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实际的合成路线，以化学复杂的天然产物家族，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进性质，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，用于鉴定我们所研究的天然产物家族的细胞靶标，这些靶标在许多情况下是未知的。这项工作的双重影响，为目标结合和目标识别提供分子，在开发新的癌症治疗方法的极具挑战性的问题中具有潜在的巨大潜力。事实上，我们目前的许多前沿癌症小分子疗法都是天然产物或来源于天然产物的先导结构，并且许多重要的癌症靶点已经通过使用天然产物化学修饰制备的探针来确定。在我们正在研究的天然产物类别中，有皮质抑素，这是一种从海绵中分离出来的甾体生物碱家族，能有效抑制人脐静脉内皮细胞的增殖；水蚤素，一种独特的植物源性物质，已被证明可以抑制淋巴瘤源性细胞系的生长；trioxacarcins，细菌发酵产物，对生长的癌细胞具有极强的抑制作用，已知具有烷基化双链DNA；salinosporamides，从一种海洋细菌中分离出来的靶向蛋白酶体（也被Velcade(R)靶向，一种批准的多发性骨髓瘤化疗药物），avrainvillamides，我们实验室显示的真菌天然产物，靶向核磷蛋白，一种蛋白质，其突变与约35%的急性髓性白血病（AMLs）有关，是化疗干预的新靶标。

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 leukemias (AMLs) and a novel target for chemotherapeutic intervention.