RATIONAL DRUG DESIGN BASED ON CHEMICAL MECHANISMS
基于化学机制的合理药物设计
基本信息
- 批准号:2087690
- 负责人:
- 金额:$ 20.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1987
- 资助国家:美国
- 起止时间:1987-01-01 至 1996-11-30
- 项目状态:已结题
- 来源:
- 关键词:antineoplastics catecholamines cell free system cell growth regulation chemical structure function chemical substitution drug adverse effect drug design /synthesis /production drug metabolism enzyme inhibitors enzyme mechanism folate folate antagonist glutamate ammonia ligase glutamates glutamyltransferase hydrolysis macromolecule methotrexate methotrexate analog methyltransferase neoplasm /cancer chemotherapy neuroblastoma polyglutamates tissue /cell culture
项目摘要
During the period of support requested in this application,
we plan to continue our efforts on the synthesis of potent and
specific enzyme inhibitors based on enzyme mechanism data
obtained in our laboratory and from the literature. The
proposed studies involve a combination of synthetic organic
chemistry, mechanistic enzymology, and biochemical pharmacology.
The overall goal of our research is to investigate the role of
specific biochemical pathways in the control of cell growth.
More specifically, in the first portion of the research proposed
herein, we will continue our use of fluoroglutamate-containing
folates and antifols to assess the role of polyglutamate
biosynthesis and hydrolysis in mammalian cells. For example, we
will complete the synthesis of gamma-fluoroleucovorin and use it
to define the role of polyglutamates in leucovorin "rescue" of
cells following high-dose methotrexate chemotherapy. We will
also exploit our recent finding that 3,3-difluoroglutamate
(F2Glu) stimulates the formation of polyglutamates in cell-free
systems. Following improvement of the synthetic route to F2Glu,
we will synthesize a series of F2Glu-containing folates and
antifols in order to investigate the biochemical pharmacology of
compounds with enhanced ability to form polyglutamate
derivatives.
In the second portion of the proposed research we will
employ our new synthetic methodology for the synthesis of complex
acetylenic nucleosides. We will complete the synthesis of our
proposed specific "multisubstrate adduct inhibitors" of
methylases with which we have many years of experience (catechol
O-methyltransferase, phenethanolamine N-methyltransferase) and
study their effect on isolated enzymes. If these proposed new
methylase inhibitors are as specific and potent as predicted, we
will use them to study catecholamine biosynthesis in
neuroblastoma cells. As with the folate work, our ultimate goal
in this work is to develop potent and specific inhibitors of each
methyltransferase in order to study their role in cell growth
and/or cell function.
在本申请所要求的支持期间,
我们计划继续努力,
基于酶机制数据的特异性酶抑制剂
在我们的实验室和文献中获得。 的
拟议的研究涉及合成有机化合物,
化学、机械酶学和生化药理学。
我们研究的总体目标是调查
控制细胞生长的特定生化途径。
更具体地说,在研究的第一部分,
在此,我们将继续使用含氟代谷氨酸盐
叶酸和抗叶酸剂来评估聚谷氨酸的作用
在哺乳动物细胞中的生物合成和水解。 比如我们
将完成γ-氟亚叶酸的合成,
为了确定聚谷氨酸在亚叶酸“拯救”
高剂量甲氨蝶呤化疗后的细胞。 我们将
我还利用了我们最近的发现,
(F2 Glu)刺激无细胞环境中聚谷氨酸的形成。
系统. 在改进F2 Glu的合成路线后,
我们将合成一系列含F2 Glu的叶酸,
antifols,以研究的生化药理学
具有增强的形成聚谷氨酸盐能力的化合物
衍生物.
在研究的第二部分,我们将
采用我们新的合成方法合成复合物
炔属核苷 我们将完成我们的
建议的特定“多底物加合物抑制剂”,
甲基化酶,我们有多年的经验(儿茶酚
0-甲基转移酶、苯乙醇胺N-甲基转移酶)和
研究它们对分离酶的影响。 如果这些新提议
甲基化酶抑制剂的特异性和有效性与预测一样,我们
将用它们来研究
神经母细胞瘤细胞 与叶酸的研究一样,我们的最终目标
这项工作的目的是开发每种药物的有效且特异性的抑制剂
甲基转移酶,以研究它们在细胞生长中的作用
和/或细胞功能。
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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JAMES K COWARD其他文献
JAMES K COWARD的其他文献
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{{ truncateString('JAMES K COWARD', 18)}}的其他基金
MICHIGAN CHEMISTRY-BIOLOGY INTERFACE TRAINING PROGRAM
密歇根化学-生物界面培训计划
- 批准号:
2872594 - 财政年份:1996
- 资助金额:
$ 20.12万 - 项目类别:
MICHIGAN CHEMISTRY-BIOLOGY INTERFACE TRAINING PROGRAM
密歇根化学-生物界面培训计划
- 批准号:
6628716 - 财政年份:1996
- 资助金额:
$ 20.12万 - 项目类别:
MICHIGAN CHEMISTRY-BIOLOGY INTERFACE TRAINING PROGRAM
密歇根化学-生物界面培训计划
- 批准号:
2331910 - 财政年份:1996
- 资助金额:
$ 20.12万 - 项目类别:
MICHIGAN CHEMISTRY-BIOLOGY INTERFACE TRAINING PROGRAM
密歇根化学-生物界面培训计划
- 批准号:
2654884 - 财政年份:1996
- 资助金额:
$ 20.12万 - 项目类别:
MICHIGAN CHEMISTRY-BIOLOGY INTERFACE TRAINING PROGRAM
密歇根化学-生物界面培训计划
- 批准号:
6498485 - 财政年份:1996
- 资助金额:
$ 20.12万 - 项目类别:
MICHIGAN CHEMISTRY-BIOLOGY INTERFACE TRAINING PROGRAM
密歇根化学-生物界面培训计划
- 批准号:
2168449 - 财政年份:1996
- 资助金额:
$ 20.12万 - 项目类别:
MICHIGAN CHEMISTRY-BIOLOGY INTERFACE TRAINING PROGRAM
密歇根化学-生物界面培训计划
- 批准号:
6150922 - 财政年份:1996
- 资助金额:
$ 20.12万 - 项目类别:
MICHIGAN CHEMISTRY-BIOLOGY INTERFACE TRAINING PROGRAM
密歇根化学-生物界面培训计划
- 批准号:
6314362 - 财政年份:1996
- 资助金额:
$ 20.12万 - 项目类别:
RATIONAL DRUG DESIGN BASED ON CHEMICAL MECHANISMS
基于化学机制的合理药物设计
- 批准号:
6124477 - 财政年份:1987
- 资助金额:
$ 20.12万 - 项目类别:
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