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 N¹¹ (H or Me) plays a critical role in modulating Topo II inhibition and DNA cross-linking activities. N¹¹-Me derivatives predispose to induce DNA crosslinks, whereas N¹¹-H derivatives potently inhibit Topo II. Computational analysis implicates that N¹¹-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 N¹¹-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）组成的双（羟甲基）吲哚并[8,7- b ]吲哚杂合物，用于抗肿瘤评估。在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敏感。这些杂种诱导细胞周期停滞在G2 / M期，触发肿瘤细胞凋亡死亡，并显示涉及拓扑异构酶II（Topo II）抑制和诱导DNA交联的多种作用机制。有趣的是，N ¹¹的取代基（H或Me）在调节Topo II抑制和DNA交联活性中起关键作用。N ¹¹ -Me衍生物倾向于诱导DNA交联，而N¹¹ -H衍生物有效抑制Topo II。计算分析表明，N ¹¹ -Me限制了吡咯上两个相邻OH的扭转角，从而有利于DNA交联。在这些杂种中，具有N ¹¹ -H的化合物17a比顺铂和依托泊苷对异种移植模型中的SCLC H526细胞的生长更有效，但与伊立替康一样有效。