Direct and Practical Synthetic Route to Pseudopterosins: Important Anti-Inflammatory, Anti-Pain, and Anti-Irritant Compounds

Summary Background: The pseudopterosins are a group of diterpene glycosides isolated from the Caribbean sea whip, Pseudopterogorgia elisabethae. The pseudopterosins represent an important structural class of anti-inflammatory and analgesic metabolites, and exhibit superior analgesic activity compared to industrial standards such as indomethacin. They appear to work by inhibiting the synthesis of eicosanoids in specific white blood cells called polymorphonuclear leukocytes. This potency and the fact that their biological mode of action appear to be novel have made these substances (and their analogues) attractive targets for synthetic as well as biological/biochemical research. Further interest in the pseudopterosins derives from their commercial use as topical antiinflammatory agents in the cosmetic field and the limited supply available from natural sources. In addition, one of the pseudopterosins is currently used in the Estée Lauder cosmetic skin care product Resilience® as an additive to prevent irritation caused by exposure to the sun or other chemical irritants. Due to the pharmaceutical potential and cosmetic applications, many have been active in the development of biotechnological production methods of the pseudopterosins.

Invention: A novel synthetic route to pseudopterosin compounds. This very direct and practical route includes a key intermediate that allows for synthesis in quantity. The important steps in the synthetic methods are also of broader interest from the viewpoint of general synthetic methodology, including (1) the use of an inexpensive, recoverable lipase to effect separation of diastereomers (2) a new procedure for aromatic annulation (3) the remarkable stereoselective cyclizations and (4) the superiority of MnO2 as a mild reagent for aromatization of cyclohexadienes.

Applications Advantages: The synthetic procedure has a number of advantages over previously known methods; including:

-Inexpensive chiral starting material (limonene)
-Use of common or readily available reagents -Stereocontrol and selectivity -Simplicity of execution -Good yields -Directness

Applications: Pseudopterosins have been shown to possess potent anti-inflammatory and analgesic (pain relief) properties as well as palliative for irritant contact dermatitis. A pseudopterosin extract has found its way to the non-pharmaceutical marketplace as an additive to prevent skin irritation in a line of Estèe Lauder cosmetic skin care products.

Publications: E.J. Corey et al., A direct and efficient stereocontrolled synthetic route to the pseudopterosins: potent marine anti-inflammatory agents. J. Am. Chem. Soc. 1998, 120, 12777-82.

E.J. Corey et al., Syntheses and stereochemical revision of pseudopterosin G-J aglycone and helioporin E. Org. Lett. 2000, 2(15), 2389-92.

Patents: 6,423,877 and 6,576,781 For Further Information Please Contact the Director of Business Development Laura Brass Email: [email protected] Telephone: (617) 495-3067

Inventor(s): Corey, Elias J

Type of Offer: Licensing



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