Synthesis of Potential Antitumor Agents

新的和更具选择性的抗癌药物的发现在我们与癌症的斗争中具有根本的重要性。1985年，Taylor等人发现了药物5，10-二氮-5，6，7，8-四氢叶酸(DDATHF)。艾尔并显示出对多种肿瘤具有良好的抗肿瘤活性。它对对甲氨蝶呤(MFX)产生抗药性的肿瘤也很有效，甲氨蝶呤是癌症化疗中常用的抗叶酸药物。DDATHF在动物试验中显示出一些显著的效果(每天6.25毫克/公斤，连续10天完全抑制肿瘤生长，而没有证据表明宿主毒性高达100毫克/公斤/天)。DDATHF的主要作用部位已被证明是抑制甘氨酰胺核糖核苷酸甲酰转移酶(GARFT)，该酶在从头合成嘌呤的过程中起关键作用。DDATHF的(6R)非对映异构体洛美曲索(LTX)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，在动物实验中观察到的这种药物在人类身上的选择性并不明显，据报道，该化合物显示出“严重毒性”。据报道，如果该药物与叶酸联合给药，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。礼来研究实验室发现了一种LTX的噻吩类类似物(LY309887；5)，据报道，与LTX相比，它的治疗指数高出3倍，最近进入了I期临床试验。此外，Taylor和Bowling最近报道了一种基于嘧啶氮杂卓类化合物的DDATHF(8b)通过抑制GARFT而显示出与DDATHF相似的抗肿瘤特性。我们最近报道了一种一碳缩短的侧链类似物8b，即8a的合成及其抗肿瘤活性。在这项建议中，我们描述了我们的基本原理和建议的方法来制备四个精选的基于嘧啶二氮卓类化合物的DDATHF和8b，其中杂环上的立体碳被氮原子取代。因此，与DDATHF和8b不同，DDATHF和8b是作为两种非对映异构体的混合物制备的，只会分离出药物的一个立体异构体，从而减轻了合成结束时繁琐的非对映异构体分离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卓类化合物的叶酸盐将通过抑制GARFT显示出良好的抗肿瘤性能。我们还希望，我们的四个靶点中至少有一个将拥有比LTX和LY309887更好的治疗指数。

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.