Gravatt G L, Baguley B C, Wilson W R, Denny W A
Department of Pathology, University of Auckland School of Medicine, New Zealand.
J Med Chem. 1991 May;34(5):1552-60. doi: 10.1021/jm00109a005.
A series of 4-anilinoquinoline-linked aniline mustards of widely varying mustard reactivity were prepared and evaluated for their antitumor activity. The compounds were designed as minor grove binding agents, where the aniline mustard ring is itself part of the DNA-binding ligand. While there was a general trend for cytotoxicity to correlate with mustard reactivity, this was much less pronounced than with untargeted mustards. The compounds were much more cytotoxic than the parent diols, and were also at least 10-fold more cytotoxic than the corresponding aniline mustards themselves. Comparative cell line studies suggested that the mechanism of cytotoxicity varied with mustard reactivity. The most reactive mustards cross-linked DNA, while cell killing by the less reactive compounds appeared to be by the formation of bulky monoadducts. The compounds were active but not particularly dose-potent against P388 leukemia in vivo. The modest potency may be related to their poor aqueous solubility, since the more soluble methyl quaternary salts were equally active at much lower doses.
制备了一系列具有广泛不同芥子反应性的4-苯胺基喹啉连接的苯胺氮芥，并评估了它们的抗肿瘤活性。这些化合物被设计为小沟结合剂，其中苯胺氮芥环本身是DNA结合配体的一部分。虽然细胞毒性与芥子反应性之间存在总体趋势相关，但这比与非靶向氮芥相比要弱得多。这些化合物比母体二醇的细胞毒性大得多，并且比相应的苯胺氮芥本身的细胞毒性至少高10倍。比较细胞系研究表明，细胞毒性机制随芥子反应性而变化。反应性最强的氮芥使DNA交联，而反应性较弱的化合物导致细胞死亡似乎是通过形成大分子单加合物。这些化合物具有活性，但在体内对P388白血病的剂量效力并不特别强。效力适中可能与其水溶性差有关，因为更易溶的甲基季铵盐在低得多的剂量下同样具有活性。
