FUNCTIONAL ANALYSIS AND MODIFICATION OF NOVEL MACROLACTAM ANTITUMOR ANTIBIOTIC

新型大内酰胺抗肿瘤抗生素的功能分析及修饰

• 批准号: 11480160
• 负责人: KAKINUMA Katsumi
• 金额: $ 9.22万
• 依托单位: TOKYO INSTITUTE OF TECHNOLOGY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11480160/
• 关键词: Macrolactam; Antitumor Antibiotic; Aminosugar; Polyketide; Total Synthesis; Vicenistatin; Cytotoxicity; 全合成

A novel 20-membered macrolactam glycoside antibiotic was studied based on its interesting chemotherapeutic activity against human solid tumors. To get some insight into the molecular basis of its function, search for related products, total synthesis, chemical modification, simplification and biosynthetic studies were carried out. A total synthesis was completed by developing a new synthetic method of vicenisamine and related aminosugars from non-carbohydrate starting materials and by constructing the macrolactam aglycon from (S)-citronellol by using Suzuki-cross coupling and asymmetric aldol reactions as key step. The fermentation of the producing organism Streptomyces sp. HC-34 was further screened and a new analog, named as vicenistatin M having a neutral sugar D-mycarose instead of vicenisamine aminosugar, was isolated. A key finding with vicenistatin M was that an aminosugar is essential for the antitumor activities. The structure was ultimately determined by its total synthesis. … More Chemically synthesized kedarosamine, a key aminosugar of antibiotic kedarcidin Chromophore, was transglycosylated to the vicenistatin aglycon and the resulting 4'-epi-vicenistatin and 4'-epi-α-vicenistatin was found to have slightly reduced cytotoxic activity. Important observation in the structural simplification studies was that 3,7-dimethyloctyl β-vicenisaminide showed a comparable intense cytotoxicity to vicenistatin. Methylation of the amide nitrogen of the aglycon induced conformational flipping of the vicenistatin aglycon, the cytotoxicity of which was reduced to 1/40. Apparently. the conformation of the aglycon plays a significant role for the activity. Fluorescence labeling was also attempted by introducing a pyrenyl function into visenisamine or the amide function. To improve the solubility of vienistatin, a lactone aglycon rather than a lactam was totally synthesized and further elaboration to vicenisaminide aglycon has been continued. The biosyrthesis pathway of vicenistatin was elucidated by isotope-tracer technology. A key feature is the formation of the starter unit of the polyketide aglycon that involves a stereospecific molecular rearrangement of glutamic acid into 3-methylaspartic acid. Less

研究了一种新型的20多元大花生酰胺糖苷抗生素，该抗生素是基于对人类实体瘤的有趣化学治疗活性的。为了深入了解其功能的分子基础，搜索相关产品，总合成，化学修饰，简化和生物合成研究。通过从非碳水化合物起始材料中开发一种新的合成方法，并通过使用suzuki-cross耦合和非对称醛醇反应来开发新的合成方法和相关的氨基糖。生产生物链霉菌的发酵。进一步筛选了HC-34，并隔离了一个新的类似物，称为具有中性糖D-甲糖而不是Vicenisamine aminosugar的新类似物。 Vicenistatin m的一个关键发现是，氨基加糖对于抗肿瘤活动至关重要。结构最终取决于其总合成。 ...更化学合成的甲撒胺胺是抗生素kedarcidin染色剂的关键氨基加糖，已被糖基化为Vicenistatin aglycon，并且发现了4'- epi-vicenistatin和4'-epi-vicenistatin和4'-epi-α-乙他蛋白，发现略微降低了毒素的活性。在结构简化研究中的重要观察结果是，3,7-二甲基β-乙酰氨酰胺表现出与乙烯蛋白相当的强烈的细胞毒性。 Aglycon诱导的Vicenistatin aglycon的酰胺氮的甲基化，其细胞毒性降低至1/40。显然。 AglyCon的构象在活动中起着重要作用。还尝试通过将肾上腺素功能引入粘烯胺或酰胺功能来尝试荧光标记。为了提高维也纳蛋白的溶解度，完全合成了内酯的aglycon而不是乳糖果，并继续对Vicenisaminiide aglycon进行进一步阐述。 Vicenistatin的生物术途径通过同位素跟踪技术阐明。一个关键特征是形成了聚酮化合物Aglycon的起动单元，该单元涉及谷氨酸立体特定分子重排成3-甲基大洲的酸。较少的

项目成果

M.Otsuka: "Biosynthetic Pathway of Macrolactam Polyketide Glycoside Antitumor Antibiotic Vicenistatins"Tetrahedron. 56[42]. 8281-8286 (2000)

M.Otsuka：“大环内酰胺聚酮糖苷抗肿瘤抗生素维尼他汀的生物合成途径”四面体。

Miyuki Otsuka: "Biosynthetic Pathway of Macrolactam Polyketide Glycoside Antitumor Antibiotic Vicenistatins"Tetrahedron. 56・[42]. 8281-8286 (2000)

Miyuki Otsuka：“大环内酰胺聚酮苷抗肿瘤抗生素维尼他汀的生物合成途径”Tetrahedron 8281-8286（2000）。

M.Ito: "A Novel Fungal Metabolite NG-061 Enhances and Mimics Neutrophic effect of Nerve Growth Factor (NGF) on Neurite Outgrowth in PC12 Cells"J.Antibiotics. 52[3]. 224-230 (1999)

M.Ito：“一种新型真菌代谢物 NG-061 增强并模拟神经生长因子 (NGF) 对 PC12 细胞神经突生长的中性营养作用”J.Antibiotics。

Y.Matsushima: "Versatile Route to 2,6-Dideoxyamino Sugars from Non-sugar Materials : Synthesis of Vicenisamine and Kedaro samine"J.Chem.Soc.Perkin Trans.I. [6]. 569-577 (2001)

Y.Matsushima：“从非糖材料制备 2,6-二脱氧氨基糖的通用途径：Vicenisamine 和 Kedaro samine 的合成”J.Chem.Soc.Perkin Trans.I。

Y.Matsushima: "Isolation and Structure Elucidation of Vicenistatin M, and Importance of the Vicenisamine Aminosugar for Exerting Cytotoxicity of Vicenistatin"J.Antibiotics. 54[3]. 211-219 (2001)

Y.Matsushima：“Vicenistatin M 的分离和结构阐明，以及 Vicenisamine 氨基糖对于发挥 Vicenistatin 细胞毒性的重要性”J.Antibiotics。