Synthesis of Potential Antitumor Agents

潜在抗肿瘤药物的合成

• 批准号: 6413119
• 负责人: PARTHA S RAY
• 金额: $ 10.65万
• 依托单位: UNIVERSITY OF WEST GEORGIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6413119
• 关键词: antineoplastics; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; hydroxymethyltransferases; pyrimidine analog; tetrahydrofolates

The discovery of new and more selective anticancer agents is of fundamental importance in our struggle against cancers. In 1985 the drug 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) was discovered by Taylor et. al. and shown to exhibit excellent antitumor activity against a broad range of tumors. It was also active against tumors that have become resistant to methotrexate (MfX), a commonly used antifolate drug used in cancer chemotherapy. DDATHF 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 DDATHF has been shown to be inhibition of the enzyme glycinamide ribonucleotide formyltransferase (GARFT) which plays a critical role in de novo purine biosynthesis. The (6R) diastereomer of DDATHF, Lometrexol (LTX), 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 the animal experiments was not apparent in humans and the compound was reported to show "severe toxicity". This delayed, cumulative toxicity is reported to be ameliorated if the drug is co-administered with folic acid. The overall effectiveness of the drug is, however, somewhat diminished. A thiophene analog of LTX, (LY309887; 5) discovered by Lilly Research Laboratories, has been reported to have a 3-fold greater therapeutic index compared to LTX, and has recently entered phase I clinical trials. Also, Taylor and bowling have recently reported that a pyrimidoazepine-based derivative of DDATHF (8b) shows similar antitumor properties to DDATHF, via inhibition of GARFT. We have recently reported the synthesis and antitumor activity of a one-carbon shortened side chain analog of 8b, namely 8a. In this proposal we describe our rationale and proposed method to prepare four selected pyrimidodiazepine-based analogs of DDATHF and 8b, where the stereogenic carbon in the heterocyclic ring is replaced with a nitrogen atom. Consequently, unlike DDATHF and 8b which were prepared as a mixture of two diastemmers, only one stereoisomer of the drug will be isolated alleviating the need for a laborious separation of the diastereomers at the end of the synthesis or an expensive asymmetric synthetic approach We are confident that our designed pyrimidodiazepine-based folates will show promising antitumor properties via inhibition of GARFT. We are also hopeful that at least one of our four targets will possess a better therapeutic index than LTX and LY309887.

发现新的和更具选择性的抗癌药物对我们与癌症的斗争具有根本的重要性。1985年，Taylor等人发现了药物5,10-二氮杂-5,6,7,8-四氢叶酸（DDATHF），并显示出对多种肿瘤具有优异的抗肿瘤活性。它还对已经对甲氨蝶呤（MfX）产生耐药性的肿瘤有活性，甲氨蝶呤是一种常用的抗叶酸药物，用于癌症化疗。DDATHF在动物试验中显示出一些显著的结果（每天6.25 mg/kg，连续10天完全抑制肿瘤生长，没有证据表明每天高达100 mg/kg的宿主毒性）。DDATHF的主要作用位点是抑制甘氨酸酰胺核糖核苷酸甲酰转移酶（GARFT），该酶在从头嘌呤生物合成中起关键作用。DDATHF的（6R）非对映体，洛美曲醇（LTX），目前正在临床试验中用于治疗人类肿瘤疾病。然而，一项研究表明，该药物在动物实验中观察到的选择性在人体中并不明显，据报道该化合物显示出“严重毒性”。据报道，如果该药与叶酸合用，这种延迟的、累积的毒性会得到改善。然而，这种药物的总体效果有所减弱。Lilly研究实验室发现了一种LTX的噻吩类似物（LY309887; 5），据报道其治疗指数比LTX高3倍，最近已进入I期临床试验。此外，Taylor和bowling最近报道了一种基于嘧啶氮平的DDATHF衍生物（8b）通过抑制GARFT表现出与DDATHF相似的抗肿瘤特性。我们最近报道了8b的一碳短侧链类似物8a的合成及其抗肿瘤活性。在这个提议中，我们描述了我们的基本原理和提出的方法来制备四种基于嘧啶二氮平的DDATHF和8b类似物，其中杂环上的立体碳被一个氮原子取代。因此，不像DDATHF和8b是作为两种非对映体的混合物制备的，药物的一个立体异构体将被分离，减轻了在合成结束时分离非对映体的繁琐工作或昂贵的不对称合成方法的需要。我们相信，我们设计的基于嘧啶二氮平的叶酸将通过抑制GARFT显示出有希望的抗肿瘤特性。我们也希望我们的四个靶点中至少有一个具有比LTX和LY309887更好的治疗指数。