Research Project
7069758
[unreadable] 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. [unreadable] [unreadable] [unreadable]
