PALYTOXIN PRODRUG SYNTHESIS, PURIFICATION, AND ANALYSES

海藻毒素前药的合成、纯化和分析

• 批准号: 2096080
• 负责人: Gary Steven Bignami
• 金额: $ 22.45万
• 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 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2096080
• 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.

在第一阶段研究期间，制备了两种海藻毒素衍生的前药。 这 前药对培养细胞的细胞毒性比 海藻毒素。 在活化酶的存在下， 证明了水萼毒素的前药。 抗肿瘤单克隆抗体 赋予抗原选择性的活化酶的缀合物 前药对培养细胞的细胞毒性高达 100 倍。 在抗原阳性和抗原阴性细胞的混合群体中，一种有效的 观察到“旁观者细胞”杀伤作用。 这是第一艘海军 用作前药的毒素衍生物。 二期研究工作将进一步优化合成、纯化、 以及海藻毒素衍生的前药的分析方法。 额外的 将制备并评估海萼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 根据合作研究协议进行调查。

项目成果

Lophozozymus pictor toxin: a fluorescent structural isomer of palytoxin.

Lophozzymus pictor 毒素：海藻毒素的荧光结构异构体。

• DOI: 10.1016/0041-0101(95)00075-w
• 发表时间: 1995
• 期刊: Toxicon : official journal of the International Society on Toxinology
• 作者: Lau,CO;Tan,CH;Khoo,HE;Yuen,R;Lewis,RJ;Corpuz,GP;Bignami,GS
• 通讯作者: Bignami,GS