Novel Targeted Anticancer Agents from Marine Cyanobacteria

项目摘要 蓝藻是地球上最古老的生物之一，已经进化出化学武器， 防御目的，我们正在利用它来发现抗癌药物。我们过去的研究已经证明了 海洋蓝细菌产生具有特别有效活性的化合物和/或具有不寻常的或第一- 具有新作用机制的同类抑制剂。我们采用广泛而专注的筛选平台， 最大化新抗癌药物的发现率。我们还将合成化学成分整合到我们的 该计划旨在进行严格的生物学研究，以迅速为我们的发现增加价值，并帮助解决 供应问题。具体来说，我们将进行海洋蓝细菌的野外采集并制备组分 文库，用于在一组创新的途径聚焦的基于细胞的测定中进行筛选， 结直肠癌细胞系和报告基因测定，以及新开发的无偏表型测定。 我们将进行去复制，通过分子分析鉴定蓝藻，并建立系统发育 底栖蓝藻之间的关系。将根据生物活性特征和遗传学特征对样本进行优先排序。 唯一性，以便进一步处理。将对优先样品进行活性成分的生物测定引导分离 化合物.将使用NMR和质谱法测定结构。生物活性基本验证 在确定进一步研究的目标之前，将进行二次测定。选化合物 具有令人感兴趣的结构和有希望的经验证的生物活性的化合物将被靶向用于全合成， 可以进行生物学表征以确定癌细胞中诱导的分子变化， 确定潜在的直接目标对于显示潜在抗转移活性的新型非细胞毒性化合物， 我们会采用一个以正交目标为基础的筛选平台。

PROJECT SUMMARY Cyanobacteria are among the most ancient organisms on Earth and have evolved chemical weapons for defensive purposes, which we are exploiting for anticancer drug discovery. Our past research has exemplified that marine cyanobacteria produce compounds with exceptionally potent activity and/or possess unusual or first- in-class inhibitors with novel mechanisms of action. We apply a broad yet focused screening platform to maximize discovery rate of new anticancer agents. We also integrate a synthetic chemistry component into our program in order to perform rigorous biological studies to rapidly add value to our discoveries and to help solve the supply problem. Specifically, we will carry out field collections of marine cyanobacteria and prepare fraction libraries for screening in a set of innovative pathway-focused cell-based assays, utilizing various isogenic colorectal cancer cell lines and reporter gene assays, as well as newly developed unbiased phenotypic assays. We will perform dereplication, identify cyanobacteria through molecular analysis and establish phylogenetic relationships among benthic cyanobacteria. Samples will be prioritized based on bioactivity profiles and genetic uniqueness for further processing. Prioritized samples will be subjected to bioassay-guided isolation of the active compounds. Structures will be determined using NMR and mass spectrometry. Basic validation of bioactivity and secondary assays will be performed before prioritizing targets for further investigation. Selected compounds with intriguing structure and promising validated bioactivity will be targeted for total synthesis so that a rigorous biological characterization can be performed to pinpoint the molecular changes induced in the cancer cell and to determine potential direct targets. For novel noncytotoxic compounds that show potential antimetastatic activity, we will apply an orthogonal target-based screening platform.