Chang Sue-Ming, Christian Wilson, Wu Ming-Hsi, Chen Tai-Lin, Lin Yi-Wen, Suen Ching-Shu, Pidugu Hima Bindu, Detroja Dilip, Shah Anamik, Hwang Ming-Jing, Su Tsann-Long, Lee Te-Chang
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Department of Chemistry, Saurashtra University, Rajkot, Gujarat, India.
Eur J Med Chem. 2017 Feb 15;127:235-249. doi: 10.1016/j.ejmech.2016.12.046. Epub 2016 Dec 24.
A novel series of bis(hydroxymethyl)indolizino[8,7-b]indole hybrids composed of β-carboline (topoisomerase I/II inhibition) and bis(hydroxymethyl)pyrrole (DNA cross-linking) are synthesized for antitumor evaluation. Of tumor cell lines tested, small cell lung cancer (SCLC) cell lines are the most sensitive to the newly synthesized compounds. These hybrids induce cell cycle arrest at the G2/M phase, trigger tumor cell apoptotic death, and display diverse mechanisms of action involving topoisomerase II (Topo II) inhibition and induction of DNA cross-linking. Intriguingly, the substituent at N (H or Me) plays a critical role in modulating Topo II inhibition and DNA cross-linking activities. N-Me derivatives predispose to induce DNA crosslinks, whereas N-H derivatives potently inhibit Topo II. Computational analysis implicates that N-Me restrict the torsion angles of the two adjacent OH on pyrrole resulting in a favorable of DNA cross-linking. Among these hybrids, compound 17a with N-H is more effective than cisplatin and etoposide, but as potent as irinotecan, against the growth of SCLC H526 cells in xenograft model.
合成了一系列由β-咔啉（拓扑异构酶I/II抑制）和双（羟甲基）吡咯（DNA交联）组成的新型双（羟甲基）中氮茚并[8,7-b]吲哚杂化物，用于抗肿瘤评估。在所测试的肿瘤细胞系中，小细胞肺癌（SCLC）细胞系对新合成的化合物最为敏感。这些杂化物诱导细胞周期阻滞在G2/M期，触发肿瘤细胞凋亡死亡，并表现出多种作用机制，包括拓扑异构酶II（Topo II）抑制和DNA交联诱导。有趣的是，N（H或Me）上的取代基在调节Topo II抑制和DNA交联活性方面起着关键作用。N-Me衍生物倾向于诱导DNA交联，而N-H衍生物则强烈抑制Topo II。计算分析表明，N-Me限制了吡咯上两个相邻OH的扭转角，从而有利于DNA交联。在这些杂化物中，具有N-H的化合物17a在异种移植模型中对SCLC H526细胞的生长比顺铂和依托泊苷更有效，但与伊立替康一样有效。
