PYRIMIDOAZEPINE BASED FOLATE--POTENTIAL ANTITUMOR AGENT

新的和更具选择性的抗癌药物的发现是 在我们与癌症的斗争中具有根本性的重要性。最近， 药物洛美曲索被发现具有良好的抗肿瘤活性 对一系列实体肿瘤的治疗，除了对 对甲氨蝶呤(MTX)产生抗药性的肿瘤 用于癌症化疗的抗叶酸药物。洛美曲索已经表现出了一些 动物试验结果显著(完全抑制肿瘤生长 每天6.25毫克/公斤，连续10天没有发现寄主毒性上升的证据 至每天100毫克/公斤)。洛美曲索的主要作用部位有 已被证明是对甘氨酰胺核糖核酸酶的抑制 甲酰转移酶(GARFT)在从头合成嘌呤中的关键作用 生物合成。 洛美曲索目前正在进行临床试验，用于治疗人类 肿瘤疾病。然而，一项研究表明，观察到的 这种药物在动物实验中的选择性不明显。 据报道，该化合物对人体有严重毒性。它是, 因此，制备结构修饰材料具有相当重要的意义 洛美曲索的类似物，目的是发现一种更有选择性、更少的 有毒，用于治疗人类癌症的试剂。 我们提出了一种通用的合成路线来选择12个 结构上与洛美曲索有关的嘧啶氮杂类叶酸盐，使用 以分子内1，3-偶极环加成化学为关键步骤。 在哺乳动物GARFT分析中测试这些化合物应该会增强我们的 了解叶酸的构效要求 与这种酶有关的抗代谢物质。我们的目标将会更远 在适当的肿瘤细胞培养试验中进行评估，以确定其 作为抗肿瘤药物的潜力。

The discovery of new and more selective anticancer agents is of fundamental importance in our struggle against cancers. Recently, the drug Lometrexol was discovered to exhibit excellent antitumor activity against a range of solid tumors, in addition to being active against tumors that have become resistant to methotrexate (MTX), a commonly used antifolate drug used in cancer chemotherapy. Lometrexol has shown some remarkable results in animal trials (complete inhibition of tumor growth at 6.25 mg/kg per day for ten days without evidence of host toxicity up to 100 mg/kg per day). The primary site of action of Lometrexol has been shown to be inhibition of the enzyme glycinamide ribonucleotide formyltransferase (GARFT) which plays a critical role in de novo purine biosynthesis. Lometrexol is currently in clinical trials for the treatment of human neoplastic diseases. However, one study has indicated that the observed selectivity of this drug in animal experiments was not apparent in humans and the compound was reported to show severe toxicity. It is, therefore, of considerable importance to prepare structurally modified analogs of Lometrexol with the aim of discovering a more selective, less toxic, agent for the treatment of human cancers. We propose a versatile synthetic route to twelve selected pyrimidoazepine-base folates, structurally related to Lometrexol, using intramolecular 1, 3-dipolar cycloaddition chemistry as a key step. Testing these compounds in mammalian GARFT assays should enhance our knowledge of the structure-activity requirements of folate antimetabolites with regard to this enzyme. Our targets will be further evaluated in appropriate tumor cell culture assays to determine their potential as antitumor agents.