SYNTHESIS OF ANTIMITOTIC NATURAL PRODUCTS

抗有丝分裂天然产物的合成

• 批准号: 08672414
• 负责人: SHIRAI Ryuichi
• 金额: $ 1.41万
• 依托单位: UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08672414/
• 关键词: CURACIN; USTILOXIN; TUBULIN; MICROTUBULES; ANTIMITOTIC AGENT; ASYMMETRIC SYNTHESIS; TOTAL SYNTHESIS; キュラシンA; ウスチロキシンD

There are number of natural and synthetic compounds that interfere with microtubule function by binding to tubulim. Curacin A,isolated from a Caribbean cyanobacterium Lyngbya majuscula, was found to be a novel antimitotic agent. Asymmetric total synthesis of curacin A was performed in a highly stereo-controlled manner. The key steps were (1) an asymmetric allylation using a chiral allyltitanium reagent and a double-asymmetric Simmons-Smith cyclopropanation to introduce three chiral centers, (2) Wittig and Wittig-Horner reactions to construct the C(3-4) and C(7-10) alkenes, and (3) a direct conversion of the thiazolidine to thiazoline. The four stereoisomers of a partial structure at the thiazoline moiety were also synthesized to elucidate the absolute configurations of three chiral centers in curacin A.In addition, A series of side chain analogs of curacin A were synthesized and the effect to in vitro micritubule polymerization was examined. These side chain analogs showed weak or no anti-tubulin activity suggesting that the side chain of curacin A was restrictly recognized by microtubule proteins. Ustiloxin D,isolated as the minor component of ustiloxins from the water extract of false smut balls, exhibits potent anti-tubulin activity. The common structure found in these class of compounds is 13-membered core structure, which seems to be responsible substructure for anti-tubulin activity. Reductive removal of sulfoxide side chain of ustiloxin A gave ustiloxin D,an important intermediate for the symthesis of its analogs. Methylation of phenolic hydroxyl group or methylamino geoup resulted in disappearance of the antitubulin activity. The 13-membered cyclic peptides, novel analogs of phomopsin-ustiloxin class of antibiotics without glycine residue, were also synthesized.

有许多天然和合成的化合物通过与微管蛋白结合来干扰微管功能。从加勒比蓝细菌Lyngbya majuscula中分离出的Curacin A被发现是一种新型抗有丝分裂剂。以高度立体控制的方式进行了箭毒素A的不对称全合成。其关键步骤为：（1）用手性烯丙基钛试剂进行不对称烯丙基化反应，并通过双不对称Simmons-Smith环丙烷化反应引入三个手性中心;（2）通过Wittig和Wittig-Horner反应构建C（3-4）和C（7-10）烯烃;此外，还合成了一系列Curacin A侧链类似物，并考察了它们对体外胶束聚合的影响。这些侧链类似物显示出弱的或没有抗微管蛋白活性，表明Curacin A的侧链被微管蛋白限制性识别。从稻曲菌球的水提取物中分离的作为稻曲菌素的次要组分的稻曲菌素D表现出有效的抗微管蛋白活性。这类化合物的常见结构是13元核心结构，这似乎是抗微管蛋白活性的负责亚结构。利用还原法除去ustiloxin A的亚砜侧链，得到了一种重要的合成其类似物的中间体--ustiloxin D。酚羟基甲基化或甲氨基甲基化导致抗微管蛋白活性消失。本论文还合成了新的无甘氨酸残基的13元环肽，即根霉素-ustiloxin类抗生素的类似物。

项目成果

Masato Takahashi 他: "Synthetic Study of Novel Ustilox-in Analogs:Benzylic Oxidation of 13-Membe-red Cyclic Peptide by Lead Tetraacetate" Heterocycles. 47. 163-166 (1998)

Masato Takahashi 等人：“新型 Ustilox-in 类似物的合成研究：四乙酸铅对 13-Membe-red 环状肽的苯甲基氧化”杂环化合物 47. 163-166 (1998)。

Toshihiko Onoda 他: "A Mild and Selective Deprotectionof p-Methoxybenzyl(PMB)Ether By Magnesi-um Bromide Diethyl Etherate-Methyl Sulf-ide" Tetrahedron Letters. 38. 1443-1446 (1997)

Toshihiko Onoda 等人：“通过溴化镁二乙醚-甲基硫醚对对甲氧基苯甲基 (PMB) 醚进行温和且选择性的脱保护”四面体快报 38。1443-1446 (1997)

Asuka Nishikawa 他: "Design and Synthesis of the Side Chain Analogs of Curacin A" Bioorganic and Medicinal Chemist-ry Letters. 7. 2657-2660 (1997)

Asuka Nishikawa 等人：“Curacin A 侧链类似物的设计和合成”《生物有机和药物化学快报》7. 2657-2660 (1997)。

Asuka Nishikawa, Ryuichi Shirai, Yukiko Koiso, Yuichi Hashimoto and Shigeo Iwasaki: "Design and Synthesis of the Side Chain Analogs of Curacin A" Bioorganic and Medicinal Chemistry Letters. 7. 2657-2660 (1997)

Asuka Nishikawa、Ryuichi Shirai、Yukiko Koiso、Yuichi Hashimoto 和 Shigeo Iwasaki：“Curacin A 侧链类似物的设计和合成”生物有机和药物化学快报。

Toshihiko Onoda 他: "Efficient Asymmetric Synthesis ofcis-2-Methylcyclopropane-carboxylic acid" Tetrahedron. 52. 13327-13338 (1996)

Toshihiko Onoda 等人：“顺式 2-甲基环丙烷-羧酸的高效不对称合成”Tetrahedron，52。13327-13338 (1996)