PALYTOXIN PRODRUG SYNTHESIS, PURIFICATION, AND ANALYSES

海藻毒素前药的合成、纯化和分析

• 批准号: 3506879
• 负责人: Gary Steven Bignami
• 金额: $ 27.55万
• 依托单位: HAWAII BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3506879
• 关键词: amidases; amides; animal extract; animal poison; antineoplastics; aquatic organism; chemical synthesis; cytotoxicity; drug design /synthesis /production; enzyme activity; enzyme substrate analog; high performance liquid chromatography; immunoconjugates; method development; monoclonal antibody; nuclear magnetic resonance spectroscopy; phenylacetates; prodrugs; protein purification; thin layer chromatography; tissue /cell culture; ultraviolet spectrometry

During Phase I research, two palytoxin-derived prodrugs were prepared. The prodrugs were up to 1000-fold less cytotoxic to cells in culture than palytoxin. In the presence of activating enzyme, full conversion of the prodrug to palytoxin was demonstrated. Anti-tumor monoclonal antibody conjugates of the activating enzyme conferred antigen-selective cytotoxicity to the prodrugs of up to 100-fold, against cells in culture. In mixed populations of antigen-positive and -negative cells, a potent "bystander-cell" killing effect was observed. This is the first marine toxin derivative used as a prodrug. The Phase II research effort will further optimize synthetic, purification, and analytical methodology for palytoxin-derived prodrugs. Additional congeners of the palytoxin derivatives will be prepared and evaluated against cells in culture. Preclinical antitumor activity will be investigated under a collaborative research agreement.

在第一阶段的研究中，我们制备了两种雀形虫毒素衍生的前药。这个 前体药物对培养细胞的细胞毒性比 孢子虫毒素。在活化酶的存在下，完全转化为 展示了对孢子虫毒素的前药。抗肿瘤单抗 赋予抗原选择性的活化酶的结合物 对前体药物的细胞毒性最高可达100倍，对培养中的细胞也是如此。 在抗原阳性和阴性细胞的混合群体中，一种有效的 观察“旁观者细胞”杀伤效应。这是第一位海军陆战队队员 用作前药的毒素衍生物。 第二阶段的研究工作将进一步优化合成，提纯， 以及分析方法，用于分析由雀形虫毒素衍生的前体药物。其他内容 将制备和评价孢子毒素衍生物的同系物。 对抗培养中的细胞。临床前抗肿瘤活性将是 根据一项合作研究协议进行调查。