Development of asymmetric syntheses and valuable bioactive compounds based on alkenylphosphonates

基于烯基膦酸酯的不对称合成和有价值的生物活性化合物的开发

• 批准号: 15590031
• 负责人: IWAKI Hiroaki
• 金额: $ 1.73万
• 依托单位: Kansai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590031/
• 关键词: phosphonate; immunosuppressant; phosphorylation; cyclic phosphate; sphingosine-1-phosphate receptor; FTY-720; Horner-Wadsworth-Emmons reaction; homing; 環状リン酸; スフィンゴシン1リン酸; アルケニルホスホナート; スフィンゴシン; 安定リン酸化誘導体; ホスファターゼ; ヒストン脱アセチル化酵素; HDAC

Phosphates are vital components in our body as an intermediate of the energy storage and the intracellular signaling. Phosphonate derivatives are analogues of phosphates and can be act as agonists or antagonists of the biochemical reactions mediated by phosphates. Some of them have already been used as real drugs. On the other hand, from the synthetic organic chemistry point of view, phosphonates are versatile as substrates for an olefin forming reaction, Horner-Wadsworth-Emmons reaction, and also as synthetic intermediates of chiral phosphine ligands for the transition metal catalysis. Thus, in the study based on phosphonates, we can expect the development of the research in which both synthetic organic chemistry and biological chemistry are combined together. The purpose of this study is the creation of useful physiologically active compounds based on phosphonates using synthetic technology we have developed.In the present study, I focused on the development of immunosuppressive agent. An immunosuppressant FTY-720 is known to be activated by phosphorylation in one of its hydroxyl groups. The activated FTY-720 binds to sphingosine-1-phosphate receptor and cause the homing of the lymphocytes to lymph node. Thereby, I expected the increase of the activity with the application of phosphorilated FTY-720. The phosphonates, however, likely to be hydrolysed in the body. It is, therefore, we synthesized cyclic phosphates as a stable phosphorilated derivatives of FTY-720 in this study. Cyclic phosphates are not only stable but also non-asymmetric compounds which is advantageous for the further development for drugs. We also synthesized phosphonate derivatives of FTY-720. The immunosuppressive activity of the derivatives is being evaluated.

作为能量存储的中间体和细胞内信号传导，磷酸盐是我们体内的重要成分。磷酸衍生物是磷酸盐的类似物，可以充当由磷酸盐介导的生化反应的激动剂或拮抗剂。其中一些已经被用作真正的药物。另一方面，从合成有机化学的角度来看，磷酸盐作为烯烃形成反应的底物，霍纳·沃德斯沃思 - emmons反应，以及手性金属金属磷脂配体的合成中间体的底物。因此，在基于磷酸盐的研究中，我们可以期望将合成有机化学和生物化学均合并在一起的研究的发展。这项研究的目的是使用我们已经开发的合成技术基于磷酸盐来创建有用的生理活性化合物。在本研究中，我着重于免疫抑制剂的发展。已知一种免疫抑制剂FTY-720在其一组羟基中被磷酸化激活。活化的FTY-720与鞘氨醇-1-磷酸受体结合，并导致淋巴细胞的归纳为淋巴结。因此，我期望通过应用磷酸化FTY-720的应用增加活动。然而，磷酸盐可能会在体内水解。因此，在本研究中，我们将循环磷酸盐合成为FTY-720的稳定磷酸化衍生物。环状磷酸盐不仅稳定，而且是非对称化合物，这对于药物的进一步发展是有利的。我们还合成了FTY-720的磷酸衍生物。正在评估衍生物的免疫抑制活性。

项目成果

Tumor Chemopreventive Effect of Orally Administered (-)-Epigallocatechin and Its 3-O-Acylated Derivatives on the two stage Mouse Skin Carcinogenesis Induced by Peroxynitrate and 12-O-Tetradecanoylphorbol-13-acetate

口服(-)-表没食子儿茶素及其3-O-酰化衍生物对过氧硝酸盐和12-O-十四烷酰佛波醇-13-乙酸酯诱导的两阶段小鼠皮肤癌的化学预防作用

• 发表时间: 2005
• 期刊: Natural Medicines 59・1
• 作者: Toshie Fujishima;Yoshinori Kojima;Isao Azumaya;Atsushi Kittaka;Hiroaki Takayama;Y.Nagaoka
• 通讯作者: Y.Nagaoka

Modern Allene Chemistry, Chiral allene synthesis. (ed. Norbert Krause.)

现代丙二烯化学，手性丙二烯合成。

• 发表时间: 2004
• 作者: H.Ohno;Y.Nagaoka;K.Tomioka
• 通讯作者: K.Tomioka

K.Nishimura, H.Tsubouchi, M.Ono, T.Hayama, Y.Nagaoka, K.Tomioka: "Asummetric Michael-aldol tandem cyclization of ω-oxo-a, b-unsaturated esters with 10-mercaptoisoborneol methyl ether"Tetrahedron Lett.. 44. 2323-2326 (2003)

K.Nishimura、H.Tsubouchi、M.Ono、T.Hayama、Y.Nagaoka、K.Tomioka：“ω-氧代-a、b-不饱和酯与 10-巯基异冰片甲基醚的 Asummetric Michael-aldol 串联环化”莱特.. 44. 2323-2326 (2003)

Effect of 3-O-Octanoyl-(+)-catechin on the Responses of GABAA Receptors and Na+/Glucose Cotransporters Expressed in Xenopus Oocytes and on the Oocyte Membrane Potential.

3-O-辛酰基-( )-儿茶素对非洲爪蟾卵母细胞中表达的 GABAA 受体和 Na/葡萄糖协同转运蛋白的反应以及卵母细胞膜电位的影响。

• 发表时间: 2005
• 期刊: Journal of Agricultural Food Chemistry 53
• 作者: H.Aoshima;Y.Okita;S.J.Hossain;K.Fukue;M.Mito;Y.Orihara;T.Yokoyama;M.Yamada;A.Kumagai;Y.Nagaoka;S.Uesato;Y.Hara
• 通讯作者: Y.Hara

Y.Nagaoka: "Ion channel properties of peptaibols and their derivatives"Membrane. 28・2. 61-69 (2003)

Y.Nagaoka：“肽醇及其衍生物的离子通道特性”28・2（2003）。