2. Academic Validation
  3. Mechanistic Insights into the Anticancer Action of Novel 2‑Hydroxy-1,4-naphthoquinone Thiol Derivatives

Mechanistic Insights into the Anticancer Action of Novel 2‑Hydroxy-1,4-naphthoquinone Thiol Derivatives

  • ACS Omega. 2025 Sep 5;10(36):41975-41992. doi: 10.1021/acsomega.5c06730.
Thaís Barreto Santos 1,  Alex de Souza Cruz Lopes Canuto 2,  João Francisco Blaudt Virgilio de Carvalho Meira 3,  Ana Caroline Santos-Diniz 4,  Rafaella Machado de Assis Cabral Ribeiro 1,  Caroline Reis Santiago Paschoal 5 6,  Vitor Won-Held Rabelo 6,  Paula Alvarez Abreu 6,  Vitor Francisco Ferreira 7,  David Rodrigues da Rocha 1,  Bruno Kaufmann Robbs 4
Affiliations

Affiliations

  • 1 Institute of Chemistry,Universidade Federal Fluminense, Niterói, Rio de Janeiro 24020-141, Brazil.
  • 2 Postgraduate Program in Sciences Applied to Health Products, Faculty of Pharmacy, Universidade Federal Fluminense, Niterói, Rio de Janeiro 24241-000, Brazil.
  • 3 Postgraduate Program in Morphological Sciences, Institute of Biomedical Sciences, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, Brazil.
  • 4 Department of Basic Sciences, Nova Friburgo Institute of Health (ISNF), Universidade Federal Fluminense, Nova Friburgo, Rio de Janeiro 28625-650, Brazil.
  • 5 Postgraduate Program in Pharmaceutical Sciences, Institute of Biodiversity and Sustainability, Universidade Federal do Rio de Janeiro, Macaé, Rio de Janeiro 27965-045, Brazil.
  • 6 Institute of Biodiversity and Sustainability, Universidade Federal do Rio de Janeiro, Macaé, Rio de Janeiro 27965-045, Brazil.
  • 7 Department of Pharmaceutical Technology, Faculty of Pharmacy, Universidade Federal Fluminense, Niterói, Rio de Janeiro 24241-000, Brazil.
PMID: 40978433 DOI: 10.1021/acsomega.5c06730
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.

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