Tyoloindicines--Potent Antitumor Compounds

描述(申请人提供)：酪氨酸是生物碱的一类 显示出深刻的抗肿瘤活性。酪氨酸甲素F和G(NSC-650393和 -650394)是有史以来出现的最有效的化合物之一 在国家癌症研究所进行筛查，显示G150值和10-10 M 在NCI的主筛查中有54个人类来源的肿瘤。此外，这些 化合物显示出对某些黑色素瘤和肺癌的活性 有效的药物即使有，也很少。酪氨酸甲素H和I(NSC-650395和 -650396)，虽然效力略有下降，但也是有希望的线索和代表 目标可能更容易合成和增强的稳定性。中的P1 在这方面的初步工作已经合成了两个G类似物，NSC-71 6802和 -717335，显示出强大的活跃度。前者计划在 NCI的活体评估(中空纤维检测)，第二项目前正在进行 正在考虑进行高级评估。显然是从天然产物 例如，以及来自两种活性合成类似物，酪氨酸类似物 表示可进行设计和修改的结构骨架 一系列有效的抗肿瘤化合物的开发。拟议中的工作 汇集了加州大学大卫·C·贝克教授的实验室 田纳西州(药物设计、合成和结构化学)。 耶鲁大学医学院的郑杨琪(肿瘤生物学、细胞 培养研究、行动模式研究、活体评估)。 具体目标包括：(1)合成酪氨酸类化合物F，G，H， 和I；(2)用于结构活性研究的选定类似物的合成；(3) 支持合成；(4)细胞培养中作用方式的研究；(5) 作为体内抗癌药物的潜在研究；(6)探索 酪氨酸类化合物F和G及其类似物的作用机理； 选定候选药物的前药的制备和评价。

Description (provided by applicant): Tyloindicines are a class of alkaloids that show profound antitumor activity. Tyloindicines F and G (NSC-650393 and -650394) are compounds that appear among the most potent compounds ever screened at the National Cancer Institute, showing G150 values <1 0-10 M against 54 human-derived tumors in the NCI's primary screen. Furthermore, these compounds show activity against certain melanomas and lung cancers for which there are few, if any, effective drugs. Tyloindicines H and I (NSC-650395 and -650396), while slightly less potent, are also promising leads and represent targets that may be easier of synthesis and of enhanced stability. The P1 in preliminary work in this area has synthesized two G analogues, NSC-71 6802 and -717335, that show potent activity. The former is scheduled for advanced in vivo evaluation (hollow fiber assay) at the NCI, and the second is presently under consideration for advanced evaluation. Clearly from the natural product examples, as well as from the two active synthetic analogues, the tyloindicines represent a structural skeleton that is amenable to design and modification for the development of a line of potent antitumor compounds. The proposed work brings together the laboratories of Prof. David C. Baker at the University of Tennessee (drug design, synthetic and structural chemistry) and those of Prof. Yeung-Chi Cheng at the Yale University School of Medicine (tumor biology, cell culture studies, mode of action studies, in vivo evaluation). Specific aims include the following: (1) Synthesis of tyloindicines F, G, H, and I; (2) Synthesis of selected analogues for structure-activity studies; (3) Supporting syntheses; (4) Studies of the mode of action in cell culture; (5) Studies of the potential as anticancer drugs in vivo; (6) Exploration of the mechanism of action for tyloindicines F and G and their analogues; (7) Preparation and evaluation of prodrugs of selected drug candidates.