Synthesis & Mechanism of Cephalostatin Anticancer Drugs

合成

基本信息

  • 批准号:
    7682534
  • 负责人:
  • 金额:
    $ 39.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1996
  • 资助国家:
    美国
  • 起止时间:
    1996-08-09 至 2011-08-31
  • 项目状态:
    已结题

项目摘要

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(由申请人提供):Philip的合成组之间建立了合作。L. Fuchs(Purdue)和包括Philip在内的三个生物/生化小组。A. Low(Purdue); Peng Huang(M. D.安德森癌症中心);和约翰Beutler(NIH贝塞斯达)。目标包括合成和测试大约四种新的机制和基于计算的超强效头孢菌素-1类似物;并定义,比较和对比结构和生物学相似化合物的作用机制:甾体糖苷OSW-1和Solamargene。 虽然新的药物正在准备和评估,合作者将继续测试现在可用的合成类似物,23'脱氧头孢菌素1(23'DCST-1)。所提出的测试将涉及制备23'DCST-1的叶酸连接的二肽酯,评价所提出的受体介导的内吞作用后对游离头孢菌素药物的自分解裂解,以及在体外和体内表征叶酸-头孢菌素药物。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,使用TEM探测线粒体超微结构来阐述新确定的基于线粒体的作用机制,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剂!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细胞组对所有新类似物的继续测试将与使用包括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(如果有的话)与这类药物形成共价键。PI小组将准备和维护一个基于网络的头孢菌素类似物化学/生物学/药理学/医学信息网站,积极招募新的合作者,并为感兴趣的科学家提供合成材料进行测试。该计划的总体目标是最终为一个或多个合作者提供多克数量的最佳药物,以便进行I期人体试验。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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PHILIP L FUCHS其他文献

PHILIP L FUCHS的其他文献

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{{ truncateString('PHILIP L FUCHS', 18)}}的其他基金

ONCOGENE DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG
癌基因定向合成抗癌药物头孢他汀
  • 批准号:
    6456877
  • 财政年份:
    1996
  • 资助金额:
    $ 39.28万
  • 项目类别:
ONCOGENE DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG
癌基因定向合成抗癌药物头孢他汀
  • 批准号:
    6370491
  • 财政年份:
    1996
  • 资助金额:
    $ 39.28万
  • 项目类别:
ONCOGENE-DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG
癌基因定向合成抗癌药物头孢他汀
  • 批准号:
    2712677
  • 财政年份:
    1996
  • 资助金额:
    $ 39.28万
  • 项目类别:
ONCOGENE DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG
癌基因定向合成抗癌药物头孢他汀
  • 批准号:
    6750698
  • 财政年份:
    1996
  • 资助金额:
    $ 39.28万
  • 项目类别:
Synthesis & Mechanism of Cephalostatin Anticancer Drugs
合成
  • 批准号:
    7121185
  • 财政年份:
    1996
  • 资助金额:
    $ 39.28万
  • 项目类别:
ONCOGENE-DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG
癌基因定向合成抗癌药物头孢他汀
  • 批准号:
    2101301
  • 财政年份:
    1996
  • 资助金额:
    $ 39.28万
  • 项目类别:
Synthesis & Mechanism of Cephalostatin Anticancer Drugs
合成
  • 批准号:
    7279924
  • 财政年份:
    1996
  • 资助金额:
    $ 39.28万
  • 项目类别:
ONCOGENE DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG
癌基因定向合成抗癌药物头孢他汀
  • 批准号:
    6512968
  • 财政年份:
    1996
  • 资助金额:
    $ 39.28万
  • 项目类别:
Synthesis & Mechanism of Cephalostatin Anticancer Drugs
合成
  • 批准号:
    6927494
  • 财政年份:
    1996
  • 资助金额:
    $ 39.28万
  • 项目类别:
ONCOGENE DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG
癌基因定向合成抗癌药物头孢他汀
  • 批准号:
    6376011
  • 财政年份:
    1996
  • 资助金额:
    $ 39.28万
  • 项目类别:

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