PYRIMIDOAZEPINE BASED FOLATE--POTENTIAL ANTITUMOR AGENT

新的和更有选择性的抗癌剂的发现， 在我们与癌症的斗争中至关重要。近日 药物洛美沙星被发现表现出优异的抗肿瘤活性 针对一系列实体瘤，除了对 对甲氨蝶呤（MTX）耐药的肿瘤， 用于癌症化疗的抗叶酸药物。 洛美沙星显示出一些 在动物试验中的显著结果（完全抑制肿瘤生长 以6.25 mg/kg/天剂量给药10天，无宿主毒性证据 至100 mg/kg/天）。 洛美沙星的主要作用部位有 已被证明是抑制酶甘氨酰胺核糖核苷酸 甲酰基转移酶（GARFT），在从头嘌呤 生物合成 洛美沙星目前正处于临床试验中，用于治疗人类 肿瘤性疾病 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并不明显， 据报道，该化合物显示出严重的毒性。 是的， 因此，制备结构修饰的 洛美沙星类似物，目的是发现一种更具选择性， 有毒的，用于治疗人类癌症的药剂。 我们提出了一种多功能的合成路线， 嘧啶氮杂基叶酸，结构上与洛美沙星有关，使用 分子内1，3-偶极环加成反应是关键步骤。 在哺乳动物GARFT试验中测试这些化合物应该可以增强我们的 了解叶酸的结构-活性要求 抗代谢物的作用。 我们的目标会更远 在适当的肿瘤细胞培养试验中进行评价，以确定其 作为抗肿瘤剂的潜力。

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.