Synthesis & Mechanism of Cephalostatin Anticancer Drugs

合成

• 批准号: 7279924
• 负责人: PHILIP L FUCHS
• 金额: $ 40.75万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-09 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7279924
• 关键词: Affinity; Animal Model; Antineoplastic Agents; Apoptotic; Biochemical; Biological; Biology; Biotin; Cancer Center; Cell Line; Cells; Cephalostatin; Chemistry; Class; Collaborations; Covalent Interaction; Depth; Dipeptides; Doctor of Medicine; End Point; Esters; Figs - dietary; Folate; Glycine; Glycosides; Goals; Human; In Vitro; Lead; Link; Malignant Neoplasms; Materials Testing; Medicine; Mitochondria; New Agents; Online Systems; Pharmaceutical Preparations; Pharmacology; Phase; Proteins; Recruitment Activity; Respiration; Scientist; Site; Testing; Therapeutic; United States National Institutes of Health; analog; anticancer activity; base; covalent bond; folate-binding protein; in vivo; inhibitor/antagonist; interest; neoplastic cell; professor; programs; receptor mediated endocytosis; research study; tool

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.

描述(申请人提供)：菲利普合成小组已建立合作关系。L.Fuchs(普渡)和包括菲利普在内的三个生物/生化组。A.Low(普渡)；Peng Huang(M.D.Anderson癌症中心)；John Beutler(NIH-Bethesda)。目标包括合成和测试大约四种新的超强效头抑素-1的作用机制和基于计算的类似物；定义、比较和对比其作用机制与结构和生物相似的化合物：类固醇糖苷OSW-1和Solamargene。 在准备和评估新药物的同时，合作者将继续测试现已上市的合成类似物23‘脱氧头孢菌素1(23’DCST-1)。拟议的测试将包括制备23‘DCST-1的叶酸连接二肽酯，评估受体介导的内吞作用后自焚裂解游离的头细胞抑素药物，以及在体外和体内表征叶酸-头细胞抑素药物。第二个前沿将以机制研究为特色，以确定23‘DCST-1和其他头孢菌素类似物的体外抗癌活性和选择性，阐述新确定的基于线粒体的作用机制，使用电子显微镜探测线粒体超微结构，探测线粒体相对于凋亡终点的功能，并测试头孢菌素类似物作为线粒体的潜在抑制物！呼吸链。然后将在动物模型中比较先导化合物的治疗活性。使用NCI 60细胞板继续测试所有新的类似物将与使用包括23‘DCST-1-甘氨酸-生物素在内的新亲和探针相结合，以确定哪些蛋白质(如果有)与这类药物形成共价键。该小组将准备和维护一个关于头孢菌素类似物的化学/生物学/药理学/医学的网上信息网站，积极招募新的合作者，并向感兴趣的科学家提供用于测试的合成材料。该计划的总体目标是最终为一个或多个合作者提供多克量的最佳制剂(S)，以便进入第一阶段人体试验。