Jatrophane Diterpenoids as Modulators of P-Glycoprotein-Dependent Multidrug Resistance (MDR): Advances of Structure-Activity Relationships and Discovery of Promising MDR Reversal Agents
Jatrophane Diterpenoids as Modulators of P-Glycoprotein-Dependent Multidrug Resistance (MDR): Advances of Structure-Activity Relationships and Discovery of Promising MDR Reversal Agents
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麻疯树二萜作为 P-糖蛋白依赖性多药耐药性 (MDR) 调节剂：结构-活性关系的进展和有前景的 MDR 逆转剂的发现
DOI：
10.1021/acs.jmedchem.6b00605
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发表时间：
2016
影响因子：
7.3
通讯作者：
Yin Sheng
中科院分区：
文献类型：
--
作者：
Zhu Jianyong;Wang Ruimin;Lou Lanlan;Li Wei;Tang Guihua;Bu Xianzhang;Yin Sheng
The phytochemical study ofPedilanthus tithymaloidesled to the isolation of 13 jatrophane diterpenoids (1–13), of which eight (1–8) are new. Subsequent structural modification of the major components by esterification, hydrolysis, hydrogenation, or epoxidation yielded 22 new derivatives (14–35). Thus, a jatrophane library containing two series of compounds was established to screen for P-glycoprotein (Pgp)-dependent MDR modulators. The activity was evaluated through a combination of Rho123 efflux and chemoreversal assays on adriamycin resistant human hepatocellular carcinoma cell line HepG2 (HepG2/ADR) and adriamycin resistant human breast adenocarcinoma cell line MCF-7 (MCF-7/ADR). Compounds19,25, and26were identified as potent MDR modulators with greater chemoreversal ability and less cytotoxicity than the third-generation drug tariquidar. The structure–activity relationship (SAR) was discussed, which showed that modifications beyond just increasing the lipophilicity of this class of Pgp inhibitors are beneficial to the activity. Compound26, which exhibited a remarkable metabolic stability in vitro and a favorable antitumor effect in vivo, would serve as a promising lead for the development of new MDR reversal agents.
