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首页> 外文期刊>Journal of Medicinal Chemistry >Epidoxoform: a hydrolytically more stable anthracycline-formaldehyde conjugate toxic to resistant tumor cells.
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Epidoxoform: a hydrolytically more stable anthracycline-formaldehyde conjugate toxic to resistant tumor cells.

机译：Epidoxoform：对抵抗性肿瘤细胞有毒的水解稳定性更强的蒽环甲醛-甲醛结合物。

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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.
机译：最近发现阿霉素和柔红霉素的甲醛结合物，阿霉素和Daunoform对耐药性人乳腺癌细胞具有细胞毒性，这促使人们寻求水解更稳定的蒽环甲醛-甲醛结合物。 Doxoform和Daunoform由与三个亚甲基结合在一起的母体药物的两个分子组成，两个分子形成恶唑烷环，一个在其3'-氨基氮原子上将恶唑烷结合在一起。阿霉素的4'-表位表柔比星在氨基醇官能团上与甲醛反应，以59％的收率生成缀合物表位氧仿，其结构由1，6-二氮杂的两个表柔比星分子和三个亚甲基结合而成-4，9-二氧杂双环[4.4.1]十一烷环系。该结构是由光谱数据确定的，与简单的邻位反式氨基醇与甲醛反应生成的产物一致。环氧表甲酸酯在pH 7.3下水解成具有二聚和单体环氧乙烷-甲醛共轭物的平衡混合物，而不会释放甲醛或环氧乙烷。如果C + D，则水解遵循速率定律（如果为B，则为A），其中A（Epidoxoform）与B处于快速平衡，而B与C和D处于缓慢平衡。A / B的前向速率常数变为C + D在37℃下给出约2小时的半衰期。在平衡下，混合物稳定至少2天。在pH 6.0时，水解以一级动力学进行，在37摄氏度下半衰期为表阿霉素和甲醛。表环氧，仿表霉素和甲醛与自互补DNA八聚体（GC）4反应生成五种药物，具有类似于阿霉素与（GC）4反应的阿霉素-DNA加合物的结构的DNA加合物。依必妥索对MCF-7人乳腺癌细胞的毒性比依多柔比星高3倍，对MCF-7 / ADR耐药细胞的毒性高120倍以上。相对于表柔比霉素而言，与它的水解产物平衡的表柔和剂对耐药细胞的毒性大25倍以上。

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