title: Novel indolizino[8,7-b]indole hybrids as anti-small cell lung cancer agents: Regioselective modulation of topoisomerase II inhibitory and DNA crosslinking activities.
abstract: 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.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Sue-Ming
authors.initials: SM
authors.lastname: Chang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Department of Chemistry, Saurashtra University, Rajkot, Gujarat, India.
authors.forename: Wilson
authors.initials: W
authors.lastname: Christian
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Ming-Hsi
authors.initials: MH
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tai-Lin
authors.initials: TL
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Ching-Shu
authors.initials: CS
authors.lastname: Suen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Hima Bindu
authors.initials: HB
authors.lastname: Pidugu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Department of Chemistry, Saurashtra University, Rajkot, Gujarat, India.
authors.forename: Dilip
authors.initials: D
authors.lastname: Detroja
authors.affiliation: Department of Chemistry, Saurashtra University, Rajkot, Gujarat, India.
authors.forename: Anamik
authors.initials: A
authors.lastname: Shah
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Ming-Jing
authors.initials: MJ
authors.lastname: Hwang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan. Electronic address: tlsu@ibms.sinica.edu.tw.
authors.forename: Tsann-Long
authors.initials: TL
authors.lastname: Su
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan. Electronic address: bmtcl@ibms.sinica.edu.tw.
authors.forename: Te-Chang
authors.initials: TC
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D055752:Small Cell Lung Carcinoma / Q000473:pathology*; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA; D004250:DNA Topoisomerases, Type II
keywords: Anti-SCLC hybrids; DNA cross-linking; Topoisomerase inhibition; bis(hydroxymethyl)pyrrole; indolizino[8,7-b]indole; β-carboline