BETA TURN PEPTIDOMIMETICS AS FARNESYL--PROTEIN TRANSFERASE INHIBITORS

最近，人们对设计和合成三聚氰胺非常感兴趣 拟肽类化合物作为蛋白质分解稳定的替代物 具有药用活性的多肽。人工合成兴趣的一个活跃领域 这方面是在末端氨基的模拟物的设计和合成方面。 RAS蛋白的酸残基。Ras蛋白的突变形式 其必需的自水解功能已经受损 与正常细胞向恶性细胞的转化有关 与高达50%的结肠和胰腺的病因学有关 癌症。在RAS蛋白需要法尼基存在的情况下 在末端残基为活性基团时，已发现 抑制法尼基转移酶，负责这一后- 翻译修饰是一种有效的化疗新策略 用于治疗癌症。最近的一些核磁共振证据表明， RAS蛋白的四个末端残基，即所谓的CAAX盒，采用 束缚态下的β转角构象。一种广泛的分子 利用天然RAS末端四肽约束的模建研究 因此，已经进行了贝塔转弯构象，并进行了一系列 非肽类双环化合物被设计成能够定向 关键识别元件转变为所需的转折构象。这些 设计合理的分子将既用作天然的探针 RAS底物与AS潜在非肽的结合构象 法尼基转移酶抑制剂及可能的新化疗药物 探员们。双环支架的合成本身提高了 关于立体化学控制的一些有趣的化学问题 在环状融合中心之一，并作为新类型受到普遍关注 我是贝塔翻转模仿者。这些化合物的生物测试将于#年进行。 与匹兹堡大学的研究人员合作。

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.