Pro-Apoptotic and Autophagy-Inducing Activity of Novel 1,4-Naphthoquinone Derivatives against Oral Squamous Cell Carcinoma without ROS Generation
- 1Universidade Federal do Rio de Janeiro , , Fundão , , ,
- 2Universidade Federal Fluminense , , , ,
- 3Universidade Federal do Rio de Janeiro , , , ,
Abstract
Oral squamous cell carcinoma (OSCC) remains a major global health burden, and current platinum-based chemotherapeutics are constrained by systemic toxicity and acquired resistance, motivating the search for novel antitumor agents. Naphthoquinones are a privileged scaffold in anticancer drug discovery. Here, we report the synthesis of 18 1,4-naphthoquinone esters (1–18), 14 of which are novel, and their first evaluation as anticancer agents against three OSCC cell lines (SCC-4, SCC-9, and SCC-25) and primary human gingival fibroblasts. Derivative 14 emerged as the lead compound, displaying a geometric mean IC50 of 5.0 μM and a geometric mean selectivity index of 9.15, outperforming, in terms of selectivity, the chemotherapeutic standards carboplatin, lapachol, and shikonin. Mechanistically, 14 induced cell death through a combined apoptotic–autophagic pathway, evidenced by membrane blebbing, G2/M arrest, sub-G1 DNA fragmentation, caspase 3/7 activation, and LC3-puncta formation, with wortmannin-mediated rescue indicating that autophagy contributes to cell death, and without detectable induction of reactive oxygen species. This phenotype was accompanied by pronounced disorganization of the actin and tubulin cytoskeletal networks, evidenced by confocal fluorescence microscopy and reduced anisotropy of both networks. Derivative 14 induced less than 5% hemolysis at concentrations up to 1000 μM and was well tolerated in C57BL/6 mice at intraperitoneal doses up to 600 mg/kg, with no mortality or morphological alterations. In silico analyses showed no violations of Lipinski’s rule of five and a topological polar surface area within the range associated with good membrane permeability, while reverse molecular docking pointed to the DNA-binding domains of topoisomerase IIα and IIβ as plausible molecular targets, with binding modes and energies comparable to doxorubicin. Together, these findings establish 14 as a selective and well-tolerated 1,4-naphthoquinone derivative, with a proposed mechanism of action, warranting further preclinical development against OSCC.
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BibTeX
@article{meira2026proapoptotic,
title = {{Pro-Apoptotic and Autophagy-Inducing Activity of Novel 1,4-Naphthoquinone Derivatives against Oral Squamous Cell Carcinoma without ROS Generation}},
author = {João Francisco Blaudt Virgilio de Carvalho Meira and Gabriel Ouverney and Caroline Reis Santiago Paschoal and Lucas Rubini-Dias and Anamel Blaudt and Bruno Pontes and Gustavo Senra G. de Carvalho and Douglas C. A. Pinto and Raquel N. Simão and Robson C. da Silva and Ryann S. Nascimento and Daniel T. G Gonzaga and Paula Alvarez Abreu and Fernando de Carvalho da Silva and Bruno Kaufmann Robbs},
journal = {ACS Omega},
year = {2026},
month = nov,
doi = {10.1021/acsomega.6c11076},
url = {https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c11076/5464735/Pro-Apoptotic-and-Autophagy-Inducing-Activity-of},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pro-Apoptotic and Autophagy-Inducing Activity of Novel 1,4-Naphthoquinone Derivatives against Oral Squamous Cell Carcinoma without ROS Generation
AU - João Francisco Blaudt Virgilio de Carvalho Meira
AU - Gabriel Ouverney
AU - Caroline Reis Santiago Paschoal
AU - Lucas Rubini-Dias
AU - Anamel Blaudt
AU - Bruno Pontes
AU - Gustavo Senra G. de Carvalho
AU - Douglas C. A. Pinto
AU - Raquel N. Simão
AU - Robson C. da Silva
AU - Ryann S. Nascimento
AU - Daniel T. G Gonzaga
AU - Paula Alvarez Abreu
AU - Fernando de Carvalho da Silva
AU - Bruno Kaufmann Robbs
PY - 2026
DA - 2026/11/05
JO - ACS Omega
DO - 10.1021/acsomega.6c11076
UR - https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c11076/5464735/Pro-Apoptotic-and-Autophagy-Inducing-Activity-of
AB - Oral squamous cell carcinoma (OSCC) remains a major global health burden, and current platinum-based chemotherapeutics are constrained by systemic toxicity and acquired resistance, motivating the search for novel antitumor agents. Naphthoquinones are a privileged scaffold in anticancer drug discovery. Here, we report the synthesis of 18 1,4-naphthoquinone esters (1–18), 14 of which are novel, and their first evaluation as anticancer agents against three OSCC cell lines (SCC-4, SCC-9, and SCC-25) and primary human gingival fibroblasts. Derivative 14 emerged as the lead compound, displaying a geometric mean IC50 of 5.0 μM and a geometric mean selectivity index of 9.15, outperforming, in terms of selectivity, the chemotherapeutic standards carboplatin, lapachol, and shikonin. Mechanistically, 14 induced cell death through a combined apoptotic–autophagic pathway, evidenced by membrane blebbing, G2/M arrest, sub-G1 DNA fragmentation, caspase 3/7 activation, and LC3-puncta formation, with wortmannin-mediated rescue indicating that autophagy contributes to cell death, and without detectable induction of reactive oxygen species. This phenotype was accompanied by pronounced disorganization of the actin and tubulin cytoskeletal networks, evidenced by confocal fluorescence microscopy and reduced anisotropy of both networks. Derivative 14 induced less than 5% hemolysis at concentrations up to 1000 μM and was well tolerated in C57BL/6 mice at intraperitoneal doses up to 600 mg/kg, with no mortality or morphological alterations. In silico analyses showed no violations of Lipinski’s rule of five and a topological polar surface area within the range associated with good membrane permeability, while reverse molecular docking pointed to the DNA-binding domains of topoisomerase IIα and IIβ as plausible molecular targets, with binding modes and energies comparable to doxorubicin. Together, these findings establish 14 as a selective and well-tolerated 1,4-naphthoquinone derivative, with a proposed mechanism of action, warranting further preclinical development against OSCC.
SN - 2470-1343
ER -