Novel Synthetic Routes to Frondosins A-E

Frondosins A-E 的新合成路线

• 批准号: 7069758
• 负责人: TIMO V. OVASKA
• 金额: $ 20.55万
• 依托单位: CONNECTICUT COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069758
• 关键词: analog; chemical addition; combinatorial chemistry; cyclization; heterocyclic polycyclic compound; hydroquinones; inhibitor /antagonist; interleukin 8; method development; protein kinase C; sesquiterpenes

DESCRIPTION (provided by applicant): The principal scientific goal for the proposed research is to develop efficient methodology for the synthesis of polycyclic cycloheptanoid ring systems analogous to those found in the biologically active frondosin family of natural products. All five of the known frondosins (A-E) are novel sesquiterpene hydroquinone derivatives, which have been found to be inhibitors of protein kinase C and antagonists of interleukin-8 (IL-8) at the low micromolar level. Two members of this class have also been found to possess anti-HIV activity. Protein kinase C has been shown to play a major role implicated in cellular signal transduction and IL-8, a neutrophil-activating peptide, is produced by several cell types in response to inflammation. Interleukin-8 has also been implicated in tumor progression and metastasis in several human cancers, and it is involved in chemoattraction, neovascularization, and stimulation of HIV-1 replication in both T-lymphocytes and macrophages. Thus, IL-8 antagonists hold therapeutic potential as valuable lead compounds for the development of novel anti-inflammatory agents to treat several acute and chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, and asthma. In addition, IL-8 represents a new target for anti-retroviral therapy against HIV-1, and inhibitors of IL-8 actions may provide useful therapeutic agents against cancer. The specific goals for the proposed research are: (A) to develop and extend the scope of the tandem cyclization-Claisen rearrangement methodology for the preparation of the ring systems of frondosins A-E; (B) to apply various synthetic strategies to synthesize the actual natural products and their close analogues, (C) to investigate the potential conversion of frondosin A and its close analogues to other members of the frondosin class, and (D) to provide samples of synthetic intermediates for biological testing.

描述(申请人提供)：拟议研究的主要科学目标是开发合成多环庚烷环状体系的有效方法，类似于生物活性的前列环素天然产物家族中发现的那些环庚烷环体系。所有已知的五个前列环素(A-E)都是新的倍半萜对苯二酚衍生物，它们被发现在低微摩尔水平上是蛋白激酶C的抑制剂和白细胞介素8(IL-8)的拮抗剂。这一类中的两名成员也被发现具有抗艾滋病毒活性。蛋白激酶C被证明在细胞信号转导中发挥重要作用，IL-8是一种中性粒细胞活化肽，由几种类型的细胞产生，以应对炎症。白介素8还参与了几种人类癌症的进展和转移，它还参与了T淋巴细胞和巨噬细胞中的化学吸引、新生血管和刺激HIV-1复制。因此，IL-8拮抗剂具有作为有价值的先导化合物的治疗潜力，可用于开发新型抗炎药来治疗几种急性和慢性炎症性疾病，如类风湿性关节炎、牛皮癣和哮喘。此外，IL-8代表了针对HIV-1的抗逆转录病毒治疗的新靶点，而IL-8作用的抑制剂可能会提供有用的癌症治疗剂。拟议研究的具体目标是：(A)开发和扩大串联环化-Claisen重排方法的范围，以制备前列环素A-E的环系；(B)应用各种合成策略来合成实际的天然产物及其接近的类似物；(C)研究前列环素A及其接近的类似物对前列环素类其他成员的潜在转化；以及(D)提供用于生物测试的合成中间体的样品。