Discovery of antitumor anthra[2,3-b]furan-3-carboxamides: Optimization of synthesis and evaluation of antitumor properties

• Published in: European journal of medicinal chemistry 2016-04, Vol.112, p.114-129
• Main Authors: Shchekotikhin, Andrey E., Dezhenkova, Lyubov G., Tsvetkov, Vladimir B., Luzikov, Yuri N., Volodina, Yulia L., Tatarskiy, Victor V., Kalinina, Anastasia A., Treshalin, Michael I., Treshalina, Helen M., Romanenko, Vladimir I., Kaluzhny, Dmitry N., Kubbutat, Michael, Schols, Dominique, Pommier, Yves, Shtil, Alexander A., Preobrazhenskaya, Maria N.
• Format: Article
• Language: English
• Subjects: Animals; Anthra[2,3-b]furan-3-carboxamides; Anthracenes - chemistry; Anthracenes - pharmacology; Anthracenes - therapeutic use; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Cell Line, Tumor; Circumvention of multidrug resistance; Cytotoxicity; DNA ligands; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Furans - chemistry; Furans - pharmacology; Furans - therapeutic use; Humans; Leukemia - drug therapy; Leukemia - metabolism; Mice; Neoplasms - drug therapy; Neoplasms - metabolism; Protein kinase inhibitors; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Structure-Activity Relationship; Topoisomerase inhibitors; Topoisomerase Inhibitors - chemistry; Topoisomerase Inhibitors - pharmacology; Topoisomerase Inhibitors - therapeutic use
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.01.050

Anthraquinones and their analogues, in particular heteroarene-fused anthracendiones, are prospective scaffolds for new compounds with improved antitumor characteristics. We herein report the use of a ‘scaffold hopping’ approach for the replacement of the core structure in the previously discovered hit compound naphtho[2,3-f]indole-5,10-dione 2 with an alternative anthra[2,3-b]furan-5,10-dione scaffold. Among 13 newly synthesized derivatives the majority of 4,11-dihydroxy-2-methyl-5,10-dioxoanthra[2,3-b]furan-3-carboxamides demonstrated a high antiproliferative potency against a panel of wild type and drug resistant tumor cell lines, a property superior over the reference drug doxorubicin or lead naphtho[2,3-f]indole-5,10-dione 2. At low micromolar concentrations the selected derivative of (R)-3-aminopyrrolidine 3c and its stereoisomer (S)-3-aminopyrrolidine 3d caused an apoptotic cell death preceded by an arrest in the G2/M phase. Studies of intracellular targets showed that 3c and 3d formed stable intercalative complexes with the duplex DNA as determined by spectral analysis and molecular docking. Both 3c and 3d attenuated topoisomerase 1 and 2 mediated unwinding of the supercoiled DNA via a mechanism different from conventional DNA-enzyme tertiary complex formation. Furthermore, 3d decreased the activity of selected human protein kinases in vitro, indicating multiple targeting by the new chemotype. Finally, 3d demonstrated an antitumor activity in a model of murine intraperitoneally transplanted P388 leukemia, achieving the increase of animal life span up to 262% at tolerable doses. Altogether, the ‘scaffold hopping’ demonstrated its productivity for obtaining new perspective antitumor drug candidates. [Display omitted] •A series of novel anthra[2,3-b]furan-3-carboxamides was designed and synthesized.•Some derivatives are highly potent against drug resistant tumor cells.•Anthrafurandiones form stable complexes with double stranded DNA.•Anthrafurandiones inhibit Top1, 2 and protein kinases.•One compound showed a remarkable antitumor potency in vivo.