Patent Number: 6,252,094

Title: Chemical switching of taxo-diterpenoids between low solubility active forms and high solubility inactive forms

Abstract: Cyclic chemical switching method is employed for solubilizing and desolubilizing taxo-diterpenoids with respect to aqueous solvents. 2-Halogenated onium salts of aza-arenes are employed to derivatize taxo-diterpenoids so as to alter their solubility in aqueous solvents. The onium salt of aza-arene includes a delocalized charge which imparts polarity and aqueous solubility to taxo-diterpenoid derivatives. Solubilization is achieved in a one step derivatization with the onium salt of 2-halogenated aza-arenes. Desolubilization is achieved by contacting onium salts of taxo-diterpenoid-C.sup.n,2-O-aza-arenes with serum protein to displace the 2-O-aza-arene and form a soluble protein:taxo-diterpenoid intermediate. This protein:taxo-diterpenoid intermediate then dissociates over time to provide a bioactive taxo-diterpenoid. These same onium salts of taxo-diterpenoid-C.sup.n,2-O-aza-arenes are employed as water soluble prodrugs. The toxicity of the activated form is comparable or greater than underivatized taxol. The invention is applicable to taxol and taxol memetics having hydroxyls that are reactive with onium salts of 2-halogenated-aza-arenes.

Inventors: Nicolaou; K. C. (La Jolla, CA), Wrasidlo; Wolfgang (Berlin, DE), Guy; Rodney K. (Alameda, CA), Pitsinos; Emmanuel (Strosbourg, FR)

Assignee: The Scripps Research Institute

International Classification: C07D 405/00 (20060101); C07D 405/12 (20060101); C07D 305/14 (20060101); C07D 405/14 (20060101); C07D 305/00 (20060101); C07D 409/00 (20060101); C07D 413/00 (20060101); C07D 409/12 (20060101); C07D 409/14 (20060101); C07D 413/14 (20060101); C07F 7/00 (20060101); C07D 417/14 (20060101); C07F 7/18 (20060101); C07D 417/00 (20060101); C07D 305/14 ()

Expiration Date: 06/26/2018