Molecular Design, Syntheses, and Utilization of New Thiazole-Related Compounds

新型噻唑相关化合物的分子设计、合成和利用

• 批准号: 14370723
• 负责人: NAGAO Yoshimitsu
• 金额: $ 8.38万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370723/
• 关键词: thiazole; thiadiazole; nonbonded interaction; X-ray analysis; DFT-calculation; acetazolamide; stromelysin; antibiotic; 抗体標識試薬; ルシフェリン; DFT計算

In the course of studies on molecular design, syntheses, and utilization of thiazole-related compounds, we have developed several new heterocyclic compounds involving intramolecular nonbonded S【triple bond】X (X = O, N, S, halogens) interactions and new syntheses of pharmaceutically interesting compounds. In each X-ray crystallographic structure of 2-(furan or thiophen-2-yl)1, 3 thiazole, chemospecific nonbonded O 【triple bond】 S or S 【triple bond】 N interaction was observed. We have synthesized a model compound of firefly luciferin and mono-, bi-, and tri-thiazole derivatives, in which the existence of each nonbonded S 【triple bond】 N interaction was confirmed by their X-ray crystallographic analyses. The DFT calculation of their model molecules could support that the molecule bearing such an S【triple bond】N interaction was most stable in relative energy among several ones. The first nonbonded S【triple bond】X(X = F, Cl, Br, I ) interactions in four kinds of 2-(2-halophenyl)-1, 3thiazole derivatives have been demonstrated in a same manner as described above. Interestingly, a tri-thiazole derivative exhibited considerable anticancer activities against some human cancer cells in vitro. The nonbonded S 【triple bond】 O interaction in the crystalline structures of diuretic acetazolamide and stromelysin-inhibitors, thiadiazolinethiones, was similarly observed even in their complex structures with carbonic anhydrase I and II and stromelysin. The pendant molecule (mercaptoazetidinyl thiazoline) of a new oral carbapenem antibiotic was efficiently synthesized by using azabicyclobutane. The antibody labeled with a new infrared fluorescent-labeling agent (indocyanine-green-acylthiazolidinethione ) was utilized for diagnosing microcancers

在噻唑类化合物的分子设计、合成和应用研究过程中，我们开发了几种新的含有分子内非键S[triple bond]X（X = O，N，S，卤素）相互作用的杂环化合物，并合成了一些新的具有药用价值的化合物。在2-（呋喃或噻吩-2-基）-1，3-噻唑的每个X-射线晶体结构中，观察到化学特异性的非键合O [三键] S或S [三键] N相互作用。我们已经合成了一个模型化合物的萤火虫flavin和单，双，和三噻唑衍生物，其中每个非键的S [三键] N相互作用的存在下，证实了他们的X-射线晶体学分析。对模型分子的密度泛函理论计算表明，具有S[三键]N相互作用的分子在能量上是最稳定的。用同样的方法证明了4种2-（2-卤代苯基）-1，3-噻唑衍生物中的第一非键S[三键]X（X = F，Cl，Br，I）相互作用。有趣的是，三噻唑衍生物在体外对一些人癌细胞表现出相当大的抗癌活性。非键S [三键] O相互作用的晶体结构中的利尿剂乙酰唑胺和基质溶解素抑制剂，噻二唑啉硫酮，类似地观察到，即使在其复杂的结构与碳酸酐酶I和II和基质溶解素。以氮杂双环丁烷为原料，高效合成了新型口服碳青霉烯类抗生素的侧链分子巯基氮杂环丁烷基噻唑啉。用一种新的红外荧光标记剂（吲哚菁绿-酰基噻唑烷酮）标记的抗体用于微癌的诊断

项目成果

Yoshimitsu Nagao et al.: "A New Infrared Fluorescent-Labeling Agent and Labeled Antibody for Diagnosing Microcancers"Bioorg.& Med.Chem.. 11. 3289-3294 (2003)

Yoshimitsu Nagao 等：“用于诊断微癌的新型红外荧光标记剂和标记抗体”Bioorg。

Yoshimitsu Nagao: "Remarkable Discrepancy in the Predominant Structures of Acyl(or thioacyl) amino-thiadlazoles, Acyl(or thioacyl)aminooxadiazoles and Related Compounds"Tetrahedron Lett.. 43・9. 1709-1712 (2002)

Yoshimitsu Nagao：“酰基（或硫酰基）氨基噻二唑、酰基（或硫酰基）氨基恶二唑及相关化合物的主要结构的显着差异”Tetrahedron Lett.. 1709-1712（2002）

Yoshimitsu Nagao: "Synthesis of New Chiral Sulfinyldiacetic Acid Derivatives and Attempt at Chemoselective Asymmetric Pummerer Reaction"Chemical & Pharmaceutical Bulletin. 50. 558-562 (2002)

Yoshimitsu Nagao：“新型手性亚磺酰基二乙酸衍生物的合成及化学选择性不对称Pummerer反应的尝试”化学

Yoshimitsu Nagao: "Cyclization, Ring-Expansion, and Several Cascade Reactions Utilizing Allenylic Molecular Structure Characteristics"J.Synth.Org.Chem.Jpn.. 61・11. 1088-1098 (2003)

永尾义光：“利用烯键式分子结构特征的环化、扩环和多个级联反应”J.Synth.Org.Chem.Jpn.. 61・11（2003）。

Yoshimitsu Nagao: "Development of New Reactions and Their Pharmaceutical Application Based on the Molecular Structure Characteristics"Yakugaku Zasshi. 122・1. 1-27 (2002)

长尾义光：“基于分子结构特征的新反应的开发及其药物应用”Yakugaku Zasshi 122・1（2002）。