RESUMEN
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.
Asunto(s)
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Naftoquinonas , Acridinas/farmacología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Proliferación Celular , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Naftoquinonas/farmacología , Naftoquinonas/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológicoRESUMEN
The title carbohydrate, C13H22O6, is a derivative of d-glycose, in which the furan-osidic and iso-propyl-idene rings are in twisted conformations. The mean plane of the furan-osidic ring makes a dihedral angle of 70.32â (18)° with the mean plane of the fused iso-propyl-idene ring. The methyl groups in the other iso-propyl-idene ring are disordered over two sets of sites, with an occupancy ratio of 0.74â (6):0.26â (6). In the crystal, mol-ecules are linked by O-Hâ¯O hydrogen bonds into chains with graph-set notation C(5) along [100]. Weak C-Hâ¯O interactions also occur.