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Development of antidiabetic agents targeting PPARγ

开发针对 PPARγ 的抗糖尿病药物

基本信息

批准号：
16590003
负责人：
YAMAMOTO Keiko
金额：
$ 1.73万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590003/
关键词：
PPAR unsaturated fatty acid Mitsunobu Reaction luciferase assay drug design nuclear receptor metabolic syndrome 糖尿病脂肪酸

项目摘要

We have reported that we designed docosahexaenoic acid (DHA) derivatives as PPARγ ligands based on the x-ray crystal structure of the ligand binding domain of PPARγ, and synthesized them from DHA. Furthermore, we found one of them, 4-OH derivative, has significant potency for PPARγ transactivation. In addition to 4-OH group, a conjugate diene structure around C(5)-position was found to be important for the transactivation indicating conformationally restricted analogs might show more potent activity. Thus, we designed new hybrid compounds composed of a head group of cinnamic acid and a tail group from polyunsaturated fatty acid. Side chain part of polyunsaturated fatty acid as a tail group was derived from eicosapentaenoic acid by iodolactonization, hydrolysis, glycol-cleavage, reduction and then bromination. Cinnamic acid derivative as a head group and the side chain bromide of polyunsaturated fatty acid as a tail group were bonded by Williamson ether production method or Mitsunobu reaction. Thus, we synthesized more than twenty new compounds. PPAR transactivation potency of these synthesized compounds was evaluated by the luciferase assay method. We found that PPARγ transactivation potencies of all compounds are weak while some of them significantly transactivate PPARα which is a subtype of PPARγ.

根据过氧化物酶体增殖物激活受体γ（PPARγ）配体结合结构域的X-射线晶体结构，设计并合成了二十二碳六烯酸（DHA）衍生物作为PPARγ配体。此外，我们还发现其中一种4-OH衍生物对PPARγ的反式激活有明显的作用。除了4-OH基团外，发现C（5）-位周围的共轭二烯结构对于反式激活是重要的，表明构象限制的类似物可能显示更有效的活性。因此，我们设计了由肉桂酸的头基和多不饱和脂肪酸的尾基组成的新的杂合化合物。以二十碳五烯酸为原料，经碘内酯化、水解、乙二醇裂解、还原、溴化等反应，得到多不饱和脂肪酸的侧链部分作为尾基。通过威廉姆森醚制备方法或Mitsunobu反应将作为头基的肉桂酸衍生物和作为尾基的多不饱和脂肪酸的侧链溴化物键合。因此，我们合成了二十多个新化合物。通过荧光素酶测定法评价这些合成化合物的PPAR反式激活效力。我们发现所有化合物的PPARγ反式激活能力都很弱，而其中一些化合物显著地反式激活了PPARγ的一个亚型--PPARα。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Two-dimensional alanine scanning mutational analysis of the interaction between the vitamin d receptor and its ligands : Studies of A

维生素 d 受体与其配体相互作用的二维丙氨酸扫描突变分析：A 的研究

DOI：
发表时间：
2004
期刊：
The Journal of Steroid Biochemistry and Molecular Biology 89-90
影响因子：
0
作者：
Shimizu M;Yamamoto_K;Mihori M;Iwasaki Y;Morizono D;Yamada;S
通讯作者：
S

Identification of Putative Metabolites of Docosahexaenoic Acid as Pot ent PPARγ Agonists and Antidiabetic Agents.

鉴定二十二碳六烯酸的假定代谢物作为有效的 PPARγ 激动剂和抗糖尿病药。

DOI：
发表时间：
2005
期刊：
Bioorganic Medicinal Chemistry Letters 15
影响因子：
0
作者：
Nakajima;M.;Orito;Y.;Ishizuka;T.;Hashimoto;S.;Masahiro Anada;Toshimasa Ito;Toshimasa Itoh;Toshimasa Itoh;Keiko Yamamoto;Keiko Yamamoto;Keiko Yamamoto
通讯作者：
Keiko Yamamoto

Identification of Putative Metabolites of Docosahexaenoic Acid as Potent PPARγ Agonists and Antidiabetic Agents.

鉴定二十二碳六烯酸的假定代谢物作为有效的 PPARγ 激动剂和抗糖尿病药。

DOI：
发表时间：
2005
期刊：
Bioorganic Medicinal Chemistry Letters. 15
影响因子：
0
作者：
Nakajima;M.;Orito;Y.;Ishizuka;T.;Hashimoto;S.;Masahiro Anada;Toshimasa Ito;Toshimasa Itoh;Toshimasa Itoh;Keiko Yamamoto;Keiko Yamamoto
通讯作者：
Keiko Yamamoto

Identification of Putative Metabolites of Docosahexaenoic Acid as Potent PPARγ Agonists and Antidiabetic Agents

鉴定二十二碳六烯酸的假定代谢物作为有效的 PPARγ 激动剂和抗糖尿病药

DOI：
发表时间：
2005
期刊：
Bioorganic Medicinal Chemistry Letters 15
影响因子：
0
作者：
Nakajima;M.;Orito;Y.;Ishizuka;T.;Hashimoto;S.;Masahiro Anada;Toshimasa Ito;Toshimasa Itoh;Toshimasa Itoh;Keiko Yamamoto
通讯作者：
Keiko Yamamoto

Synthesis of docosahexaenoic acid derivatives designed as novel PPARγ agonists and antidiabetic agents