Novel Targeted Anticancer Agents from Marine Cyanobacteria

项目总结 蓝藻是地球上最古老的生物之一，它进化出了化学武器 防御性目的，我们正在利用这些目的来发现抗癌药物。我们过去的研究证明了 海洋蓝藻产生具有极强活性的化合物和/或具有不寻常的或第一个- 具有新作用机制的同类抑制剂。我们将广泛而专注的筛查平台应用于 最大限度地提高抗癌新药的发现率。我们还将合成化学组件集成到我们的 计划，以便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。具体地说，我们将进行海洋蓝藻的野外采集，并制备部分 文库用于在一组创新的以途径为中心的细胞分析中进行筛选，利用各种等基因 结直肠癌细胞株和报告基因分析，以及新开发的无偏倚表型分析。 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。样本将根据生物活性特征和遗传基因进行优先排序 唯一性，便于进一步加工。按优先顺序排列的样本将接受生物测定指导下的活性物质的分离 化合物。结构将使用核磁共振和质谱学来确定。生物活性的基本验证 在确定进一步调查的目标的优先顺序之前，将进行二次化验。精选化合物 具有耐人寻味的结构和前景被证实的生物活性将被作为全合成的目标，因此严格的 可以进行生物学表征，以确定癌细胞中诱导的分子变化，并 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， 我们将应用基于目标的正交筛选平台。

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.