Synthesis & Mechanism of Cephalostatin Anticancer Drugs

描述（由申请人提供）：Philip的合成小组已经建立了合作关系。L. Fuchs （Purdue）和三个生物/生化小组，包括Philip。A. Low（普渡大学）；黄鹏（安德森癌症中心）；John Beutler （NIH-Bethesda）。目标包括合成和测试大约四种新的机制和基于计算的强效头孢他汀-1类似物；并定义、比较和对比结构和生物学上相似的化合物的作用机制：甾体苷OSW-1和Solamargene。

DESCRIPTION (provided by applicant): A collaboration has been established between the synthesis group of Philip. L. Fuchs (Purdue) and three biological/biochemical groups including Philip. A. Low (Purdue); Peng Huang (M. D. Anderson Cancer Center); and John Beutler (NIH-Bethesda). The goals involve synthesis and testing of about four new mechanism and calculation based analogs of the hyper-potent cephalostatin-1; and to define, compare, and contrast the mechanism of action with structurally and biologically similar compounds: the steroidal glycosides OSW-1 and Solamargene. While new agents are being prepared and evaluated, the collaborators will continue testing the now available, synthetic analog, 23'deoxy-cephalostatin 1 (23'DCST-1). Proposed testing will involve preparing folate-linked dipeptide esters of 23'DCST-1, evaluating a proposed self-immolative cleavage to the free cephalostatin drug after receptor-mediated endocytosis, and characterizing the folate-cephalostatin drugs in vitro and in vivo. A second front will feature mechanistic studies to determine the anticancer activity and selectivity of 23'DCST-1 and other cephalostatin analogs in vitro, elaborating the newly-determined mitochondrial-based mechanism of action using TEM to probe the mitochondria ultrastructure, probing the mitochondria function with respect to the apoptotic end point, and testing cephalostatin analogs as potential inhibitors of the mitochondria! respiration chain. Therapeutic activity of lead compounds will then be compared in animal models. Continued testing of all new analogs using the NCI 60 cell panel will be combined with using new affinity probes including 23'DCST-1-glycine-biotin to determine which proteins, if any, undergo formation of covalent bonds to this class of drugs. The PI's group will prepare and maintain a web-based information site on the chemistry/biology/pharmacology/ medicine of the cephalostatin analogs, actively recruit new collaborators, and supply interested scientists with synthetic material for testing. The overall goal of this program is to ultimately provide one or more collaborators with multi-gram quantities of the best agent(s) in order to proceed to Phase I human trials.