66 research outputs found
Neural networks
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Napabucasin and Related Heterocycle-Fused Naphthoquinones as STAT3 Inhibitors with Antiproliferative Activity against Cancer Cells
Napabucasin (<b>6</b>) and
its angularly anellated isomer
(<b>7</b>), for which the synthesis is described, together with
related plant-derived naphthoquinones, were evaluated in vitro against
human breast cancer (MDA-MB-231) and chronic myelogenous leukemia
(K562) cells. As observed for β-lapachone (<b>3</b>),
the active naphthoquinones all induced apoptosis in a cell-cycle-independent
fashion. In contrast to the pyran-fused β-lapachone (<b>3</b>), however, the most potent furan-fused naphthoquinones were able
to redox cycle and generate superoxide in cell-based assays, which
was independent of NAD(P)H:quinone oxido-reductase 1. In a homogeneous
time-resolved fluorescence (HTRF) assays with MDA-MB-231 cells, both
napabucasin (<b>6</b>) and isonapabucasin (<b>7</b>) were
identified as targeting STAT3 phosphorylation. In addition, drug affinity
responsive target stability assays were performed to validate a direct
interaction of the naphthoquinones with STAT3. Isonapabucasin (<b>7</b>) turned out to be twice as potent against STAT3 as napabucasin
(<b>6</b>) in the HTRF assay, with an EC<sub>50</sub> in the
submicromolar range, which was in excellent agreement with the potency
of both agents to inhibit the growth of MDA-MB-231 cells. Moreover,
molecular docking experiments predicted different binding modes to
the STAT3 SH2 domain for the linearly anellated napabucasin (<b>6</b>) and its angularly anellated isomer (<b>7</b>)
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