Facile photochemical synthesis of mixed siloxyacetal glycosides as potential pH-sensitized prodrugs for selective treatment of solid tumors.
Photochemical reactions of a variety of acylsilanes with peracetylated free glycosides in anhydrous benzene at ambient temperature yielded novel, highly acid-sensitive siloxyacetal glycosides in 75-90% yields with complete retention of configuration at the anomeric center. Subsequent deacetylation of triisopropylsiloxy- and tert-butyldimethylsiloxy derivatives with sodium methoxide in methanol afforded deprotected siloxyacetal glycosides in nearly quantitative yields. Acid hydrolysis of trimethylsilyl siloxyacetals proceeded with a half-life of 17.5 minutes at pH 6.2 which is vastly superior to the decomposition rate of conventional acetals under similar conditions. The structure of one of the novel siloxyacetals was confirmed by X-ray crystallography. In vitro biological studies showed that glucose-derived siloxyacetals may serve as potential pH-activated prodrugs for selective treatment of solid tumors.
Svarovsky
Serge A
SA
Laboratory of Medicinal Chemistry, National Cancer Institute, 376 Boyles Street, Frederick, MD 21702, USA. ssvarovs@ncifcrf.gov
Taraban
Marc B
MB
Barchi
Joseph J
JJ
D000080:Acetals / Q000138:chemical synthesis* / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010777:Photochemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use*; D012821:Silanes / Q000138:chemical synthesis / Q000737:chemistry
D000080:Acetals; D006027:Glycosides; D011355:Prodrugs; D012821:Silanes