Background: Oral squamous cell carcinoma (OSCC) is an aggressive cancer closely associated with smoking and alcohol consumption, with a higher incidence in men. Despite changes in treatment strategies, poor survival persists in most patients, highlighting the need for novel and improved therapeutic options. Naphthoquinone analogs are being investigated because of their active redox structure and broad pharmacological profile; they demonstrate cytotoxic antitumor activity, making them potential candidates for new drug agents. Objective: This study investigated new benzyl-naphthoquinone compounds as potential anticancer agents for various genotypes of oral squamous cell carcinoma (OSCC) and other cancer cells. Methods: This study reports the synthesis and evaluation of a series of eight benzyl-naphthoquinone compounds against oral squamous cell carcinoma. Results: Four compounds 1–4 showed the best cytotoxic profiles, with a selectivity index ≥ 3 for all OSCC cell lines tested. Compound 1 was the most selective compound in all OSCC models, showing a higher selectivity index than both carboplatin and shikonin. Furthermore, compound 1 induced DNA fragmentation, cell-cycle arrest, and caspase-3/7 activation, changes consistent with apoptosis, and time-lapse imaging corroborated the apoptotic phenotype. Hemolysis assays showed minimal toxicity in human erythrocytes, and acute in vivo evaluation in mice revealed no evident adverse effects under the conditions tested, indicating low acute toxicity, although more detailed histopathological and biochemical studies will be required to fully establish the safety profile. Molecular modeling suggested that compound 1 may interact with topoisomerase II, RSK2, and PKM2, which could contribute to the activation of apoptotic pathways, although these interactions remain predictive and require biochemical validation. Finally, in silico analysis of physicochemical and ADMET parameters indicated properties compatible with oral absorption and systemic exposure, together with predicted low toxicity; however, these results are model-based and should be confirmed experimentally. Conclusions: Based on these findings, compound 1 emerges as a promising lead candidate for the development of a novel chemotherapeutic agent against OSCC, with potential therapeutic efficacy against other cancer types.

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.

Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy of the head and neck region, and current chemotherapeutic regimens, based largely on platinum compounds, are limited by low selectivity and severe adverse effects. Aiming to identify selective cytotoxic agents from the Brazilian Atlantic Forest, we screened seventeen ethanolic extracts derived from ten plant species collected in Restinga ecosystems (Myrciaria floribunda, Myrcia amazonica, Myrsine parvifolia, Myrcia ovata, Pilocarpus spicatus, Eugenia sulcata, Eugenia pruniformis, Ocotea indecora, Ocotea notata, and Ocotea pulchella) against the OSCC cell line SCC-9 and primary human gingival fibroblasts. Among the active extracts, those from M. floribunda leaves and stem were the most potent and selective, with IC₅₀ values of 78.7 and 56.9 µg/mL and selectivity indices of 7.14 and 6.80, respectively. Liquid–liquid partitioning of the stem extract yielded an ethyl acetate fraction (MfEA) that was further evaluated against a panel of eight tumor cell lines and against primary fibroblasts, displaying IC₅₀ values ranging from 9.4 to 92.7 µg/mL and selectivity indices between 6.1 and 60.5. Chemical profiling of MfEA by UPLC-DAD-QTOF-ESI-HRMS/MS tentatively annotated gallic and ellagic acids, hydrolyzable tannins, and pentacyclic triterpenoids, several of which have individually been reported to exhibit antitumor activity. In SCC-9 cells, MfEA induced morphological hallmarks of apoptosis, activated effector caspases-3/7, increased the sub-G0/G1 population, and promoted phosphatidylserine externalization, without a detectable increase in H₂O₂ levels. MfEA exhibited negligible hemolytic activity (<3%) and, in C57BL/6 mice, an estimated intraperitoneal LD₅₀ close to 200 mg/kg, with full tolerability at 100 mg/kg. Together, these findings identify the ethyl acetate fraction from Myrciaria floribunda as a promising lead from the Brazilian Restinga for further anticancer drug development.

Chronic kidney disease (CKD) progression has been considered a global public health crisis, affecting over 700 million people worldwide and the ninth leading cause of death, with increasing mortality rates. It involves the progressive loss of kidney function, which can occur asymptomatically. Among the causal conditions of CKD, metabolic syndrome (MetS) has proven to be one of the most important etiopathogenic mechanisms for the loss of kidney function. MetS, in turn, is a set of interconnected cardiovascular risk factors, driven by the interaction of genetic, environmental, and behavioral factors, with insulin resistance as its central mechanism, which, along with visceral obesity and chronic inflammation, drives the condition. Furthermore, MetS and its individual components are associated with the premature development and progression of CKD due to pro-inflammatory states, oxidative stress, and endothelial dysfunction. MetS diagnosis is generally confirmed when an individual presents with at least three of the five main criteria, which include central adiposity, elevated triglycerides, reduced levels of high-density lipoprotein, hypertension, and impaired fasting glucose. This chapter proposes to gather current information on the interaction between MetS and CKD. Obesity, glomerular damage, diabetes, and insulin variability are among the topics covered. Similarly, thrombotic, inflammatory, and hypertensive markers are also addressed. Innovative approaches such as microbiome interaction and pharmacogenomics-supported treatments complete this review. This chapter is a collective work of Medical Genetics students, class of 2026-1, from the Nova Friburgo Health Institute, at the Federal Fluminense University, and addresses the ultimate information found in the main health databases.