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系统 生物活性天然产物及其结构类似物。 这些 合成注定要依靠概念上的新颖环向 先例。 具体而言，我们建议开发对映选择性合成 用于依靠黄唑仑的生物碱和假定的树突状丁烷 Ylide 1,3-二极性环加成反应。 水仙生物碱 假发胸胺具有显着的治疗潜力。 这 物质显示出对埃里希腹水癌的显着活性 老鼠。 更重要的是，个体的治疗活动 标准药物adrimycin和环磷有酰胺针对渗透率 辅助治疗与 特心诚。 另外，独立的抑制作用 在adriamycin存在下，美妥廷的细胞蛋白合成 在KB细胞培养物中已证明。 重要的是，假夏表示有 被发现增加了小鼠的存活率和生存时间 与刘易斯肺癌相比，在低水平上给药。 天。 另外，各种标准的治疗有效性 药物（例如环磷酰胺，放线霉素D，5-氟尿嘧啶，甲氨蝶呤， 6-硫代氨酸和vincristine）针对i.p.植入的刘易斯肺癌 与 特心诚。 生物活性生物碱的简明合成丝核和 提出了Eburnamonine。 这些天然产品的预期路线 将利用一种新程序来实现酰基硝基离子环化 我们最近开发的。 我们预测这本小说的意思是 有效构建可变环大小的杂环将创建一个 对生物碱合成区域的显着影响。