Tailoring 3,3′-Dihydroxyisorenieratene to Hydroxystilbene: Finding a Resveratrol Analogue with Increased Antiproliferation Activity and Cell Selectivity
Tailoring 3,3′-Dihydroxyisorenieratene to Hydroxystilbene: Finding a Resveratrol Analogue with Increased Antiproliferation Activity and Cell Selectivity
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DOI：
10.1002/chem.201403024
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发表时间：
2014-07-14
影响因子：
4.3
通讯作者：
Zhang, Jie
中科院分区：
文献类型：
--
作者：
Kang, Yan-Fei;Yan, Wen-Jing;Zhang, Jie
基于异戊二烯单元保留截短策略，通过“剪裁”3，3 '-二羟基异异戊二烯胡萝卜素（天然类胡萝卜素），设计了四个新化合物。其中最小的分子1（2，3，6，2 '，3'，6 '-六甲基-4，4'-二羟基-反式-二苯乙烯）是以一锅法合成的，并通过阻断NCI-H460细胞周期于G1期而具有选择性抗增殖活性，是一个很有前途的先导分子。此外，理论计算和细胞摄取实验表明，化合物1的独特的多甲基化模式显著诱导构象变化移出平面性，并增加其细胞摄取和代谢稳定性。本研究结果有助于合理设计白藜芦醇类抗增殖药物。
Four novel compounds were designed by "tailoring" 3,3'-dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 (2,3,6,2', 3', 6'-hexamethyl-4,4'-dihydroxy-trans-stilbene) was concisely synthesized in a one-pot Stille-Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity mediated by blocking the NCI-H460 cell cycle in G1 phase. Additionally, theoretical calculations and cell uptake experiments indicate that the unique polymethylation pattern of compound 1 significantly induces a conformational change shift out of planarity and increases its cell uptake and metabolic stability. The observation should be helpful to rationally design resveratrol-inspired antiproliferative agents.