Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Bioorg Med Chem. 2010 Jul 15;18(14):4997-5006. doi: 10.1016/j.bmc.2010.06.001. Epub 2010 Jun 8.
Nitro seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-ones (nitroCBIs) are a new class of prodrugs for antitumor therapy that undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents. Although hindered by poor aqueous solubility, several examples have shown activity against hypoxic tumor cells in vivo. Here we investigate structural properties that influence hypoxic selectivity in vitro, and show that for high hypoxic selectivity nitroCBIs should combine an electron-withdrawing group of H-bond donor capacity on the A-ring, with a basic substituent on the minor groove-binding side chain. Substitution on the A-ring is compatible with the introduction of functionality that can improve water solubility.
硝酮-1,2,9,9a-四氢环丙[a]苯并[e]吲哚-4-酮（硝基 CBIs）是一类新型的抗肿瘤治疗前药，它们在缺氧条件下选择性代谢为有效的 DNA 小沟烷化剂。尽管受到较差的水溶性限制，但已有多个实例表明它们在体内对缺氧肿瘤细胞具有活性。在此，我们研究了影响体外缺氧选择性的结构特性，并表明对于高缺氧选择性，硝基 CBIs 应在 A 环上结合具有氢键供体能力的吸电子基团，同时在小沟结合侧链上带有碱性取代基。A 环上的取代与引入可提高水溶性的官能团是兼容的。
