Post Glen C, Barthel Benjamin L, Burkhart David J, Hagadorn John R, Koch Tad H
Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309-0215, USA.
J Med Chem. 2005 Dec 1;48(24):7648-57. doi: 10.1021/jm050678v.
A crystal structure establishes doxoform as a dimeric formaldehyde conjugate of the oxazolidine of doxorubicin. Doxoform is a prodrug of doxazolidine, a monomeric doxorubicin formaldehyde-oxazolidine. Both doxoform and doxazolidine inhibit the growth of cancer cells at 1-4 orders of magnitude lower concentration than doxorubicin. They also inhibit the growth of cancer cells better than doxsaliform, a prodrug for an acyclic doxorubicin-formaldehyde conjugate. Doxoform rapidly hydrolyzes to doxazolidine, which then hydrolyzes to doxorubicin with a half-life of 3 min in human serum at 37 degrees C. Both doxoform and doxazolidine are taken up by multidrug-resistant MCF-7/Adr cells 3- to 4-fold better than doxorubicin. A molecular model suggests that doxazolidine can cross-link DNA by direct reaction with a G-base in a tautomeric form with synchronous ring opening of the oxazolidine. These results point to doxoform being a prodrug for doxazolidine that is the reactive species that directly cross-links DNA.
晶体结构确定多柔比星形式为多柔比星恶唑烷的二聚体甲醛共轭物。多柔比星形式是恶唑烷的前药，恶唑烷是一种单体多柔比星甲醛 - 恶唑烷。多柔比星形式和恶唑烷在比多柔比星低1至4个数量级的浓度下就能抑制癌细胞的生长。它们抑制癌细胞生长的效果也比阿霉素无环甲醛共轭物的前药阿霉素盐形式更好。多柔比星形式迅速水解为恶唑烷，然后在37℃的人血清中恶唑烷再水解为多柔比星，半衰期为3分钟。多柔比星形式和恶唑烷被多药耐药的MCF - 7/Adr细胞摄取的能力比多柔比星强3至4倍。分子模型表明，恶唑烷可以通过与互变异构形式的G碱基直接反应并使恶唑烷同步开环来交联DNA。这些结果表明多柔比星形式是恶唑烷的前药，而恶唑烷是直接交联DNA的活性物质。
