ANTIFOLATES INHIBITORY TO FOLYLPOLYGLUTAMATE SYNTHETASE

哺乳动物叶多聚-γ-谷氨酸合成酶(FPGS)转换 叶酸的运输形式--叶酸单谷氨酸盐 由谷氨酸连续加成的多谷氨酸同系物 使用，三磷酸腺苷作为能量来源的单体。的基本命题 这项工作表明，FPGS的抑制剂将是一类独特的新的 可作为癌症化疗药物的抗代谢药物 毒品。相比之下，叶基多谷氨酸盐保留在细胞内 到可流出的单谷氨酸盐，并且是 叶酸依赖酶的辅因子。FPGS已经被证明是 对于分裂的细胞群体来说是一个必不可少的功能。目标是 这个建议的目的是设计和合成有效的和有选择性的 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物化学效应 抗代谢药。一些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反应的产物和相互作用 其中含有纯化的FPGS的化合物将被研究。第二 有效的FPGS抑制剂4-氨基-4-氨基-4- 将制备可穿透细胞的脱氧蝶酰-L-鸟氨酸 有效的膜或前药转化为抑制剂 在牢房里。其他将要制造的化合物将会更有效 该先导化合物的类似物或将不具有任何活性 二氢叶酸还原酶。最后，双方的互动 具有FPGS活性部位的叶酸类似物的链将是 进一步调查。这些新化合物的影响将是 哺乳动物FPGS的纯化及其功能的研究 整个细胞。 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，新陈代谢一直是一致的 二氢叶酸还原酶抑制剂)对 人类肿瘤的治疗。抗叶酸对一种 发生在不同组织中的各种恶性肿瘤，有 毒性可控，具有很低或根本不存在的诱变性和 具有致癌威胁，并可通过减少叶酸而逆转。我们 建议FPGS的抑制剂将分享这些益处 特征，但将有一个不同于 经典的抗叶酸，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.