Synthesis and antitumor activity of bis(hydroxymethyl)propionate analogs of pterostilbene in cisplatin-resistant human oral cancer cells

[Display omitted] 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)pr...

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Published in:Bioorganic & medicinal chemistry 2018-08, Vol.26 (14), p.3909-3916
Main Authors: Hsieh, Min-Tsang, Huang, Li-Jiau, Wu, Tian-Shung, Lin, Hui-Yi, Morris-Natschke, Susan L., Lee, Kuo-Hsiung, Kuo, Sheng-Chu
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Proliferation - drug effects
Cisplatin
Cisplatin - chemistry
Cisplatin - pharmacology
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm - drug effects
Drug resistant
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Mouth Neoplasms - drug therapy
Mouth Neoplasms - pathology
Oral cancer
Prodrug
Propionates - chemistry
Propionates - pharmacology
Pterostilbene
Resveratrol
Stilbenes - chemical synthesis
Stilbenes - chemistry
Stilbenes - pharmacology
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2018.06.011