ABSTRACT
The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is involved in multiple physiological pathways including targeting of lysosomal enzymes, degradation of IGF2, and cicatrization through TGFbeta activation. To target potential therapeutics to this membrane receptor, four carboxylate analogues of mannose 6-phosphate (M6P) were synthesized. Three of them, two isosteric carboxylate analogues and a malonate derivative, showed a binding affinity for the M6P/IGF2R equivalent to or higher than that of M6P. Contrary to M6P, all these analogues were particularly stable in human serum. Moreover, these derivatives did not present any cytotoxic activity against two human cell lines. These analogues represent a new potential for the lysosomal targeting of enzyme replacement therapy in lysosomal diseases or to prevent the membrane-associated activities of the M6P/IGF2R.
Subject(s)
Binding, Competitive , Carboxylic Acids/chemistry , Carboxylic Acids/chemical synthesis , Mannosephosphates/metabolism , Receptor, IGF Type 2/metabolism , Biomarkers/chemistry , Carbohydrate Sequence , Carboxylic Acids/pharmacology , Cell Line , Cell Proliferation/drug effects , Cells, Cultured , Humans , Mannosephosphates/chemistry , Mannosephosphates/pharmacology , Molecular Sequence Data , Protein BindingABSTRACT
The valorization of extracts from Brazilian vetiver (Vetiveria zizanioides (L.) Nash ex Small) roots was studied. This study took into account the extraction method, the chemical composition of the extracts, their sensorial characteristics, and the possibility of chemical transformations of the product. The performed extraction methods were hydrodistillation and extraction with supercritical carbon dioxide. Some pretreatment methods were tested on the vetiver roots and evaluated in terms of extraction yield, process time, chemical composition, and sensorial properties. Supercritical carbon dioxide extraction resulted in high yield (3.2%) in significantly less time than the other methods. The chemical compositions of the extracts obtained by the different methods were also compared to those of commercial vetiver oils from other sources, showing that Brazilian samples had a greater acid amount. An extraction in basic medium from Brazilian vetiver oil was done to remove its main acid (zizanoic acid), which was chemically transformed into an alcohol (khusimol) of desirable sensorial properties. Sensory evaluation indicated that the Brazilian volatile oil without acid could be used in perfumery and the extract obtained with supercritical carbon dioxide could have application in food.
Subject(s)
Plant Oils/chemistry , Poaceae/chemistry , Acids/analysis , Chromatography, Gas , Humans , Odorants/analysis , Plant Extracts/chemistry , Plant Roots/chemistry , SmellABSTRACT
A new enzyme-labile group called S-acyl-3-thiopropyl group (SATP) has been synthesized from allylic esters of phosphonate. After demonstration of the enzyme-labile character of the SATP in cellular extracts, it has been introduced onto the phosphonate moiety of PFA (Foscarnet) to obtain potential lipophilic prodrugs. To ponder the lipophilicity of the triesters of PFA, esters of monomethylether of polyethyleneglycols and of thioglycerol were introduced on the PFA carboxylate moiety. The SATP groups were introduced in an attempt to deliver PFA after bioactivation inside the cells. The PFA prodrugs were evaluated in vitro for their activity against human immunodeficiency viruses (HIV-1 and HIV-2).
Subject(s)
Anti-HIV Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Foscarnet/analogs & derivatives , Foscarnet/chemical synthesis , Glycerol/analogs & derivatives , Prodrugs/chemical synthesis , Sulfhydryl Compounds/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Carboxylic Acids/chemistry , Carboxylic Acids/metabolism , Evaluation Studies as Topic , Foscarnet/pharmacology , Glycerol/chemistry , HIV-1/drug effects , HIV-2/drug effects , Humans , In Vitro Techniques , Organophosphonates/metabolism , Polyethylene Glycols/chemistry , Prodrugs/chemistry , Prodrugs/pharmacology , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacologyABSTRACT
The regioselective monobenzyloxycarbonylation of secondary alcohols in methyl 6-O-(4-methoxytrityl)-alpha-D-manno-, gluco- and galactopyranoside has been achieved in high yields (74-85%) by using benzyl chloroformate in the presence of 4-dimethylaminopyridine and/or 1,4-diazabicyclo[2.2.2]octane.
Subject(s)
Alcohols/chemistry , Formates/chemistry , Sugar Alcohols/chemical synthesis , Magnetic Resonance Spectroscopy , Molecular Structure , Sugar Alcohols/chemistryABSTRACT
The synthesis of new prodrugs of PALA characterised by the presence of S-acyl-3-thiopropyl, as enzyme-labile groups on the phosphonate moiety of PALA, is reported. The cytotoxic activities of PALA prodrugs were determined against human cell line (SW1573 lung carcinoma cells). A number of prodrugs bearing S-pivaloyl as acyl groups displayed cytotoxic activity in the same order of magnitude of PALA.
Subject(s)
Antineoplastic Agents/chemical synthesis , Aspartic Acid/analogs & derivatives , Aspartic Acid/chemical synthesis , Aspartic Acid/pharmacology , Phosphonoacetic Acid/analogs & derivatives , Phosphonoacetic Acid/chemical synthesis , Phosphonoacetic Acid/pharmacology , Prodrugs/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Structure-Activity Relationship , Sulfhydryl CompoundsABSTRACT
Four new analogues of Targretin where the carboxylic acid function was replaced by an N,N-dimethyl-S-aryl carbamate or N,N-dimethyl-O-arylthiocarbamate function, were synthesized. Compounds 5, 6 and 7 have shown to be more potent than the parent compound to induce apoptosis of HL-60 cells.