Resveratrol analogs: promising chemopreventive agents
Resveratrol analogs: promising chemopreventive agents
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DOI：
10.1111/nyas.12196
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发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Pezzuto, John M.
中科院分区：
文献类型：
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作者：
Ogas, Talysa;Kondratyuk, Tamara P.;Pezzuto, John M.
尽管白藜芦醇可以调节致癌作用的多个阶段，但按照最常见的标准，它并不是一个好的候选药物。白藜芦醇缺乏效力、高效性和靶点特异性；它代谢迅速，血清浓度低。使用白藜芦醇作为支架，我们生产了 100 多种衍生物，其中一些具有纳摩尔范围内的目标特异性。使用 1,3-噻唑作为白藜芦醇的中心环，芳香酶抑制作用增强了 6000 倍以上。优化两个苯环和中心杂环连接基的取代模式导致选择性 QR1 诱导，CD 值为 87 nM。已选择几种衍生物来评估协同效应。化合物对的初步结果是有希望的，进一步的实验，以恒定的多药物方式，将使我们能够为更大的衍生物组合创建多边形图。目的是开发一种基于白藜芦醇结构的高效衍生物混合物。
Although resveratrol can modulate multiple stages of carcinogenesis, by most common standards it is not a good drug candidate. Resveratrol lacks potency, high efficacy, and target specificity; it is rapidly metabolized and serum concentrations are low. Using resveratrol as a scaffold, we produced over 100 derivatives, some of which have target specificity in the nanomolar range. Aromatase inhibition was enhanced over 6000-fold by using 1,3-thiazole as the central ring of resveratrol. Optimizing the substitution pattern of the two phenyl rings and the central heterocyclic linker led to selective QR1 induction with a CD value of 87 nM. Several derivatives have been selected for evaluation of synergistic effects. Preliminary results with pairs of compounds are promising and further experiments, in a constant multidrug manner, will allow us to create polygonograms for larger combinations of derivatives. The objective is to develop a highly efficacious cocktail of derivatives based on the structure of resveratrol.