Synthesis and antitumor activity of bis(hydroxymethyl)propionate analogs of pterostilbene in cisplatin-resistant human oral cancer cells |
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Authors: | Min-Tsang Hsieh Li-Jiau Huang Tian-Shung Wu Hui-Yi Lin Susan L Morris-Natschke Kuo-Hsiung Lee Sheng-Chu Kuo |
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Institution: | 1. School of Pharmacy, China Medical University, Taichung 404, Taiwan;2. Chinese Medicinal Research and Development Center, China Medical University Hospital, Taichung 404, Taiwan;3. School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;4. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States |
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Abstract: | 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. |
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Keywords: | Pterostilbene Resveratrol Cisplatin Oral cancer Prodrug Drug resistant |
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