New Approaches to Anticancer Agents from Cyanobacteria

该项目的总体目标是利用针对表观遗传靶点的基于机制的测定，从海洋蓝细菌和藻类中发现具有抗癌应用的新天然产物。热带浅水底栖蓝藻和藻类是生产药用天然产物的丰富类群。然而，大多数海洋的蓝藻和许多大型藻类在以前的抗癌药物发现计划中很少被采样和忽视，主要是因为大多数物种在自然条件下获得的生物量很少。这项拟议工作中正在检验的一个重要且潜在的假设是，属于迄今为止研究的许多属以外的海洋蓝细菌也将富含抗癌型天然产物。 实现这一长期目标的具体目标是：1。通过研究新的栖息地和新的收集和培养策略，获得以前未研究的海洋蓝藻和大型藻类2。应用改进和创新的范例，以提高检测蓝藻/大型藻类提取物的生物活性化合物，包括预分馏和纯化合物库的形成3。在诺华公司（NIBR），使用针对表观遗传靶点的当代基于机制的筛选，筛选海洋蓝藻和藻类衍生化合物以及复杂性降低的抗癌型活性混合物 4.通过应用组合的LC-MS和微线圈NMR分析程序来去除有害化合物5.为了分离和结构上确定蓝藻和藻类代谢物，这些代谢物在基于NIBR机制的测定中具有活性，使用HPLC，然后使用高效的NMR和MS方法6。扩大活性化合物的分离，以协助NIBR药物开发工作，使用回收，培养，基于遗传的方法，或合成/半合成方法，适当和有效7。为重大发现申请专利，并在同行评议的文献中发表所有结果。

The overarching goal of this project is to discover new natural products with anticancer applications from marine cyanobacteria and algae using mechanism-based assays against epigenetic targets. Tropical shallow water benthic cyanobacteria and algae have been rich taxonomic groups for the production of medicinally-relevant natural products. However, the majority of the ocean's cyanobacteria and many macroalgae have been little sampled and largely overlooked in previous anticancer drug discovery programs, mainly because most species attain little biomass under natural conditions. One important and underlying hypothesis being examined in this proposed work is that marine cyanobacteria belonging to many genera other than those studied to date will also be rich in their production of anticancer-type natural products. The specific aims which lead to this long term goal are: 1. To access previously unstudied marine cyanobacteria and macroalgae through examination of new habitats and new strategies for their collection and culture 2. To apply improved and innovative paradigms to enhance the detection of bioactive compounds from cyanobacterial/macroalgal extracts, including prefractionation and pure compound library formation 3. To screen marine cyanobacterial and algal derived compounds and reduced complexity mixtures for anticancer-type activities at Novartis (NIBR) using contemporary mechanism-based screening against epigenetic targets 4. To derepticate nuisance compounds through application of combined LC-MS and Microcoil NMR profiling procedures 5. To isolate and structurally define cyanobacterial and algal metabolites that are active in the NIBR mechanism-based assays using HPLC followed by efficient NMR and MS methodologies 6. To scale-up the isolation of active compounds to assist NIBR drug development efforts using recollection, culture, genetic-based methods, or synthetic/semi-synthetic methods, as appropriate and efficient 7. To patent notable discoveries and publish all results in the peer-reviewed literature.