Novel Synthetic Routes to Frondosins A-E

描述（由申请人提供）：拟议研究的主要科学目标是开发合成多环类环庚烷环系统的有效方法，该系统类似于在天然产物的生物活性frondosin家族中发现的系统。所有五个已知的frondosins（A-E）都是新的倍半萜氢醌衍生物，已发现它们是低微摩尔水平的蛋白激酶C抑制剂和白细胞介素-8（IL-8）拮抗剂。这类的两个成员也被发现具有抗艾滋病毒活性。蛋白激酶C已被证明在细胞信号传导中发挥重要作用，而IL-8（一种中性粒细胞激活肽）是由多种细胞类型响应炎症而产生的。白细胞介素-8也与几种人类癌症的肿瘤进展和转移有关，并且它参与T淋巴细胞和巨噬细胞中的化学吸引、新血管形成和HIV-1复制的刺激。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，用于开发新的抗炎剂以治疗几种急性和慢性炎性疾病，如类风湿性关节炎、银屑病和哮喘。此外，IL-8代表了针对HIV-1的抗逆转录病毒疗法的新靶点，并且IL-8作用的抑制剂可以提供有用的抗癌治疗剂。本研究的具体目标是：（A）发展和扩大串联环化-Claisen重排方法制备frondosins A-E环体系的范围;（B）应用各种合成策略来合成实际的天然产物及其紧密类似物，（C）研究frondosin A及其紧密类似物向frondosin类的其它成员的潜在转化，和（D）提供用于生物学试验的合成中间体样品。

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.