Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
J Med Chem. 2013 May 23;56(10):4104-15. doi: 10.1021/jm400413r. Epub 2013 May 10.
Two novel cyclic N-acyl O-amino phenol prodrugs are reported as new members of a unique class of reductively cleaved prodrugs of the duocarmycin family of natural products. These prodrugs were explored with the expectation that they may be cleaved selectively within hypoxic tumor environments that have intrinsically higher concentrations of reducing nucleophiles and were designed to liberate the free drug without the release of an extraneous group. In vivo evaluation of the prodrug 6 showed that it exhibits extraordinary efficacy (T/C > 1500, L1210; 6/10 one year survivors), substantially exceeding that of the free drug, that its therapeutic window of activity is much larger, permitting a dosing ≥ 40-fold higher than the free drug, and yet that it displays a potency in vivo that approaches the free drug (within 3-fold). Clearly, the prodrug 6 benefits from either its controlled slow release of the free drug or its preferential intracellular reductive cleavage.
报告了两种新型的环状 N-酰基 O-氨基苯酚前药，它们是天然产物 duocarmycin 家族中还原性切割前药的一类新成员。这些前药的探索预期是它们可能在具有内在更高浓度还原亲核试剂的缺氧肿瘤环境中选择性地被切割，并设计为在不释放外来基团的情况下释放游离药物。体内评估前药 6 表明，它表现出非凡的疗效（T/C > 1500，L1210；6/10 一年幸存者），大大超过游离药物的疗效，其活性治疗窗口大得多，允许剂量比游离药物高 40 倍以上，而且其在体内的效力接近游离药物（相差 3 倍以内）。显然，前药 6 受益于其游离药物的受控缓慢释放或其优先的细胞内还原切割。
