Maleimide-substituted 1,4-naphthoquinone flaviolin mimetic (FM7) induces S-phase arrest and mitochondria-mediated apoptosis in multiple myeloma cells.

Effective treatment for multiple myeloma remains a significant clinical challenge due to multidrug resistance and the side effects of current chemotherapies, indicating the need for new interventions. Flaviolin, a 1,4-naphthoquinone derivative isolated from Aspergillus sp., possesses favourable cytotoxic activity against the RPMI-8226 multiple myeloma cell line. This study provides the first in-vitro biological evidence of its cytotoxicity against multiple myeloma by inducing S-phase arrest and apoptosis. We further investigated the structure-activity relationship of 16 flaviolin mimetics. The results showed that Flaviolin mimetic FM7, featuring an NHiBu group at R2 and a maleimide group at R4, exhibited two-fold greater potency (IC₅₀ = 0.56 µM) than flaviolin, inducing dose-dependent S-phase cell-cycle arrest and apoptosis via mitochondrial membrane dysregulation and caspase-9 activation. Furthermore, in-silico studies predicted strong binding affinity (- 8.9 kcal/mol) of FM7 towards Poly (ADP-ribose) Polymerase 1 (PARP1), while molecular dynamics simulations confirmed the stability of the complex. Collectively, our data suggest that FM7 arrest cell cycle in S-phase and induces apoptosis, via canonical mitochondrial pathway with activation of caspase 9. These data warrants further experimental validation of FM7 mediated PARP1 inhibition.