Synthesis and Study of Natural and Non-natural Antiproliferative Agents

天然和非天然抗增殖剂的合成与研究

• 批准号: 8227972
• 负责人: ANDREW G MYERS
• 金额: $ 71.31万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8227972
• 关键词: Acute; Advanced Development; Affinity; Alkaloids; Antibodies; Area; Bacteria; Binding; Biological Assay; Biological Factors; Cell Line; Cell Proliferation; Cells; Chemicals; Chemistry; Clinical; Communities; Complex; Computer Simulation; Coupling; Cytoplasm; DNA; Employee Strikes; Endothelial Cells; Evaluation; Family; Family Study; Fermentation; Goals; Growth; Human; Immunoprecipitation; Intervention; Laboratories; Lead; Lymphoma; Malignant Neoplasms; Marines; Methodology; Methods; Modification; Molecular; Molecular Target; Monitor; Multiple Myeloma; Mutation; Myelogenous; Patients; Plants; Porifera; Preparation; Property; Proteins; Reagent; Research; Route; Side; Specificity; Structure; Structure-Activity Relationship; Synthesis Chemistry; Therapeutic Agents; Umbilical vein; Velcade; Work; X-Ray Crystallography; advanced system; analog; antiproliferative agents; avrainvillamide; base; cancer cell; cancer therapy; cellular targeting; chemotherapeutic agent; cortistatin; design; flexibility; improved; multicatalytic endopeptidase complex; mutant; novel; nucleophosmin; public health relevance; research study; small molecule; sugar; tool

DESCRIPTION (provided by applicant): Our laboratory is developing practical synthetic routes to families of chemically complex natural products that have been shown to inhibit the growth of human cancer cells. In this way, we are able to prepare large numbers of related structures (analogs) for evaluation as new chemotherapeutic agents, compounds with potentially improved properties that would be otherwise unavailable for study. The synthetic routes we are developing also allow us to prepare chemical probes that are useful for the identification of the cellular targets of the natural products families we study, which in many cases are not known. The dual impacts of this work, providing molecules for target binding and target identification, are of potentially great potential utility in the extraordinarily challenging problem of developing new cancer therapies. Indeed, many of our current front-line small-molecule therapies for cancer are natural products or were derived from natural products lead structures, and many important targets of cancer have been identified through the use of probes prepared by chemical modification of natural products. Among the classes of natural products we are studying are the cortistatins, a family of steroidal alkaloids isolated from a marine sponge that potently inhibit the proliferation of human umbilical vein endothelial cells; the daphniglaucins, unique plant-derived substances that have been shown to inhibit the growth of a lymphoma-derived cell line; the trioxacarcins, bacterial fermentation products with extremely potent inhibitory properties toward growing cancer cells and known to alkylate duplex DNA; salinosporamides, isolates from a marine bacterium that target the proteasome (also targeted by Velcade(R), an approved chemotherapeutic agent for multiple myeloma), and avrainvillamides, fungal natural products shown in our laboratory to target nucleophosmin, a protein whose mutation has been implicated in ~35% of all acute myelogenous lukemias (AMLs) and a novel target for chemotherapeutic intervention. PUBLIC HEALTH RELEVANCE: Many current front-line small-molecule therapies for cancer are natural products, or were derived from natural products as lead structures, and many important targets of cancer have been identified through the use of probes that are structural analogs of natural products; our research seeks to develop highly convergent, highly flexible synthetic routes to five different classes of natural products so as to enable large numbers of analogs to be synthesized and explored as potential leads for cancer therapy. These compounds would not be available for study by any other means. We also seek to use the chemistry we develop to synthesize chemical probes for the identification of the cellular targets of the natural products families we study, in cases where their targets are not known.

描述(申请人提供)：我们的实验室正在开发实用的合成路线，以获得一系列化学复杂的天然产品，这些产品已被证明可以抑制人类癌细胞的生长。通过这种方式，我们能够制备大量相关的结构(类似物)，作为新的化疗药物进行评估，这些化合物具有潜在的改善性能，否则无法进行研究。我们正在开发的合成路线还允许我们准备化学探针，这些探针有助于识别我们研究的天然产品家族的细胞靶标，这些天然产物家族在许多情况下是未知的。这项工作的双重影响，为靶标结合和靶标识别提供了分子，在开发新的癌症疗法这一极具挑战性的问题上具有潜在的巨大潜力。事实上，我们目前治疗癌症的许多一线小分子疗法都是天然产物或来自天然产物的铅结构，许多重要的癌症靶点已经通过使用天然产物的化学修饰制备的探针来识别。在我们正在研究的天然产品类别中，有皮质素，这是从海绵中分离出来的类固醇生物碱家族，可以有效地抑制人脐静脉内皮细胞的增殖；瑞香素，这是一种独特的植物衍生物质，已被证明可以抑制淋巴瘤来源的细胞系的生长；三恶卡菌素，细菌发酵产物，对癌细胞生长具有极强的抑制作用，已知能烷化双链DNA；从海洋细菌中分离出的以蛋白酶体为靶点(也是经批准的多发性骨髓瘤化疗药物VELCADE(R)的靶标)的盐孢酰胺，以及我们实验室展示的靶向核磷蛋白的真菌天然产物avrainvillamide，这种蛋白的突变已涉及约35%的急性骨髓性狼疮(AML)，也是化疗干预的新靶点。 与公共健康相关：目前治疗癌症的许多一线小分子疗法都是天然产物，或来自天然产物作为先导结构的产物，通过使用作为天然产物结构类似物的探针已经确定了许多癌症的重要靶点；我们的研究旨在开发针对五类不同天然产物的高度收敛、高度灵活的合成路线，以便能够合成和探索大量类似物，作为潜在的癌症治疗线索。这些化合物将不能通过任何其他手段进行研究。我们还寻求使用我们开发的化学来合成化学探针，以识别我们研究的天然产品家族的细胞目标，在其目标未知的情况下。