FUNCTIONAL ANALYSIS AND MODIFICATION OF NOVEL MACROLACTAM ANTITUMOR ANTIBIOTIC

研究了一种新型20元大环内酰胺糖苷类抗生素对人实体瘤的化疗活性。为了深入了解其功能的分子基础，进行了相关产物的寻找、全合成、化学修饰、简化和生物合成研究。以（S）-香茅醇为原料，通过Suzuki-cross偶联反应和不对称羟醛缩合反应构建了大环内酰胺苷元，并以（S）-香茅醇为起始原料，发展了一种新的合成维西尼沙胺及其相关氨基糖的方法，完成了大环内酰胺苷元的全合成。进一步筛选了产生菌Streptomycessp. HC-34的发酵产物，分离得到一种新的类似物，命名为维辛他汀M，其中性糖D-真菌糖取代维辛胺氨基糖。维西他汀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。 关于我们 化学合成的酮洛糖胺是抗生素kedarcidin生色团的关键氨基糖，将其转糖基化为vicenistatin糖苷配基，发现所得的4 '-epi-vicenistatin和4'-epi-α-vicenistatin具有轻微降低的细胞毒活性。结构简化研究中的重要观察结果是，3，7-二甲基辛基β-维西尼脒显示出与维西他汀相当的强烈细胞毒性。糖苷配基的酰胺氮的甲基化诱导了维西他汀糖苷配基的构象翻转，其细胞毒性降低至1/40。显然是的糖苷配基的构象对活性起重要作用。荧光标记也试图通过引入芘基功能到visenisamine或酰胺功能。为了提高维尼替丁的溶解度，完全合成了内酯苷元而不是内酰胺，并继续进一步阐述维尼明苷元。利用同位素示踪技术对维西他汀的生物合成途径进行了研究。一个关键特征是聚酮苷元的起始单元的形成，其涉及谷氨酸到3-甲基天冬氨酸的立体特异性分子重排。少

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