Department of Biochemistry, La Trobe University, Victoria 3086, Australia.
J Med Chem. 2010 Oct 14;53(19):6851-66. doi: 10.1021/jm901894c.
Mitoxantrone is an anticancer agent that acts as a topoisomerase II poison, however, it can also be activated by formaldehyde to form DNA adducts. Pixantrone, a 2-aza-anthracenedione with terminal primary amino groups in its side chains, forms formaldehyde-mediated adducts with DNA more efficiently than mitoxantrone. Molecular modeling studies indicated that extension of the "linker" region of anthracenedione side arms would allow the terminal primary amino greater flexibility and thus access to the guanine residues on the opposite DNA strand. New derivatives based on the pixantrone and mitoxantrone backbones were synthesized, and these incorporated primary amino groups as well as extended side chains. The stability of DNA adducts increased with increasing side chain length of the derivatives. A mitoxantrone derivative bearing extended side chains (7) formed the most stable adducts with ∼100-fold enhanced stability compared to mitoxantrone. This finding is of great interest because long-lived drug-DNA adducts are expected to perturb DNA-dependent functions at all stages of the cell cycle.
米托蒽醌是一种抗癌药物，作为拓扑异构酶 II 抑制剂，但其也可以被甲醛激活，形成 DNA 加合物。比米托蒽醌更有效地与 DNA 形成甲醛介导的加合物。分子建模研究表明，延长蒽二酮侧臂的“连接”区域将使末端伯氨基具有更大的灵活性，从而可以进入相反 DNA 链上的鸟嘌呤残基。基于 pixantrone 和米托蒽醌骨架的新衍生物被合成，这些衍生物含有伯氨基和延伸的侧链。DNA 加合物的稳定性随衍生物侧链长度的增加而增加。具有延伸侧链的米托蒽醌衍生物（7）与米托蒽醌相比，形成最稳定的加合物，稳定性提高了约 100 倍。这一发现非常有趣，因为预期长寿命的药物-DNA 加合物会在细胞周期的所有阶段扰乱 DNA 依赖性功能。
