这促使人们寻找水解稳定性更高的蒽环类-甲醛共轭物。多柔比星甲醛和柔红霉素甲醛由两分子母体药物通过三个亚甲基连接在一起组成，其中两个亚甲基形成恶唑烷环，另一个在其3'-氨基氮处将恶唑烷连接在一起。阿霉素的4'-差向异构体表柔比星在其氨基醇官能团处与甲醛反应，以59%的产率生成一种共轭物表柔比星甲醛（Epidoxoform），其结构由两分子表柔比星通过三个亚甲基在1,6-二氮杂-4,9-二氧杂双环[4.4.1]十一烷环系统中连接在一起组成。该结构由光谱数据确定，与更简单的邻位反式氨基醇与甲醛反应的产物一致。表柔比星甲醛在pH 7.3时水解为与二聚体和单体表柔比星-甲醛共轭物的平衡混合物，不会释放甲醛或表柔比星。水解遵循速率定律（A若B）则C + D，其中A（表柔比星甲醛）与B快速平衡，B与C和D缓慢平衡。A/B转化为C + D的正向速率常数在37℃时给出的半衰期约为2小时。在平衡时，混合物至少稳定2天。在pH 6.0时，水解以一级动力学进行生成表柔比星和甲醛，在37℃时半衰期为15分钟。表柔比星甲醛和表柔比星加甲醛与自互补DNA八聚体（GC）4反应生成五种药物-DNA加合物，其结构类似于多柔比星甲醛与（GC）4反应生成的阿霉素-DNA加合物。表柔比星甲醛对MCF-7人乳腺癌细胞的毒性是表柔比星的3倍，对MCF-7/ADR耐药细胞的毒性比对表柔比星大120倍以上。与水解产物处于平衡状态的表柔比星甲醛相对于表柔比星对耐药细胞的毒性大25倍以上。
