Tercel Moana, Stribbling Stephen M, Sheppard Hilary, Siim Bronwyn G, Wu Kent, Pullen Susan M, Botting K Jane, Wilson William R, Denny William A
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
J Med Chem. 2003 May 22;46(11):2132-51. doi: 10.1021/jm020526p.
A set of 10 compounds, each combining the seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (seco-CBI) and pyrrolo[2,1-c][1,4]benzodiazepine (PBD) pharmacophores, was designed and prepared. These compounds were anticipated to cross-link between N3 of adenine and N2 of guanine in the minor groove of DNA. The compounds, which differ in the chain length separating the two alkylation subunits, and the configuration of the CBI portion, showed great variation in cellular toxicity (over 4 orders of magnitude in a cell line panel) with the most potent example exhibiting IC50s in the pM range. Cytotoxicity correlated with the ability of the compounds to cross-link naked DNA. Cross-linking was also observed in living cells, at much lower concentrations than for a related symmetrical PBD dimer. A thermal cleavage assay was used to assess sequence selectivity, demonstrating that the CBI portion controlled the alkylation sites, while the PBD substituent increased the overall efficiency of alkylation. Several compounds were tested for in vivo activity using a tumor growth delay assay against WiDr human colon carcinoma xenografts, with one compound (the most cytotoxic and most efficient cross-linker) showing a statistically significant increase in survival time following a single iv dose.
设计并制备了一组10种化合物，每种化合物都结合了开环-1,2,9,9a-四氢环丙并[c]苯并[e]吲哚-4-酮（seco-CBI）和吡咯并[2,1-c][1,4]苯并二氮杂卓（PBD）药效基团。预计这些化合物会在DNA小沟中腺嘌呤的N3和鸟嘌呤的N2之间发生交联。这些化合物在分隔两个烷基化亚基的链长以及CBI部分的构型上存在差异，在细胞毒性方面表现出极大的差异（在一组细胞系中超过4个数量级），其中最有效的例子IC50值在pM范围内。细胞毒性与化合物交联裸DNA的能力相关。在活细胞中也观察到了交联现象，其浓度远低于相关的对称PBD二聚体。使用热裂解试验评估序列选择性，结果表明CBI部分控制烷基化位点，而PBD取代基提高了烷基化的整体效率。使用针对WiDr人结肠癌异种移植瘤的肿瘤生长延迟试验对几种化合物进行了体内活性测试，其中一种化合物（细胞毒性最大且交联效率最高）在单次静脉注射后显示出生存时间有统计学意义的增加。
