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Keywords = indenoisoquinoline

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35 pages, 7587 KB  
Article
Design, Synthesis and Bioactive Evaluation of Topo I/c-MYC Dual Inhibitors to Inhibit Oral Cancer via Regulating the PI3K/AKT/NF-κB Signaling Pathway
by Bin Zheng, Yi-Xiao Wang, Zi-Yan Wu, Xin-Wei Li, Li-Qing Qin, Nan-Ying Chen, Gui-Fa Su, Jun-Cheng Su and Cheng-Xue Pan
Molecules 2025, 30(4), 894; https://doi.org/10.3390/molecules30040894 - 14 Feb 2025
Cited by 4 | Viewed by 1638
Abstract
The significantly rising incidence of oral cancer worldwide urgently requires the identification of novel, effective molecular targets to inhibit the progression of malignancy. DNA topoisomerase I (Topo I) is a well-established target for cancer treatment, and many studies have shown that different cancer [...] Read more.
The significantly rising incidence of oral cancer worldwide urgently requires the identification of novel, effective molecular targets to inhibit the progression of malignancy. DNA topoisomerase I (Topo I) is a well-established target for cancer treatment, and many studies have shown that different cancer cell genes could be targeted more selectively with one type of Topo I inhibitor. In this report, a new scaffold pyridothieno[3,2-c]isoquinoline 11,11-dioxide was designed via the combination of the key fragment or bioisoster of Topo I inhibitor azaindenoisoquinolines and G-quadruplex binder quindoline. Thirty-two target derivatives were synthesized, among which compounds 7be, with potent Topo I inhibition, exhibited effective antiproliferative activity against Cal27, one of the oral cancer cell lines highly expressing Topo I protein. Further studies indicated that 7be could also inhibit the activation of PI3K/AKT/NF-κB pathway and downregulate the level of c-MYC, repress the colony formation and the migration of Cal27 cells and trigger apoptosis and autophagy. Molecular docking indicated that 7be could interact with the complex of Topo I and DNA via a mode similar to the indenoisoquinolines. The results of the Cal27 xenograft model confirmed that 7be exhibited promising anticancer efficacy in vivo, with tumor growth inhibition (TGI) of 64.7% at 20 mg/kg. Full article
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17 pages, 4627 KB  
Article
Synthesis and Biological Activity of a New Indenoisoquinoline Copper Derivative as a Topoisomerase I Inhibitor
by Caroline Molinaro, Nathalie Wambang, Sylvain Pellegrini, Natacha Henry, Marc F. Lensink, Emmanuelle Germain, Till Bousquet, Jérôme de Ruyck, Katia Cailliau, Lydie Pélinski and Alain Martoriati
Int. J. Mol. Sci. 2023, 24(19), 14590; https://doi.org/10.3390/ijms241914590 - 26 Sep 2023
Cited by 6 | Viewed by 2814
Abstract
Topoisomerases are interesting targets in cancer chemotherapy. Here, we describe the design and synthesis of a novel copper(II) indenoisoquinoline complex, WN198. The new organometallic compound exhibits a cytotoxic effect on five adenocarcinoma cell lines (MCF-7, MDA-MB-231, HeLa, HT-29, and DU-145) with the [...] Read more.
Topoisomerases are interesting targets in cancer chemotherapy. Here, we describe the design and synthesis of a novel copper(II) indenoisoquinoline complex, WN198. The new organometallic compound exhibits a cytotoxic effect on five adenocarcinoma cell lines (MCF-7, MDA-MB-231, HeLa, HT-29, and DU-145) with the lowest IC50 (0.37 ± 0.04 μM) for the triple-negative MDA-MB-231 breast cancer cell line. Below 5 µM, WN198 was ineffective on non-tumorigenic epithelial breast MCF-10A cells and Xenopus oocyte G2/M transition or embryonic development. Moreover, cancer cell lines showed autophagy markers including Beclin-1 accumulation and LC3-II formation. The DNA interaction of this new compound was evaluated and the dose-dependent topoisomerase I activity starting at 1 μM was confirmed using in vitro tests and has intercalation properties into DNA shown by melting curves and fluorescence measurements. Molecular modeling showed that the main interaction occurs with the aromatic ring but copper stabilizes the molecule before binding and so can putatively increase the potency as well. In this way, copper-derived indenoisoquinoline topoisomerase I inhibitor WN198 is a promising antitumorigenic agent for the development of future DNA-damaging treatments. Full article
(This article belongs to the Special Issue Emerging Topics in Metal Complexes: Pharmacological Activity)
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17 pages, 648 KB  
Article
Quantitative Structure-Activity Relationship Studies on Indenoisoquinoline Topoisomerase I Inhibitors as Anticancer Agents in Human Renal Cell Carcinoma Cell Line SN12C
by Yi Zhi, Jin Yang, Shengchao Tian, Fang Yuan, Yang Liu, Yi Zhang, Pinghua Sun, Bo Song and Zhiwen Chen
Int. J. Mol. Sci. 2012, 13(5), 6009-6025; https://doi.org/10.3390/ijms13056009 - 18 May 2012
Cited by 8 | Viewed by 6912
Abstract
Topoisomerase I is important for DNA replication and cell division, making it an attractive drug target for anticancer therapy. A series of indenoisoquinolines displaying potent Top1 inhibitory activity in human renal cell carcinoma cell line SN12C were selected to establish 3D-QSAR models using [...] Read more.
Topoisomerase I is important for DNA replication and cell division, making it an attractive drug target for anticancer therapy. A series of indenoisoquinolines displaying potent Top1 inhibitory activity in human renal cell carcinoma cell line SN12C were selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were investigated, as well as some measures taken, including region focusing, bootstrapping and the “leave-group-out” cross-validation method. The satisfactory CoMFA model predicted a q2 value of 0.659 and an r2 value of 0.949, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, electrostatic and H-bond acceptor descriptors, predicted a q2 value of 0.523 and an r2 value of 0.902. The models were graphically interpreted by contour plots which provided insight into the structural requirements for increasing the activity of a compound, providing a solid basis for future rational design of more active anticancer agents. Full article
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