Anthraquinones and their analogues, in particular heteroarene-fused anthracendiones, are prospective scaffolds for new compounds with improved antitumor characteristics. We herein report the use of a ‘scaffold hopping’ approach for the replacement of the core structure in the previously discovered hit compound naphtho[2,3-f]indole-5,10-dione 2 with an alternative anthra[2,3-b]furan-5,10-dione scaffold. Among 13 newly synthesized derivatives the majority of 4,11-dihydroxy-2-methyl-5,10-dioxoanthra[2,3-b]furan-3-carboxamides demonstrated a high antiproliferative potency against a panel of wild type and drug resistant tumor cell lines, a property superior over the reference drug doxorubicin or lead naphtho[2,3-f]indole-5,10-dione 2. At low micromolar concentrations the selected derivative of (R)-3-aminopyrrolidine 3c and its stereoisomer (S)-3-aminopyrrolidine 3d caused an apoptotic cell death preceded by an arrest in the G2/M phase. Studies of intracellular targets showed that 3c and 3d formed stable intercalative complexes with the duplex DNA as determined by spectral analysis and molecular docking. Both 3c and 3d attenuated topoisomerase 1 and 2 mediated unwinding of the supercoiled DNA via a mechanism different from conventional DNA-enzyme tertiary complex formation. Furthermore, 3d decreased the activity of selected human protein kinases in vitro, indicating multiple targeting by the new chemotype. Finally, 3d demonstrated an antitumor activity in a model of murine intraperitoneally transplanted P388 leukemia, achieving the increase of animal life span up to 262% at tolerable doses. Altogether, the ‘scaffold hopping’ demonstrated its productivity for obtaining new perspective antitumor drug candidates.

蒽醌及其类似物，特别是杂亚芳基融合的蒽二酮，是具有改善的抗肿瘤特性的新化合物的预期支架。我们在此报告“脚手架跳跃”方法用于替换以前发现的命中化合物萘[2,3 - f ]吲哚-5,10-二酮2和另一种蒽[2,3- ]的核心结构的替换。b ]呋喃-5，10-二酮支架。在13种新合成的衍生物中，大多数4,11-二羟基-2-甲基-5,10-二氧杂蒽[2,3 - b ]呋喃-3-羧酰胺对一组野生型和耐药性肿瘤表现出很高的抗增殖能力细胞系，其性质优于参考药物阿霉素或萘并铅[2,3- f] indole-5,10-dione 2。在低微摩尔浓度下，（R）-3-氨基吡咯烷3c及其立体异构体（S）-3-氨基吡咯烷3d的选定衍生物引起凋亡细胞死亡，随后被阻滞在G2 / M期。细胞内靶标的研究表明3c和3d与双链DNA形成了稳定的嵌入复合物，这是通过光谱分析和分子对接确定的。3c和3d都通过不同于常规DNA-酶三级复合物形成的机制减弱了拓扑异构酶1和2介导的超螺旋DNA的展开。此外，3d降低了所选人类蛋白激酶的体外活性，表明该新化学型可进行多种靶向。最后，3d在小鼠腹膜内移植的P388白血病模型中显示了抗肿瘤活性，在可耐受剂量下，动物寿命延长了262％。总之，“支架跳跃”展示了其获得新的抗肿瘤候选药物的生产力。