Synthesis and Characterization of 4,11-Diaminoanthra[2,3‑<i>b</i>]furan-5,10-diones: Tumor Cell Apoptosis through tNOX-Modulated NAD⁺/NADH Ratio and SIRT1

A series of new 4,11-diaminoanthra­[2,3-b]­furan-5,10-dione derivatives with different side chains were synthesized. Selected 2-unsubstituted derivatives 11–14 showed high antiproliferative potency on a panel of mammalian tumor cell lines including multidrug resistance variants. Compounds 11–14 utilized multiple mechanisms of cytotoxicity including inhibition of Top1/Top2-mediated DNA relaxation, reduced NAD+/NADH ratio through tNOX inhibition, suppression of a NAD+-dependent sirtuin 1 (SIRT1) deacetylase activity, and activation of caspase-mediated apoptosis. Here, for the first time, we report that tumor-associated NADH oxidase (tNOX) and SIRT1 are important cellular targets of antitumor anthracene-9,10-diones.