Design and synthesis of a series of a-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved a queous solubility.
Design and synthesis of a series of a-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved a queous solubility.
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设计和合成一系列具有改善的水溶解度的α-苄基苯丙酸型过氧化物酶体增殖物激活受体（PPAR）γ部分激动剂。
DOI：
10.1016/j.bmc.2013.02.003
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
et.al.
中科院分区：
文献类型：
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作者：
Masao Ohashi;et.al.
在针对过氧化物酶体增殖物激活受体γ（hPPARγ）激动剂的开发的持续研究中，我们试图通过采用两种策略来改善我们先前开发的hPPARγ选择性激动剂3的水溶性，该激动剂3对于实际应用而言溶解度不足：引入取代基以降低其分子平面性，以及通过用杂芳环取代金刚烷基来降低其疏水性。第一种方法证明是无效的，但第二种方法是有效的。本文设计合成了一系列具有良好水溶性的α-苄基苯丙酸型hPPARγ部分激动剂。其中，我们选择了（R）-7j，其激活hPPARγ的程度约为使用完全激动剂观察到的最大值的65%，用于进一步评估。通过X射线衍射分析，结合配体-LDB结构，讨论了hPPARγ配体结合结构域（LBD）与（R）-7 j复合物的配体结合模式及部分激动活性的原因。还描述了（R）-7 j对人硬癌胃癌细胞系OCUM-2 MD 3的抗凋亡作用。
In the continuing study directed toward the development of peroxisome proliferator-activated receptor gamma (hPPARγ) agonist, we attempted to improve the water solubility of our previously developed hPPARγ-selective agonist 3, which is insufficiently soluble for practical use, by employing two strategies: introducing substituents to reduce its molecular planarity and decreasing its hydrophobicity via replacement of the adamantyl group with a heteroaromatic ring. The first approach proved ineffective, but the second was productive. Here, we report the design and synthesis of a series of α-benzyl phenylpropanoic acid-type hPPARγ partial agonists with improved aqueous solubility. Among them, we selected (R)-7j, which activates hPPARγ to the extent of about 65% of the maximum observed with a full agonist, for further evaluation. The ligand-binding mode and the reason for the partial-agonistic activity are discussed based on X-ray-determined structure of the complex of hPPARγ ligand-binding domain (LBD) and (R)-7j with previously reported ligand-LDB structures. Preliminal apoptotic effect of (R)-7j against human scirrhous gastric cancer cell line OCUM-2MD3 is also described.