BETA TURN PEPTIDOMIMETICS AS FARNESYL--PROTEIN TRANSFERASE INHIBITORS

作为法尼基蛋白转移酶抑制剂的β转肽模拟物

• 批准号: 5212300
• 负责人: SAMUEL E WATSON
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5212300
• 关键词: chemical models; conformation; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; farnesyl compound; transferase

There has been enormous recent interest in the design and synthesis of peptidomimetic compounds as proteolytically stable surrogates for medicinally active peptides. One active area of synthetic interest in this regard is in the design and synthesis of mimics of the terminal amino acid residues of the Ras proteins. Mutated forms of the Ras proteins in which the necessary autohydrolytic function has been impaired have been implicated in the transformation of normal cells into malignant cells and are involved in the etiology of up to 50% of all colon and pancreatic cancers. In so far as the Ras proteins require the presence of a farnesyl group at a terminal residue for activity, it has been found that inhibition of farnesyl transferase, the enzyme responsible for this post- translational modification, is an effective new chemotherapeutic strategy for the treatment of cancer. There is some recent NMR evidence that the terminal four residues of the Ras protein, the so-called CAAX box, adopt a beta-turn conformation in the bound state. An extensive molecular modeling study using the native Ras terminal tetrapeptide constrained into a beta-turn conformation has therefore been undertaken and a series of non-peptide bicyclic compounds has been designed so as to orient the critical recognition elements into the desired turn conformation. These rationally designed molecules will be used both as probes of the natural bound conformation of the Ras substrate and as potential non-peptidic inhibitors of farnesyl transferase and possible new chemotherapeutic agents. The synthesis of the bicyclic ring scaffolds themselves raises some interesting chemical questions as to the control of stereochemistry at one of the ring fusion centers and are of general interest as new type I beta-turn mimics. Biological testing of the compounds will be done in collaboration with researchers at the University of Pittsburg.

最近，人们对以下化合物的设计和合成产生了极大的兴趣： 作为蛋白水解稳定替代物的肽模拟化合物 药用活性肽。 一个活跃的综合领域， 这方面是在末端氨基的模拟物的设计和合成 Ras蛋白的酸性残基。 Ras蛋白的突变形式 其必要的自水解功能已被削弱， 参与正常细胞向恶性细胞的转化， 与高达50%的结肠和胰腺癌的病因有关， 癌的 由于Ras蛋白需要法呢基的存在， 在末端残基上具有活性基团时，已经发现， 法尼基转移酶的抑制，该酶负责这一后- 翻译修饰是一种有效的新的化疗策略 用于治疗癌症。 最近有一些核磁共振证据表明， Ras蛋白的末端四个残基，即所谓的CAAX盒，采用 结合状态下的β-转角构象。 一种广泛的分子 使用天然Ras末端四肽限制到 因此，进行了β-转角构象，并进行了一系列 已经设计了非肽双环化合物， 关键的识别元素转化为所需的转弯构象。 这些 合理设计的分子将被用作自然界的探针， Ras底物的结合构象和作为潜在的非肽 法呢基转移酶抑制剂和可能的新的化学治疗剂 剂. 双环骨架本身的合成提高了 一些关于立体化学控制的有趣的化学问题 在环融合中心之一，并作为新的类型普遍感兴趣 我是模仿者 化合物的生物学试验将在 这是一项与汉堡大学的研究人员合作的研究。