Synthesis and evaluation of new 2-substituted anthra[2,3-b]furan-5,10-diones: tumor cell apoptosis through DNA binding and topoisomerases inhibition.

The clinical utility of anthracyclines is limited by severe cardiotoxicity and multidrug resistance (MDR) necessitates the development of improved analogues and new chemotherapeutics. In this work a series of 2-substituted 4,11-diaminoanthra[2,3-b]furan-5,10-diones (anthrafurans) was synthesized via Pd-catalyzed cross-coupling/heterocyclization followed by the amination reaction. Several derivatives demonstrated low submicromolar cytotoxicity against five tumor cell lines comparable to doxorubicin and reduced cytotoxicity toward non-cancerous cells. Structure-activity relationship analysis demonstrated that hydrophobic 2-substituents (phenyl, trimethylsilyl) and N-methylated aminoalkyl side chains at the 4,11-positions enhanced potency and effectively circumvented Pgp- and p53-mediated MDR, while hydrophilic groups (hydroxymethyl, aminomethyl) decreased activity. Mechanistic studies showed that the 2-phenyl derivative 2b acts as a DNA-intercalating dual topoisomerase I and II inhibitor, causing DNA damage and apoptosis in leukemia cells, whereas the 2-aminomethyl analog 2j displayed weaker cellular activity due to poor intracellular accumulation despite similar in vitro DNA and topoisomerase interactions. None of the tested compounds generated significant reactive oxygen species, suggesting low oxidative stress and potentially reduced cardiotoxicity. Overall, the 4,11-diaminoanthra[2,3-b]furan-5,10-dione scaffold represents a promising and tunable platform for next-generation anthraquinone-based anticancer agents, offering potent antiproliferative activity, improved safety profile, and the ability to overcome MDR mechanisms.