Tyoloindicines--Potent Antitumor Compounds

性状（由申请方提供）：Tyloindicines是一类生物碱 显示出很强的抗肿瘤活性。Tyloindicines F和G（NSC-650393和 -650394）是有史以来最有效的化合物之一 在国家癌症研究所筛选，显示G150值<10 -10 M 在NCI的初步筛选中，而且这些 化合物显示出对某些黑色素瘤和肺癌的活性， 有效的药物即使有的话也很少。Tyloindicines H和I（NSC-650395和 -650396），虽然效力略低，但也是有希望的线索，代表了 这些靶点可能更容易合成并具有增强的稳定性。P1在 在这一领域的初步工作已经合成了两个G类似物，NSC-71 6802和 -717335，显示出有效的活性。前者定于2003年提前 在NCI的体内评价（中空纤维测定），第二个目前是 正在考虑进行高级评估。很明显是天然产物 实例，以及来自两种活性合成类似物， 代表一种结构骨架，它可以进行设计和修改， 一系列有效的抗肿瘤化合物的开发。拟议工作 汇集了大卫教授的实验室。贝克， 田纳西州（药物设计，合成和结构化学）和教授。 耶鲁大学医学院的Yeung-Chi Cheng（肿瘤生物学，细胞 培养研究、作用模式研究、体内评价）。 具体目标包括以下：（1）合成野牡丹碱F、G、H， （2）合成用于结构-活性研究的选定类似物;（3） 支持合成;（4）研究细胞培养中的作用方式;（5） 作为体内抗肿瘤药物的潜力研究;（6）探索 莲心碱F和G及其类似物的作用机制;（7） 所选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.