ANTIFOLATES INHIBITORY TO FOLYLPOLYGLUTAMATE SYNTHETASE

哺乳动物叶酸聚-γ-谷氨酸合成酶（FPGS）将 叶酸单谷氨酸盐，叶酸的运输形式，进入它们的 通过连续加入谷氨酸 ATP是能量的来源。 的基本论点 这项工作是，抑制剂的FPGS将是一个独特的新类别， 可用作癌症化疗剂的抗代谢物 毒品 相比之下，叶酸聚谷氨酸被保留在细胞中， 与可流出的单谷氨酸盐有关，并且是 叶酸依赖酶的辅助因子。 FPGS已被证明 是分裂细胞群的基本功能。 目标 设计和合成有效的和选择性的 哺乳动物FPGS的抑制剂，并研究细胞和 这种独特的新型叶酸的生化作用 抗代谢物 叶酸类似物的合成预测 是过渡态和中间体的类似物 将进行FPGS反应的产物， 将研究这些化合物与纯化的FPGS的反应。 二 有效的FPGS抑制剂4-氨基-4- 将制备穿透细胞的脱氧蝶酰-L-鸟氨酸 膜有效地或前药转化为抑制剂 在牢房里 其他的化合物会更有效 这种先导化合物的类似物或将不具有活性， 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。 这些新化合物的效果将是 研究了哺乳动物FPGS的纯化及其在哺乳动物中的功能。 全细胞 现有叶酸拮抗剂对叶酸代谢的抑制作用 新陈代谢（直到最近， 二氢叶酸还原酶抑制剂）已经非常有用， 治疗人类肿瘤。 抗叶酸剂对一种 不同组织中出现的恶性肿瘤谱， 毒性可控，具有低致突变性或不存在致突变性， 致癌的威胁，并通过减少叶酸可逆。 我们 我认为FPGS的抑制剂将分享这些有益的 特征，但将有一个机制不同于 典型的抗叶酸剂如甲氨蝶呤。

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.