2‑Hydroxy-1,4-naphthoquinone Thiol Derivative 7a (Universidade Federal Fluminense)

Oral cavity cancer, with squamous cell carcinoma (SCC) representing more than 90% of cases, remains a significant global public health challenge. Novel molecules are urgently needed to combat SCC while reducing adverse effects compared with current therapies. Naphthoquinones, a subgroup of quinones, exhibit diverse pharmacological activities, including antibacterial, antifungal, antiviral, anti-inflammatory, antiparasitic, and anticancer effects. In this study, we evaluated the cytotoxic potential of ten derivatives of α-xyloidone combined with thiols against oral SCC cell lines (SCC-4, SCC-9, and SCC-25). Although eight of these new thionaphthoquinone derivatives were effective against the sensitive SCC-9, only two compounds (7a and 7e) achieved a selectivity index (SI) > 2 against all SCC cell lines. Further evaluation in colorectal (HCT-116), liver (HepG2), and melanoma (B16-F10) cancer models confirmed high selectivity (SI > 2). Both compounds caused less than 2% membrane rupture at concentrations nearly 20-fold above their IC₅₀ values, and acute toxicity tests in mice showed no morbidity or mortality. Morphological analysis and caspase activity indicated cell death induced by apoptosis and accompanied by autophagy while inhibiting cell migration efficiently. In silico studies predicted favorable human oral bioavailability for 7a, and both derivatives are expected to inhibit Pg-P with a low predicted toxicity (LD₅₀). Docking analyses suggest that 7e targets key tumor progression enzymes including RSK2 and topoisomerases IIα/IIβ. These findings underscore the cytotoxic potential and safety of thionaphthoquinones 7a and 7e, highlighting their promise for oral cancer drug development.