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Mechanistic Insights into the Anticancer Action of Novel 2‑Hydroxy-1,4-naphthoquinone Thiol Derivatives
Thaís Barreto Santos1, Alex de Souza Cruz Lopes Canuto2, João Francisco Blaudt Virgilio de Carvalho Meira3
1Institute of Chemistry,Universidade Federal Fluminense, Niterói, Rio de Janeiro 24020-141, Brazil.
Abstract:
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.
Insights
New thionaphthoquinone derivatives show promise as oral cancer treatments. Compounds 7a and 7e demonstrated significant cytotoxicity against oral squamous cell carcinoma (SCC) with high selectivity and low toxicity in preclinical models.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pharmacology
Background:
- Oral cavity cancer, predominantly squamous cell carcinoma (SCC), is a major global health concern.
- Current therapies for SCC have limitations and adverse effects, necessitating novel treatment strategies.
- Naphthoquinones possess diverse pharmacological properties, including anticancer potential.
Purpose of the Study:
- To synthesize and evaluate novel thionaphthoquinone derivatives for their cytotoxic activity against oral SCC cell lines.
- To assess the selectivity and safety profile of promising compounds in various cancer models and animal studies.
- To investigate the mechanism of action and predict pharmacokinetic properties of the lead compounds.
Main Methods:
- Synthesis of ten α-xyloidone and thiol-derived thionaphthoquinone compounds.
- Cytotoxicity assays against oral SCC cell lines (SCC-4, SCC-9, SCC-25) and other cancer cell lines (HCT-116, HepG2, B16-F10).
- Cell membrane integrity, apoptosis and autophagy analysis, cell migration assays, *in silico* pharmacokinetic predictions, and molecular docking studies.
Main Results:
- Two compounds, 7a and 7e, exhibited significant selectivity (SI > 2) against all tested oral SCC cell lines.
- Compounds 7a and 7e showed high selectivity in colorectal, liver, and melanoma cancer models.
- Minimal membrane rupture (<2%) and no acute toxicity in mice were observed for 7a and 7e.
- Apoptosis and autophagy were identified as mechanisms of cell death, with efficient inhibition of cell migration.
- *In silico* analysis predicted favorable oral bioavailability and low toxicity for both compounds, with 7e targeting key enzymes like RSK2 and topoisomerases.
Conclusions:
- Thionaphthoquinones 7a and 7e possess potent cytotoxic effects against oral SCC with a favorable safety profile.
- These compounds demonstrate promise as lead candidates for the development of novel oral cancer therapeutics.
- Further investigation into their therapeutic potential and mechanism of action is warranted.
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