ANTIFOLATES INHIBITORY TO FOLYLPOLYGLUTAMATE SYNTHETASE

抑制叶酰聚谷氨酸合成酶的抗叶酸剂

• 批准号: 3179005
• 负责人: RICHARD G MORAN
• 金额: $ 21.45万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 1993-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3179005
• 关键词: adenosine triphosphate; antimetabolites; antineoplastics; cell cycle; dihydrofolate reductase; drug design /synthesis /production; drug metabolism; drug screening /evaluation; enzyme inhibitors; folate antagonist; glutamates; laboratory mouse; ligase; methotrexate; neoplasm /cancer chemotherapy; neoplastic cell; ornithine; polyglutamates; tissue /cell culture

Mammalian folypoly-gamma-glutamate synthetase (FPGS) converts folylmonoglutamates, the transport form of folates, into their polyglutamate congeners by the successive addition of glutamic acid monomers using, ATP a source of energy. The underlying thesis of this work is that inhibitors of FPGS will be a unique new class of antimetabolites that will be useful as cancer chemotherapeutic drugs. The folylpolyglutamates are retained in cells, in contrast to the effluxable monoglutamates, and are the preferred form of cofactor for the folate-dependent enzymes. FPGS has been shown to be an essential function for a dividing cell population. The goal of this proposal is to design and synthesize potent and selective inhibitors of mammalian FPGS and to study the cellular and biochemical effects of this unique new class of folate antimetabolites. The synthesis of some folate analogs predicted to be analogs of the transition states and of the intermediate product of the FPGS reaction will be undertaken and the interaction of these compounds with purified FPGS will be studied. Second generation analogs of the potent FPGS inhibitor 4-amino-4- deoxypteroyl-L-ornithine will be prepared that penetrate the cell membrane efficiently or that are prodrugs converted to inhibitors in the cell. Other compounds to be made would be more potent analogs of this lead compound or would have no activity as dihydrofolate reductase. Finally, the interaction of the side chain of folate analogs with the active site of FPGS would be further investigated. The effects of these new compounds will be studied on purified mammalian FPGS and on the function of FPGS in whole cells. Inhibition of folate metabolism by existing antagonists of folate metabolism (which, until recently, have been uniformly dihydrofolate reductase inhibitors) has been very useful for treatment of human neoplasms. Antifolates are active against a spectrum of malignancies arising in different tissues, have managable toxicities, have low or non-existent mutagenic and carcinogenic threat and are reversible by reduced folates. We propose that inhibitors of FPGS will share these beneficial characteristics, yet will have a mechanism distinct from that of classical antifolates such as methotrexate.

哺乳动物叶酸聚-γ-谷氨酸合成酶 (FPGS) 转化 叶酰单谷氨酸盐，叶酸的运输形式，进入其 通过连续添加谷氨酸形成聚谷氨酸同系物 单体利用ATP作为能量来源。 的基础论文 这项工作表明 FPGS 抑制剂将成为一类独特的新型药物 可用作癌症化疗药物的抗代谢药 药物。 相比之下，叶酰聚谷氨酸保留在细胞中 到可流出的单谷氨酸盐，并且是优选的形式 叶酸依赖性酶的辅助因子。 FPGS 已被证明可以 是分裂细胞群的一个重要功能。 目标 该提案的目的是设计和合成有效且有选择性的 哺乳动物 FPGS 抑制剂并研究细胞和 这种独特的新型叶酸的生化作用 抗代谢药。 一些叶酸类似物的合成预测 是过渡态和中间态的类似物 FPGS反应的产物将被进行并且相互作用 将研究这些化合物与纯化 FPGS 的关系。 第二 强效 FPGS 抑制剂 4-amino-4- 的一代类似物 将制备可穿透细胞的脱氧蝶酰-L-鸟氨酸 膜有效或前药转化为抑制剂 在细胞中。 其他要制造的化合物会更有效 该先导化合物的类似物或没有活性 二氢叶酸还原酶。 最后是侧面的互动 具有 FPGS 活性位点的叶酸类似物链将是 进一步调查。 这些新化合物的作用将是 对纯化的哺乳动物 FPGS 及其在 FPGS 中的功能进行了研究 全细胞。 现有叶酸拮抗剂对叶酸代谢的抑制 新陈代谢（直到最近，人们一直一致认为 二氢叶酸还原酶抑制剂）对于 人类肿瘤的治疗。 抗叶酸剂可有效对抗 不同组织中出现的一系列恶性肿瘤 毒性可控，致突变性低或不存在 致癌威胁，并且可以通过减少叶酸来逆转。 我们 提出 FPGS 抑制剂将分享这些有益的 特征，但将具有与 经典的抗叶酸药物，例如甲氨蝶呤。