NATURAL PRODUCT SYNTHESIS VIA IMINIUM YLIDE & NITRILIUM

通过亚胺叶立德合成天然产物

• 批准号: 3280504
• 负责人: THOMAS Stuart LIVINGHOUSE
• 金额: $ 8.53万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 1989-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3280504
• 关键词: Ehrlich's tumor; alkaloids; alkenes; antineoplastics; ascites; azo compounds; chemical structure function; cyanides; drug design /synthesis /production; neurotoxins; physostigmine; ylide

The objectives will be to develop improved chemical systheses for biologically active natural products and their structural analogs. These syntheses are destined to rely on conceptually novel annulation precedures. Specifically, we propose to develop enantioselective syntheses for the alkaloids dendrobine and pretazettine which rely on oxazolinium ylide 1,3-dipolar cycloaddition reactions. The narcissus alkaloid pretazettine has exhibited remarkable therapeutic potential. This substance has shown marked activity against Ehrlich ascites carcinoma in mice. More importantly, the therapeutic activity of the individual standard drugs adriamycin, and cycloposphamide against the forementioned carcinoma was increased tremendously by the adjuvant therapy with pretazettine. In addition, the independent inhibitory action of pretazettine on cellular protein synthesis in the presence of adriamycin has been demonstrated in KB-cell cultures. Significantly, pretazettine has been revealed to increase both the survival rate and survival time of mice with Lewis lung carcinoma when administered at low levels over several days. In addition, the therapeutic effectiveness of a variety of standard drugs (e.g. cyclophosphamide, actinomycin D, 5-fluorouracil, methotrexate, 6-thioguanine, and vincristine) against i.p. implanted Lewis lung carcinoma was increased synergistically or additively when coadministered with pretazettine. Concise syntheses for the biologically active alkaloids erythraline and eburnamonine are proposed. The intended routes to these natural products will utilize a new procedure for effecting acylnitrilium ion cyclizations which we have recently developed. We predict that this novel means for efficiently constructing heterocycles of variable ring size will create a significant impact in the area of alkaloid synthesis.

目标是开发改进的化学合成方法， 生物活性天然产物及其结构类似物。 这些 合成注定依赖于概念新颖的环化 程序。 具体来说，我们建议开发对映选择性合成 对于依赖于恶唑啉的生物碱石斛碱和pretazettine， 叶立德1，3-偶极环加成反应。 水仙生物碱 普瑞西汀显示出显著的治疗潜力。 这 该物质显示出显著抗埃利希腹水癌活性， 小鼠 更重要的是，个体的治疗活性 标准药物阿霉素和环磷酰胺对上述 癌症的辅助治疗大大增加， 普他西汀 此外，独立的抑制作用， 普瑞西汀在阿霉素存在下对细胞蛋白质合成的影响 已经在KB细胞培养中得到证实。 值得注意的是，Pretazettine 可以提高小鼠的存活率和存活时间 与刘易斯肺癌，当以低水平给药， 天 此外，治疗效果的各种标准 药物（例如环磷酰胺，放线菌素D，5-氟尿嘧啶，甲氨蝶呤， 6-硫鸟嘌呤和长春新碱）对腹膜内植入的刘易斯肺癌的抑制作用 当与以下药物联合给药时， 普他西汀 具有生物活性的生物碱赤藓碱和赤藓糖醇的简明合成 建议使用燃烧器。 这些天然产品的预定路线 将采用一种新的方法进行酰基亚硝酸根离子环化反应， 这是我们最近开发的。 我们预测，这部小说意味着 有效地构建可变环尺寸的杂环将产生 在生物碱合成领域的重大影响。