Synthesis and Study of Natural and Non-natural Antiproliferative Agents

描述（由申请人提供）：我们的实验室正在开发化学复杂天然产物家族的实用合成路线，这些天然产物已被证明可以抑制人类癌细胞的生长。通过这种方式，我们能够制备大量的相关结构（类似物），用于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质，否则将无法用于研究。我们正在开发的合成路线也使我们能够制备化学探针，用于识别我们研究的天然产物家族的细胞靶点，在许多情况下，这些靶点是未知的。这项工作的双重影响，提供分子的目标结合和目标识别，是潜在的巨大的潜在效用，在非常具有挑战性的问题，开发新的癌症疗法。事实上，我们目前用于癌症的许多一线小分子疗法是天然产物或源自天然产物的先导结构，并且通过使用通过天然产物的化学修饰制备的探针已经鉴定了癌症的许多重要靶标。我们正在研究的天然产物类别包括：皮质抑素，一种从海绵中分离的甾体生物碱家族，可有效抑制人脐静脉内皮细胞的增殖;瑞香素，一种独特的植物衍生物质，已被证明可抑制淋巴瘤衍生细胞系的生长; trioxacarcins，细菌发酵产物，对生长的癌细胞具有极强的抑制特性，并且已知可烷基化双链体DNA; salinosporamides，从海洋细菌中分离出来，（也被Velcade（R）靶向，Velcade（R）是一种批准的用于多发性骨髓瘤的化疗剂），和avrainvillamides，我们实验室中显示的靶向核磷蛋白的真菌天然产物，一种蛋白质，其突变与约35%的急性髓细胞性白血病（AML）有关，是化疗干预的新靶点。 公共卫生相关性：目前许多用于癌症的一线小分子疗法是天然产物，或衍生自天然产物作为先导结构，并且许多重要的癌症靶点已经通过使用作为天然产物的结构类似物的探针来鉴定;我们的研究旨在开发高度融合的，高度灵活的合成路线，以五种不同类别的天然产物，使大量的类似物被合成和探索作为潜在的导致癌症疗法这些化合物将无法通过任何其他方法进行研究。我们还寻求使用我们开发的化学合成化学探针，用于识别我们研究的天然产物家族的细胞靶点，在它们的靶点未知的情况下。

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.