Chemical Biology of Caged Garcinia Xanthones

描述（由申请人提供）：笼状藤黄属氧杂蒽酮具有独特的结构、有效的生物活性和基本上未探索的生物作用模式。包括我们自己的实验室在内的几个实验室的最新研究结果表明，这些分子在几种癌细胞（包括多药耐药克隆）中诱导凋亡，并在药物发现的潜在应用中具有良好的治疗窗口。这些化合物的作用模式被认为涉及与转铁蛋白受体（TfR）的结合，但这种结合在细胞信号传导中的结合位点和后果尚未被研究。在这里，我们提出了一个跨学科的研究计划，将解决有关的问题，笼中藤黄氧杂蒽酮的化学生物学。我们建议，以确定这些分子的晶体结构与人类转铁蛋白受体胞外域的复合物，并确定其结合位点。这些信息将用于识别和优化其药效基序。我们将测量这些化合物与TfR的结合常数，并将其与其细胞毒性值相关联。我们还将评估小分子与TfR的结合是否会影响TfR的内吞作用，并确定激活导致细胞凋亡的信号通路。这项工作将为靶向转铁蛋白受体的基于结构的药物设计提供新的信息，并产生关于转铁蛋白受体结构及其在细胞信号传导和凋亡中的作用的基础知识。公共卫生相关性：从热带树木的藤黄科提取物产生了具有独特结构和有前途的生物活性的天然产物。我们的团队已经开发出一种化学策略来生产这些化合物，不仅消除了与天然供应相关的问题，而且还提供了一个机会来设计各种各样的具有增强生物活性的相关分子。通过合作，我们发现几种合成类似物具有令人印象深刻的生物活性，并诱导选择性杀死某些癌细胞，包括那些对目前化疗有抗性的癌细胞。在这里，我们建议详细研究这些化合物的作用，并确定它们如何杀死癌细胞。这项研究的结果将产生关于癌症细胞生物学的新信息，也将导致新的有效抗癌药物的开发。因此，这项研究将对公共卫生产生重大影响。

DESCRIPTION (provided by applicant): The caged Garcinia xanthones have unique structures, potent bioactivities and largely unexplored biological mode of action. Recent findings from several laboratories, including our own, have shown that these molecules induce apoptosis in several cancer cells including multidrug resistant clones and have a good therapeutic window for potential applications in drug discovery. The mode of action of these compounds is proposed to involve binding to the transferrin receptor (TfR) but the binding site and consequences of this binding in cell signaling have not been examined. Here we present an interdisciplinary research program that would address issues related to the chemical biology of the caged Garcinia xanthones. We propose to determine the crystal structure of these molecules in complex with the human TfR ectodomain and identify their binding site. This information will be used to identify and optimize their pharmacophoric motif. We will measure binding constants of these compounds to TfR and correlate them to their cytotoxicity values. We will also evaluate whether binding of the small molecules to TfR affects TfR endocytosis and determine signaling pathways that become activated leading to apoptosis. This work will produce new information for structure-based drug design targeting the transferrin receptor and generate fundamental knowledge on the structure of the transferrin receptor and its role in cell signaling and apoptosis. PUBLIC HEALTH RELEVANCE: Extracts from the Garcinia family of tropical trees have yielded natural products with unique structure and promising biological activity. Our group has developed a chemical strategy to produce these compounds that not only eliminates problems associated with natural supply but also provides an opportunity to design a wide variety of related molecules with enhanced bioactivity. Through a collaborative effort we have found that several synthetic analogues have impressive bioactivities and induce selective killing of certain cancer cells including those that are resistant to current chemotherapy treatments. Here we propose to study in detail the actions of these compounds and determine how they kill cancer cells. Results from this investigation will produce new information on the cellular biology of cancer and will also lead to the development of new and effective anticancer drugs. As such, this research will have a significant impact to public health.