School of Pharmacy, China Medical University, Taichung 404, Taiwan; Chinese Medicinal Research and Development Center, China Medical University Hospital, Taichung 404, Taiwan.
School of Pharmacy, China Medical University, Taichung 404, Taiwan.
Bioorg Med Chem. 2018 Aug 7;26(14):3909-3916. doi: 10.1016/j.bmc.2018.06.011. Epub 2018 Jun 8.
The aim of this study was to develop a new drug substance with low toxicity and effective inhibitory activity against cisplatin-resistant oral cancer. The naturally produced pterostilbene was selected as the lead compound for design and synthesis of a series of bis(hydroxymethyl)propionate-based prodrugs. All derivatives were screened for antiproliferative effects against the cisplatin-resistant oral squamous (CAR) cell line and the results indicated that several compounds demonstrated superior inhibitory activity compared with pterostilbene and resveratrol. Among them, the most promising compound, 12, was evaluated for in vivo antitumor activity in a CAR xenograft nude mouse model. Obvious antitumor activity was observed at the lowest oral dose (25 mg/kg/day). Increasing the dose of 12 to 100 mg/kg/day reduced the tumor size to 22% of the control group. Based on these findings as well as the extremely low toxicity seen in the in vivo studies, we believe that compound 12 could serve as a new lead for further development.
本研究旨在开发一种新的药物物质，具有低毒性和对顺铂耐药口腔癌的有效抑制活性。选择天然产生的白藜芦醇作为先导化合物，用于设计和合成一系列基于双（羟甲基）丙酸酯的前药。所有衍生物均针对顺铂耐药口腔鳞状细胞（CAR）细胞系进行了抗增殖作用筛选，结果表明，与白藜芦醇相比，几种化合物表现出更好的抑制活性。其中，最有前途的化合物 12 在 CAR 异种移植裸鼠模型中进行了体内抗肿瘤活性评估。在最低口服剂量（25mg/kg/天）下观察到明显的抗肿瘤活性。将 12 的剂量增加到 100mg/kg/天，可将肿瘤大小缩小至对照组的 22%。基于这些发现以及体内研究中极低的毒性，我们认为化合物 12 可能成为进一步开发的新先导化合物。
