Pro-Apoptotic Antitumoral Effect of Novel Acridine-Core Naphthoquinone Compounds against Oral Squamous Cell Carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are essential to improve disease prognosis and reduce toxicity. In the present study, acridine-core naphthoquinone compounds were synthesized and evaluated for their antitumor activity in OSCC cells. The mechanism of action, pharmacokinetics, and toxicity parameters of the most promising compound was further analyzed using in silico, in vitro, and in vivo methods. Among the derivatives, compound 4e was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound 4e proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound 4e promoted cell death by apoptosis in the OSCC cell, and molecular docking studies suggested this compound possibly targets enzymes important for tumor progression, such as RSK2, PKM2, and topoisomerase IIα. Importantly, compound 4e presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials.

New Chalcogen-Functionalized Naphthoquinones: Design, Synthesis, and Evaluation, In Vitro and In Silico, against Squamous Cell Carcinoma

“…Also, tellurium-derived compounds, especially the compound ( 10a ), showed an increased antineoplastic potential with sufficient selectivity in relation to nontumor cells. Since OSSC still presents itself as a challenging malignancy for effective treatment, , several studies are being conducted to evaluate new synthetic or derivatives of natural compounds to improve OSSC prognosis and reduce chemotherapy comorbidities. , Considering the promising results obtained in terms of synthesis, yields, antiproliferative activity, cell migration inhibition, induction of cell death, and low toxicity, this work suggests the potential of the compound ( 10a ) as a promising antineoplastic agent for further study.…”

Molecular Modeling and In Vitro Evaluation of Piplartine Analogs against Oral Squamous Cell Carcinoma

“…Compared to other chemotherapies and to new putative compounds for treatment of OSCC cells, the selectivity results for the tested derivatives were significantly high [ 47 , 48 , 49 , 50 ].…”