Novel indolizino[8,7-b]indole hybrids as anti-small cell lung cancer agents: Regioselective modulation of topoisomerase II inhibitory and DNA crosslinking activities

摘要

A novel series of bis(hydroxymethyl)indolizino[8,7-b]indole hybrids composed of beta-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-11 (H or Me) plays a critical role in modulating Topo II inhibition and DNA cross-linking activities. N-11-Me derivatives predispose to induce DNA crosslinks, whereas N-11-H derivatives potently inhibit Topo II. Computational analysis implicates that N-11-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.