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Chemical studies of anti-inflammatory secondary metabolites from marine sponges Yang, Lu

Abstract

SHIP is a 145 kDa SH2-domain-containing inositol 5-phosphatase. It has been proposed that upregulation of SHIP activity with small molecule agonists of SHIP could control inflammation. At the outset of the research there were no known modulators of SHIP activity. A library of marine invertebrate extracts was screened for SHIP activators. A previously described meroterpenoid, pelorol, that represents the first known SHIP activator was isolated from a tropical sponge Dactylospongia elegans (Thiele, 1899). In vitro studies of pelorol have shown that it is able to activate SHIP'S enzyme activity in intact cells and inhibits activation of macrophages, an essential component of the innate and acquired immune response in inflammatory diseases. A total synthesis of pelorol and its analogs was undertaken in order to flesh out the structure activity of this family of anti-inflammatory compounds. One of these analogs, AQX-16A, showed a 3-fold higher activation of SHIP than pelorol at the same molar concentration. It represents a novel class of drugs which activates a physiologically important negative regulator of the PI3K pathway in hemopoietic cells. Stereoselectivity is an important impact factor in drug action. Several stereo- and regio- isomers of pelorol and its analogs have been synthesized to answer the questions of how [Chemical Diagrams] the regiochemistry of the aromatic ring of pelorol affects its activity and whether the stereochemistry of the C-ring is important for the SHIP activating properties of pelorol. Contignasterol was isolated by our group in 1992 from the sponge Petrosia contignata collected in Papua New Guinea. It was the first example of an emerging family of sponge steroids that have a number of unprecedented structural features. Contignasterol was found to inhibit the release of histamine from sensitized rat mast cells stimulated with anti-lge. IZP576-092, an antiasthma drug developed from the contignasterol lead structure, is now in Phase II human clinical trials. The structure of contignasterol was initially solved by interpretation of spectroscopic data. At the time, the absolute configuration of the side chain chiral centers was not determined. A reinvestigation of the structure of contignasterol using a combination of spectroscopic analysis and chemical degradation has now resulted in the determination of the complete absolute configuration of the molecule. [Chemical Diagrams]

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