Oral squamous cell carcinoma is the most common malignancy of oral tumor. In this study, two novel hybrids of podophyllotoxin and coumarin were designed using molecular hybridization strategy and synthesized. Pharmacological evaluation showed that the potent compound 12b inhibited the proliferation of three human oral squamous carcinoma cell lines with nanomolar IC₅₀ values, as well as displayed less toxicity on normal cells. Mechanistic studies indicated that 12b triggered HSC-2 cell apoptosis, induced cell cycle arrest, and inhibited cell migration. Moreover, 12b could disturb the microtubule network via binding into the tubulin. It was noteworthy that induction of autophagy by 12b was associated with the upregulation of Beclin1, as well as LC3-II. Furthermore, 12b significantly stimulated the AMPK pathway and restrained the AKT/mTOR pathway in HSC-2 cells. These results indicated that compound 12b was a promising candidate for further investigation.

口腔鳞状细胞癌是口腔肿瘤最常见的恶性肿瘤。在这项研究中，使用分子杂交策略设计并合成了鬼臼毒素和香豆素的两种新型杂种。药理评估表明该有效化合物12b用纳摩尔IC ₅₀值抑制三种人类口腔鳞状细胞癌细胞的增殖，并且对正常细胞的毒性较小。机理研究表明12b触发HSC-2细胞凋亡，诱导细胞周期停滞并抑制细胞迁移。此外，12b可能通过与微管蛋白结合而干扰微管网络。值得注意的是，自噬的诱导12b与Beclin1以及LC3-II的上调有关。此外，12b在HSC-2细胞中显着刺激AMPK途径并抑制AKT / mTOR途径。这些结果表明12b 是有希望进行进一步调查的候选人。