PALYTOXIN PRODRUG SYNTHESIS, PURIFICATION, AND ANALYSES

在I期研究期间，制备了两种来源于海葵毒素的前药。 的 前药对培养物中细胞的细胞毒性比 海葵毒素 在活化酶的存在下， 证明了海葵毒素的前药。 抗肿瘤单克隆抗体 活化酶的缀合物赋予抗原选择性 前药对培养细胞的细胞毒性高达100倍。 在抗原阳性和阴性细胞的混合群体中， 观察到“旁观者细胞”杀伤效应。 这是第一个 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，纯化， 和分析方法。 额外 将制备并评价海葵毒素衍生物的同源物 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。

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.