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CHEMICAL SWITCHING OF TAXO-DITERPENOIDS BETWEEN LOW SOLUBILITY ACTIVE FORMS AND HIGH SOLUBILITY INACTIVE FORMS
CHEMICAL SWITCHING OF TAXO-DITERPENOIDS BETWEEN LOW SOLUBILITY ACTIVE FORMS AND HIGH SOLUBILITY INACTIVE FORMS
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机译:低溶解度活性形式和高溶解度非活性形式之间的税基二萜类化合物的化学交换
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摘要
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-Cn,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. Preferred taxo-diterpenoids include taxol, C-2 substituted taxol, and TaxotereTM. These same onium salts of taxo-diterpenoid-Cn,2-O-aza-arenes are employed as water soluble prodrugs. For example, taxol-2'-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'-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 mimetics having hydroxyls that are reactive with onium salts of 2-halogenated-aza-arenes. For example, taxol and Taxotere each have reactive hydroxyls at the 2' and 7 positions. The invention is also applicable to a wide array of 2-halogenated-aza-arenes.
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