The Scripps Research Institute

Rodney K Guy

K C Nicolaou

Philippe G Nantermet

Hiroaki Ueno

Wolfgang Wrasidlo

Emmanuel Pitsinos

Kyriacos Costa Nicolaou

Kc Nicolaou

Onium salts of taxo-diterpenoid-C,,2-O-aza-arenes form water soluble self-assembling nanostructures above a critical aggregation concentration. The onium salt of aza-arene includes a delocalized charge which renders derivatized taxo-diterpenoids amphoteric, enhances their solubility in water, and promotes self-assembly of water soluble nanostructures, e.g., helical fibular structures and spherical micellular structures. These same onium salts of taxo-diterpenoid-C,,2-O-aza-arenes are employed as water soluble prodrugs. For example, taxol-2&prime;-methylpyridinium tosylate (MPT) is characterized by an elevated aqueous solubility, rapid activation by serum protein, good stability in most other aqueous solutions, formation of a protein:taxol intermediate and good retention within the circulatory system. The toxicity of the activated form is comparable or greater than underivatized taxol. Furthermore, taxol-2&prime;-MPT can be synthesized by a simple one step reaction between taxol and 2-fluoro-1-MPT. The invention is applicable to taxol and taxol memetics having hydroxyls that are reactive with onium salts of 2-halogenated-aza-arenes. For example, taxol, C-2 substituted taxol and Taxotere each have reactive hydroxyls at the 2&prime; and 7 positions. The invention is also applicable to a wide array of 2-halogenated-aza-arenes.

Self-assembled taxo-diterpenoid nanostructures

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,,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,,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.

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

A method for esterifying C13 deoxy taxoid intermediates employs three steps, i.e., oxygenation of the C13 deoxy taxoid intermediate to produce a C13 enone taxoid intermediate; reduction of the C13 enone to produce an alcohol; followed by esterification of the C13 alcohol. Key intermediates include C13 deoxy taxoids; C13 enone substituted taxoids; and C1-C2 cyclo carbonate esters of taxoids.

Transformations of taxol

Water soluble onium salt of taxo-diterpenoid

Transformations of taxol, baccatin III and of 10-deacetyl baccatin III provide access to novel taxol analogs and key intermediates thereto.

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San Diego, CA, United States of America

Rodney K Guy