Discovery of 4-alkoxy-2-aryl-6,7-dimethoxyquinolines as a new class of topoisomerase I inhibitors endowed with potent in vitro anticancer activity

• Published in: European journal of medicinal chemistry 2021-04, Vol.215, p.113261-113261, Article 113261
• Main Authors: Elbadawi, Mostafa M., Eldehna, Wagdy M., Wang, Wenjie, Agama, Keli K., Pommier, Yves, Abe, Manabu
• Format: Article
• Language: English
• Subjects: Anticancer; Quinoline; Regioselectivity; Synthesis; Topoisomerase I
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113261

In our attempt to develop potential anticancer agents targeting Topoisomerase I (TOP1), two novel series of 4-alkoxy-2-arylquinolines 14a-p and 19a-c were designed and synthesized based on structure activity relationships of the reported TOP1 inhibitors and structural features required for stabilization of TOP1-DNA cleavage complexes (TOP1ccs). The in vitro anticancer activity of these two series of compounds was evaluated at one dose level using NCI-60 cancer cell lines panel. Compounds 14e-h and 14m-p, with p-substituted phenyl at C2 and propyl linker at C4, were the most potent and were selected for assay at five doses level in which they exhibited potent anticancer activity at sub-micromolar level against diverse cancer cell lines. Compound 14m was the most potent with full panel GI50 MG-MID 1.26 μM and the most sensitive cancers were colon cancer, leukemia and melanoma with GI50 MG-MID 0.875, 0.904 and 0.926 μM, respectively. Melanoma (LOX IMVI) was the most sensitive cell line to all tested compounds displaying GI50 from 0.116 to 0.227 μM, TGI from 0.275 to 0.592 μM and LC50 at sub-micromolar concentration against almost of the tested compounds. Compounds 14e-h and 14m-p were assayed using TOP1-mediated DNA cleavage assay to evaluate their ability to stabilize TOP1ccs resulting in cancer cell death. The morpholino analogs 14h and 14p exhibited moderate TOP1 inhibitory activity compared to 1 μM camptothecin suggesting their use as lead compounds that can be optimized for the development of more potent anticancer agents with potential TOP1 inhibitory activity. Finally, Swiss ADME online web tool predicted that compounds 14h and 14p possessed good oral bioavailability and druglikeness characteristics. [Display omitted] •4-Alkoxy-2-arylquinolines (14a-p and 19a-c) were synthesized as Topoisomerase I inhibitors.•Most the synthesized 2-arylquinolines exhibited promising anticancer activity.•Morpholino derivatives 14h and 14p stabilized Topoisomerase I cleavage complexes.•14h and 14p were predicted to possess good oral bioavailability and druglikeness characteristics.