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Function oriented synthesis of bioactive marine natural products and their pharmacophore analogues

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Title: Function oriented synthesis of bioactive marine natural products and their pharmacophore analogues
Author: Meimetis, Labros George
Degree Doctor of Philosophy - PhD
Program Chemistry
Copyright Date: 2012
Publicly Available in cIRcle 2012-07-16
Abstract: Natural products play a central role in drug discovery. The Andersen lab focuses its efforts on the isolation and structure elucidation of compounds from the marine environment. Many of these compounds possess biological activity, and often their total synthesis is undertaken, to provide structure-activity relationship (SAR) studies for new pharmacophores, and to provide material to probe in vivo biological effects. Several projects probing the biological activities of natural products and their analogues by synthesis were completed. It has been proposed that small molecule activators of SHIP1 may be used as a novel therapy for hematopoietic malignancies as well as inflammatory disorders. Activation of the SHIP1 enzymatic pathway may also provide an alternative to PI3K inhibition. An SAR study based on the SHIP1 activating marine natural product pelorol was completed. The goal of the SAR study was to construct water-soluble analogues for the purpose of enhancing drug-like properties. The study yielded analogues that were active in vitro and in vivo. Small molecule antagonists of the N-terminal domain (NTD) of the androgen receptor (AR) are an appealing avenue of exploration for treating CRPC, an advanced form of prostate cancer resistant to current therapies. The marine natural products niphatenone A and B represent a novel NTD-AR antagonist pharmacophore. Their total syntheses were completed to aid in structure determination and provide additional material for biological testing. Furthermore, a click chemistry probe was constructed and it was shown that the natural product covalently binds to the NTD of the AR. Small molecule AR antagonists are currently used as a therapeutic treatment for prostate cancer. Studies towards the total synthesis of a terpene marine natural product discovered to be an AR antagonist are described. The biological role of cathepsin K in bone resorption has led to the development of inhibitors of cathepsin K as potential therapeutics to combat osteoporosis. Lichostatinal, a novel peptide-aldehyde natural product isolated from cultures of a terrestrial actinomycete was found to be a potent inhibitor of cathepsin K. Synthetic efforts towards lichostatinal, in order to verify its structure and to provide additional material for biological testing is described.
URI: http://hdl.handle.net/2429/42710
Scholarly Level: Graduate

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