Departamento de Química Orgânica, Instituto de Química, Campus do Valonguinho, Universidade Federal Fluminense, Niterói CEP 24020-141, Brazil.
Departamento de Ciência Básica, Campus Universitário de Nova Friburgo, Universidade Federal Fluminense, Nova Friburgo CEP 28625-650, Brazil.
Molecules. 2022 Aug 12;27(16):5148. doi: 10.3390/molecules27165148.
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 was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound 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 presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials.
口腔鳞状细胞癌（OSCC）是一个具有高发病率和死亡率的全球性公共健康问题。临床上使用的化疗药物，单独或联合使用，通常会导致重要的副作用。因此，发现和开发新的抗肿瘤药物对于改善疾病预后和降低毒性至关重要。在本研究中，合成了吖啶核萘醌类化合物，并评估了它们在 OSCC 细胞中的抗肿瘤活性。利用计算机模拟、体外和体内方法进一步分析了最有前途的化合物的作用机制、药代动力学和毒性参数。在这些衍生物中，化合物 具有高细胞毒性（29.99µM）和选择性（SI 2.9），与化疗对照药物相当，且通常更优。此外，化合物 在所有测试剂量下均未表现出溶血作用，在动物体内稳定且耐受良好。在机制上，化合物 通过诱导 OSCC 细胞凋亡促进细胞死亡，分子对接研究表明，该化合物可能靶向 RSK2、PKM2 和拓扑异构酶 IIα 等对肿瘤进展重要的酶。重要的是，化合物 表现出了有希望用于未来临床前试验的药物开发的理想参数特征。
