319426-57-8Relevant articles and documents
Compositions and methods for targeted enzymatic release of cell regulatory compounds
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Page column 15, (2010/02/05)
Novel pro-drugs and methods for their use to alter the growth and biological characteristics of living cells, tissues, or whole organisms are described. The methods allow for selective activation of the pro-drugs at or near transformant host cells expressing a gene for an enzyme that activates the pro-drugs. Pro-drugs according to a preferred embodiment of the invention are conjugates of a bioactive compound and a chemical group that is capable of being cleaved from the bioactive compound by action of an enzyme. Methods according to this invention include, (a) introducing into targeted cells a gene encoding an enzyme and (b) administering a pro-drug, wherein the enzyme releases the pro-drug from conjugation. In a preferred embodiment of the invention, the gene encoding the enzyme is a marker gene.
Drug Glycosydes: Potential Prodrugs for Colon-Specific Drug Delivery
Friend, David R.,Chang, George W.
, p. 51 - 57 (2007/10/02)
The influence of prodrug structure on specifity of glycoside/glycosidase based colon-specific drug delivery was studied by preparing nine steroid glycosides, measuring their relative lipophilicities, and hydrolyzing them with bacterial glycosidases from rat intestines.The 21-yl β-D-glucosides and galactosides of dexamethasone, prednisolone, hydrocortisone, and fludrocortisone and the 21-yl β-D-cellobioside of prednisolone were prepared by a modified Koenigs-Knorr reaction.The deacetylated glycoside prodrugs, along with the p-nitrophenyl derivatives of β-D-glucoside , galactoside, and cellobioside, were subjected to hydrolysis by the contents of the rat stomach, proximal small intestine (PSI), distal small intestine (DSI), and cecum.All the prodrugs were hydrolyzed slowly by PSI and stomach contents, more rapidly by contents of the DSI, and most rapidly by cecal contents.This is the basis of the site-specific drug delivery reported earlier (Friend, D.R.; Chang, G.W.J.Med.Chem. 1984, 27, 261).Furthermore, the prodrugs themselves had very different susceptibilities to hydrolysis.Hydrolysis rates catalyzed by DSI contents decreased in the following order: prednisolon-21-yl β-D-galactoside (10) > prednisolon-21-yl β-D-glucoside (2) > prednisolon-21-yl β-D-cellobioside (13) > dexamethason-21-yl β-D-galactoside (9) > dexamethason-21-yl β-D-glucoside (1).Hydrolysis of cellobioside 13 was only half that of glucoside 2 and one-fourth that of galactoside 10.Hydrolysis of all the prodrugs in cecal contents was rapid, with the exceptions of hydrocortison-21-yl β-D-glucoside (5) and fludrocortison-21-yl β-D-glucoside (7), which were hydrolyzed more slowly than the other glucoside prodrugs.Eadie-Hofstee plots for hydrolysis of the glucoside compounds suggested that bacterial β-D-glucosidase activity in the colon may be more heterogeneous in nature than β-D-galactosidase activity.Relative lipophilicities of the prodrugs and free steroids were compared by measuring their octanol-buffer partition coefficients (P).The logarithm of the P of cellobioside 13 (-0.56) was considerably lower than that of the other prodrugs, which ranged from 0.11 to 0.84.Log P of the free steroids ranged from 1.54 to 1.73.These relative rates of hydrolysis and relative lipophilicities, along with previously reported animal experiments, enable one to estimate the site specificity of glycoside prodrugs prior to extensive animal studies.
A Colon-Specific Drug-Delivery System Based on Drug Glycosides and the Glycosidases of Colonic Bacteria
Friend, David R.,Chang, George W.
, p. 261 - 266 (2007/10/02)
Steroid glycosides and the unique glycosidase activity of the colonic microflora form the basis of a new-colon-specific drug-delivery system.Drug glycosides are hydrophilic and, thus, poorly absorbed from the small intestine.Once such a glycoside reaches the colon it can be cleaved by bacterial glycosidases, releasing the free drug to be absorbed by the colonic mucosa.This concept was illustrated with dexamethasone 21-β-D-glucoside (1) and prednisolone 21-β-D-glucoside (2), two prodrugs that may be useful in treating inflammatory bowel disease.Hydrolysis of theprodrugs by β-glucosidase and fecal homogenates in vitro released the free steroids.Glucosides 1 and 2 were administered to rats intragastrically to determine when when and where the free steroids were released.Unmodified dexamethasone (3) and prednisolone (4) were also given to rats intragastrically to compare absorption of the glucosides with the free steroids.Both glucosides were found to reach the rat lower intestine in 4-5 h, where they were rapidly hydrolyzed, releasing the free steroids.Delivery of steroid 3 (via glucoside 1) was more specific than that of steroid 4 (via glucoside 2): nearly 60percent of an oral dose of glucoside 1 reached the cecum, whereas less than 15percent of glucoside 2 reached the cecum.When free steroids 3 and 4 were administered orally, they were almost exclusively absorbed in the small intestine: less than 1percent of an oral dose of each reached the cecum.
