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元大环内酰胺糖苷类抗生素，该抗生素对人体实体瘤具有良好的化疗活性。为了深入了解其功能的分子基础，搜索相关产品，进行了全合成、化学修饰、简化和生物合成研究。以非碳水化合物为起始原料，通过铃木交叉偶联和不对称羟醛缩合反应，以(S)-香茅醇为原料，构建了大内酰胺苷元，完成了全合成。产生菌链霉菌的发酵。对HC-34进行了进一步筛选，得到一个新的类似物，命名为新的类似物，其中性糖为D-麦芽糖，而不是维克西胺氨基糖。维菌素M的一个关键发现是，氨基糖对于抗肿瘤活性是必不可少的。其结构最终由其全合成决定。…通过更多的化学合成，将抗生素Kedarsidin发色团的关键氨基糖基--kedarosamine转糖基化为邻位苷元，得到的4‘-epi-α-vicenistatin和4’-epi-vicenistatin的细胞毒活性略有降低。在结构简化研究中的重要观察结果是，3，7-二甲基-β-维菌胺显示出与维森菌素类似的强烈的细胞毒性。配基的酰胺氮的甲基化诱导了配基的构象翻转，其细胞毒性降低到1/40。很显然。配基的构象对活性起着重要的作用。还尝试了通过将吡喃基官能团引入到Visenisamine或酰胺官能团来进行荧光标记。为了改善维尼司他丁的溶解性，我们合成了内酯苷元而不是内酰胺，并对维维尼辛苷元进行了进一步的精制。利用同位素示踪技术对维菌素的生物合成途径进行了研究。一个关键的特征是聚酮苷元的起始单元的形成，它涉及到谷氨酸到3-甲基天冬氨酸的立体特异性分子重排。较少

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。

K.Kakinuma: "Vicenistatin"季刊化学総説. 45. 261-262 (2000)

K. Kakinuma：“Vicenistatin”化学评论季刊 45. 261-262 (2000)。