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No auxiliary, no byproduct strategy for water-soluble prodrugs of taxoids: scope and limitation of O-N intramolecular acyl and acyloxy migration reactions. 2005

Mariusz Skwarczynski, and Youhei Sohma, and Mayo Noguchi, and Maiko Kimura, and Yoshio Hayashi, and Yoshio Hamada, and Tooru Kimura, and Yoshiaki Kiso
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.

Since numerous new taxoids active against multidrug resistant (MDR) tumors have been developed and their poor water-solubility is a very real problem in intravenous administration, we have designed and synthesized a series of novel water-soluble taxoid prodrugs (isotaxoids). These prodrugs, a 2'-O-isoform of taxoids, showed promising results with higher water solubility (0.8-1.1 mg/mL) and proper kinetics for parent drug release by a simple pH-dependent chemical mechanism via O-N intramolecular acyl migration. No additional functional auxiliaries are released during the conversion to parent drugs, which would be an advantage in toxicology and general pharmacology, and the cost for the evaluations of auxiliary units in these fields could be saved in prodrug development. In addition, we demonstrate for the first time the successful application of the O-N intramolecular acyloxy migration reaction in the prodrug design, with the exception of the tert-butyloxycarbonyl group, and that this reaction can be provided with no organic solvent and no side products.

UI MeSH Term Description Entries
D011355 Prodrugs A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug. Drug Precursor,Drug Precursors,Pro-Drug,Prodrug,Pro-Drugs,Precursor, Drug,Precursors, Drug,Pro Drug,Pro Drugs
D004355 Drug Stability The chemical and physical integrity of a pharmaceutical product. Drug Shelf Life,Drugs Shelf Lives,Shelf Life, Drugs,Drug Stabilities,Drugs Shelf Life,Drugs Shelf Live,Life, Drugs Shelf,Shelf Life, Drug,Shelf Live, Drugs,Shelf Lives, Drugs
D006863 Hydrogen-Ion Concentration The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH pH,Concentration, Hydrogen-Ion,Concentrations, Hydrogen-Ion,Hydrogen Ion Concentration,Hydrogen-Ion Concentrations
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D012995 Solubility The ability of a substance to be dissolved, i.e. to form a solution with another substance. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed) Solubilities
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014867 Water A clear, odorless, tasteless liquid that is essential for most animal and plant life and is an excellent solvent for many substances. The chemical formula is hydrogen oxide (H2O). (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed) Hydrogen Oxide
D043823 Taxoids A group of diterpenoid CYCLODECANES named for the taxanes that were discovered in the TAXUS tree. The action on MICROTUBULES has made some of them useful as ANTINEOPLASTIC AGENTS. Taxanes,Taxoid

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