Chemical Biology of Caged Garcinia Xanthones

说明(申请人提供)：笼养的藤黄口香酮具有独特的结构、强大的生物活性和很大程度上未被探索的生物作用模式。包括我们自己在内的几个实验室的最新发现表明，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，在药物发现中具有潜在的治疗窗口。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转导中的结合位置和后果尚未被研究。在这里，我们提出了一个跨学科的研究计划，将解决与笼养藤黄的化学生物学相关的问题。我们建议确定这些分子与人TFR胞外结构域的络合物的晶体结构，并确定它们的结合位置。这些信息将被用来识别和优化它们的药效基序。我们将测量这些化合物与转铁蛋白受体的结合常数，并将它们与它们的细胞毒性值关联起来。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。这项工作将为针对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的结构及其在细胞信号和细胞凋亡中的作用的基础知识。与公共健康相关：从藤黄属热带树木中提取出的天然产物具有独特的结构和良好的生物活性。我们团队开发了一种生产这些化合物的化学策略，不仅消除了与自然供应相关的问题，而且提供了设计具有增强生物活性的各种相关分子的机会。通过合作，我们发现几种合成的类似物具有令人印象深刻的生物活性，并诱导对某些癌细胞的选择性杀伤，包括那些对当前化疗耐药的癌细胞。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，并将导致新的有效抗癌药物的开发。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.