Heterocyclic ring expansion yields anthraquinone derivatives potent against multidrug resistant tumor cells

• Published in: Bioorganic chemistry 2022-10, Vol.127, p.105925-105925, Article 105925
• Main Authors: Tikhomirov, Alexander S., Tsvetkov, Vladimir B., Volodina, Yulia L., Litvinova, Valeria A., Andreeva, Daria V., Dezhenkova, Lyubov G., Kaluzhny, Dmitry N., Treshalin, Ivan D., Shtil, Alexander A., Shchekotikhin, Andrey E.
• Format: Article
• Language: English
• Subjects: Anthraquinone; Antitumor drug design; Heterocycles; Multidrug resistance; P-glycoprotein; Topoisomerase 1
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105925

[Display omitted] •Anthraquinone derivatives annelated with six-membered heterocycles were synthesized.•Naphthoquinoline-3-carboxamide 17 potently kills Pgp-positive K562/4 leukemia cells.•Compound 17 circumvents Pgp efflux.•Heterocyclic ring expansion is efficacious against MDR tumor cells. Chemical modifications of anthraquiones are aimed at novel derivatives with improved antitumor properties. Emergence of multidrug resistance (MDR) due to overexpression of transmembrane ATP binding cassette transporters, in particular, MDR1/P-glycoprotein (Pgp), can limit the use of anthraquinone based drugs. Previously we have demonstrated that annelation of modified five-membered heterocyclic rings with the anthraquinone core yielded a series of compounds with optimized antitumor properties. In the present study we synthesized a series of anthraquinone derivatives with six-membered heterocycles. Selected new compounds showed the ability to kill parental and MDR tumor cell lines at low micromolar concentrations. Molecular docking into the human Pgp model revealed a stronger interaction of 2-methylnaphtho[2,3-g]quinoline-3-carboxamide 17 compared to naphtho[2,3-f]indole-3-carboxamide 3. The time course of intracellular accumulation of compound 17 in parental K562 leukemia cells and in Pgp-positive K562/4 subline was similar. In contrast, compound 3 was readily effluxed from K562/4 cells and was significantly less potent for this subline than for K562 cells. Together with reported strategies of drug optimization of the anthracycline core, these results add ring expansion to the list of perspective modifications of heteroarene-fused anthraquinones.