Chemical Biology of Caged Garcinia Xanthones

描述（由申请人提供）：笼型藤黄酮具有独特的结构，有效的生物活性和大部分未开发的生物作用方式。包括我们自己的实验室在内的几个实验室最近的研究结果表明，这些分子可以诱导包括多药耐药克隆在内的几种癌细胞的凋亡，并且在药物发现方面具有良好的治疗窗口。这些化合物的作用模式被认为与转铁蛋白受体（TfR）结合，但结合位点和这种结合在细胞信号传导中的后果尚未被研究。在这里，我们提出了一个跨学科的研究计划，将解决与笼型藤黄酮的化学生物学相关的问题。我们建议确定这些分子与人类TfR外域复合物的晶体结构，并确定它们的结合位点。这些信息将用于鉴定和优化它们的药效基序。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。这项工作将为基于结构的转铁蛋白受体药物设计提供新的信息，并对转铁蛋白受体的结构及其在细胞信号传导和细胞凋亡中的作用产生基本的认识。公共卫生相关性：从藤黄属热带树木中提取的提取物产生了具有独特结构和有前景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，不仅消除了与自然供应相关的问题，而且还提供了设计各种具有增强生物活性的相关分子的机会。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，包括那些对当前化疗有抵抗力的癌细胞。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。这项研究的结果将为癌症的细胞生物学提供新的信息，也将导致新的和有效的抗癌药物的开发。因此，这项研究将对公众健康产生重大影响。

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.