Synthesis and Study of Natural and Non-natural Antiproliferative Agents

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。

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.