Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Doxorubicin/administration & dosage , Doxorubicin/pharmacology , Drug Delivery Systems , Folate Receptors, GPI-Anchored/metabolism , beta-Galactosidase/metabolism , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Ligands , Neoplasms/drug therapySubject(s)
Commitment of Mentally Ill , Dangerous Behavior , Hospitals, Psychiatric , Mental Disorders/nursing , Nursing, Team , Patient Care Team , Psychiatric Aides , Aggression/psychology , Commitment of Mentally Ill/legislation & jurisprudence , Communication , Cooperative Behavior , Crisis Intervention/legislation & jurisprudence , France , Hospitals, Psychiatric/legislation & jurisprudence , Humans , Motivation , Patient Care Team/legislation & jurisprudenceABSTRACT
Two glucuronide prodrugs of the histone deacetylase inhibitor CI-994 were synthesized. These compounds were found to be soluble in aqueous media and stable under physiological conditions. The carbamoyl derivatisation of CI-994 significantly decreased its toxicity towards NCI-H661 lung cancer cells. Prodrug incubation with beta-glucuronidase in the culture media led efficiently to the release of the parent drug and thereby restoring its ability to decrease cell proliferation, to inhibit HDAC and to induce E-Cadherin expression.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Enzyme Inhibitors/pharmacology , Glucuronides/pharmacology , Histone Deacetylase Inhibitors , Lung Neoplasms/drug therapy , Phenylenediamines/pharmacology , Prodrugs/pharmacology , Antineoplastic Combined Chemotherapy Protocols/chemical synthesis , Antineoplastic Combined Chemotherapy Protocols/chemistry , Benzamides , Cadherins/genetics , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Gene Expression Regulation, Neoplastic/drug effects , Glucuronides/chemical synthesis , Glucuronides/chemistry , Humans , Hydrolysis , Molecular Structure , Phenylenediamines/chemical synthesis , Phenylenediamines/chemistry , Prodrugs/chemical synthesis , Prodrugs/chemistry , Reverse Transcriptase Polymerase Chain Reaction , Solubility , Stereoisomerism , Structure-Activity Relationship , Time Factors , Tumor Cells, CulturedABSTRACT
The first O-glycosylation of hydroxamic acids is reported. This process involves the use of glycosyl N-phenyl trifluoroacetimidates as glycosyl donors in the presence TMSOTf and 4 A molecular sieves in dichloromethane. Under such conditions, a wide range of new glycosyl donors including glucosyl, galactosyl, mannosyl, glucuronyl, and ribosyl hydroxamates were prepared in good to high yields. This procedure appears to be an advantageous alternative for the synthesis of glycosyl hydroxamates of biological interest.
Subject(s)
Fluoroacetates , Hydroxamic Acids/chemistry , Acetamides , Carbohydrate Conformation , Glycosylation , Molecular Structure , Trifluoroacetic Acid/chemistryABSTRACT
The beta-O-glucuronide and beta-O-galactoside of SAHA have been prepared and evaluated as prodrugs for selective cancer chemotherapy (ADEPT, PMT). These new compounds are stable under physiological conditions and do not exhibit any antiproliferative activity compared to the parent drug after a 48-h treatment of H661 cells. The glucuronide derivative did not lead to the release of the drug in the presence of either Escherichia coli or bovine liver beta-glucuronidase. On the other hand, under enzymatic cleavage of galactoside prodrug by the corresponding enzyme, a rapid release of SAHA was observed demonstrating that the beta-O-galactoside of SAHA is a promising candidate for in vivo investigations.
