ABSTRACT
The 3- and 21-monosulfates of pentadeuterated 5ß-tetrahydrocorticosteroides were synthesized, starting from cortisol and 11-deoxycotisol. The principal reactions used were (1) perdeuteration of the methylene groups adjacent to the 3-oxo group of 17,20:20,21-bismethylendioxy-5ß-3-ketosteroids with NaOD in CH(3)OD followed by stereoselective reduction with NaBD(4), (2) sulfation of hydroxy groups with sulfur trioxide-trimethylamine complex, and (3) removal of the 17,20:20,21-bismethylendioxy group with hydrogen fluoride. The labeled compounds can be used as internal standards in liquid chromatography/mass spectrometry assays for clinical and biochemical studies.
Subject(s)
Adrenal Cortex Hormones/chemical synthesis , Ketosteroids/chemistry , Adrenal Cortex Hormones/chemistry , Chromatography, Liquid/methods , Mass Spectrometry/methods , Reference StandardsABSTRACT
Four analogs with 3'-O-alkyl groups (9a: CH(3), 9b: C(2)H(5), 9c: C(13)H(27) or 9d: CH(2)Ph) instead of the 3'-O-sulfate anion in salacinol (1), a naturally occurring potent α-glucosidase inhibitor, were synthesized by the coupling reaction of 1,4-dideoxy-1,4-epithio-d-arabinitols (18a and 18b) with appropriate epoxides (10a-10d). These analogs showed equal or considerably higher inhibitory activity against rat small intestinal α-glucosidases than the original sulfate (1), and one of them (9d) was found more potent than currently used α-glucosidase inhibitors as antidiabetics. Thus, introduction of a hydrophobic moiety at the C3' position of this new class of inhibitor was found beneficial for onset of stronger inhibition against these enzymes.
Subject(s)
Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors , Sugar Alcohols/chemistry , Sugar Alcohols/pharmacology , Sulfates/chemistry , Sulfates/pharmacology , Hydrophobic and Hydrophilic Interactions , Magnetic Resonance Spectroscopy , Molecular StructureABSTRACT
Synthesis and evaluation of four diastereomers (9a, 9b, 9c and 9d) of kotalanol, a potent α-glucosidase inhibitor isolated from an Ayurvedic medicinal plant Salacia species, are described. Stereo-inversion at C-3' and C-4' of kotalanol (2) caused significant decrease of the inhibitory activities against maltase and sucrase, whereas inhibitory activity against isomaltase sustained, thus resulted in exerting selectivity against isomaltase.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors , Monosaccharides/chemistry , Monosaccharides/pharmacology , Sulfates/chemistry , Sulfates/pharmacology , alpha-Glucosidases/chemistry , Molecular Structure , Plant Extracts/chemistry , Plant Extracts/pharmacology , Stereoisomerism , Structure-Activity Relationship , alpha-Glucosidases/metabolismABSTRACT
Two hitherto missing members of sulfonium salts family in Salacia genus plants as a new class of α-glucosidase inhibitors, neoponkoranol (7) and neosalaprinol (8), were isolated from the water extracts, and their structures were unambiguously identified. For further SAR studies on this series of sulfonium salts, several epimers of 7 and 8 were synthesized, and their inhibitory activities against rat small intestinal α-glucosidases were evaluated. Among them, 3'-epimer of 7 was found most potent in this class of molecules, and revealed as potent as currently used antidiabetics, voglibose and acarbose.
Subject(s)
Enzyme Inhibitors/chemistry , Glycoside Hydrolase Inhibitors , Hypoglycemic Agents/chemistry , Sugar Alcohols/chemistry , Thiophenes/chemistry , Thiosugars/chemistry , Animals , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/isolation & purification , Hypoglycemic Agents/pharmacology , Rats , Salacia/chemistry , Structure-Activity Relationship , Sugar Alcohols/isolation & purification , Sugar Alcohols/pharmacology , Thiophenes/isolation & purification , Thiophenes/pharmacology , Thiosugars/isolation & purification , Thiosugars/pharmacology , alpha-Glucosidases/metabolismABSTRACT
Facile synthesis of de-O-sulfated salacinols (3) was developed by employing the coupling reaction of an epoxide, 1,2-anhydro-3,4-di-O-benzyl-D-erythritol (9) with 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-epithio-D-arabinitol (10) as the key reaction. The reported structure of a potent alpha-glucosidase inhibitor named neosalacinol (8), isolated recently from Ayurvedic medicine Salacia oblonga, was proved incorrect, and revised to be de-O-sulfated salacinol formate (3c) by comparison of the spectroscopic properties with those of the authentic specimen synthesized. Discrepancies and confusion in the literature concerning the NMR spectroscopic properties of salacinol (1) have also been clarified.
Subject(s)
Glycoside Hydrolase Inhibitors , Salacia , Sugar Alcohols/chemical synthesis , Sulfates/chemical synthesis , Medicine, Ayurvedic , Plant Extracts/chemical synthesis , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Plant Roots/chemistry , Plant Stems/chemistry , Sugar Alcohols/isolation & purification , Sugar Alcohols/pharmacology , Sulfates/isolation & purification , Sulfates/pharmacology , alpha-Glucosidases/metabolismABSTRACT
Three novel Cu(I)-C2H4 adducts bearing 4-(2-pyridyl)pyrimidine were self-assembled, and the roles of anion and solvent were proved in the formation process.
Subject(s)
Anions , Boranes/chemistry , Boron/chemistry , Copper/chemistry , Fluorides/chemistry , Chemistry/methods , Crystallography, X-Ray/methods , Ethylenes/chemistry , Magnetic Resonance Spectroscopy , Metals/chemistry , Models, Chemical , Molecular Conformation , Molecular Structure , Polymers/chemistry , Solvents/chemistry , ThermogravimetryABSTRACT
To understand better the role of subsites E and F in lysozyme-catalyzed reactions, mutant enzymes, in which Arg114, located on the right side of subsites E and F in hen egg-white lysozyme (HEL), was replaced with Lys, His, or Ala, were prepared. Replacement of Arg114 with His or Ala decreased hydrolytic activity toward an artificial substrate, glycol chitin, while replacement with Lys had little effect. Kinetic analysis with the substrate N-acetylglucosamine pentamer, (GlcNAc)(5), revealed that the replacement for the Arg residue reduced the binding free energies of E-F sites and the rate constant of transglycosylation. The rate constant of transglycosylation for R114A was about half of that for the wild-type enzyme. (1)H-NMR analysis of R114H and R114A indicated that the structural changes induced by the mutations were not restricted to the region surrounding Arg114, but rather extended to the aromatic side chains of Phe34 and Trp123, of which the signals are connected with each other through nuclear Overhauser effect (NOE) in the wild-type. We speculate that such a conformational change causes differences in substrate and acceptor binding at subsites E and F, lowering the efficiency of glycosyl transfer reaction of lysozyme.
Subject(s)
Arginine/chemistry , Muramidase/metabolism , Amino Acid Substitution , Animals , Catalysis , Catalytic Domain , Chickens , Female , Kinetics , Magnetic Resonance Spectroscopy , Muramidase/chemistry , Protein Binding , Protein ConformationABSTRACT
Three novel Cu(I) metallacalixarenes with C(2)H(4) and CO legs, in which an anion is accommodated in the inside cavity, were self-assembled by anion templation and have been structurally characterized.
Subject(s)
Calixarenes/chemistry , Carbon Monoxide/chemistry , Copper/chemistry , Ethylenes/chemistry , Macrocyclic Compounds/chemistry , Organometallic Compounds/chemistry , Crystallography, X-Ray , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Spectroscopy/standards , Models, Molecular , Molecular Structure , Reference StandardsABSTRACT
De-O-sulfonated analogs (10a, Y(-)=CH(3)OSO(3) and 10b, Y(-)=Cl) of salacinol, a naturally occurring glycosidase inhibitor, and its diastereomer (12a, Y(-)=CH(3)OSO(3)) with L-thiosugar moiety (1,4-dideoxy-1,4-epithio-L-arabinitol) were prepared. Their inhibitory activities against intestinal maltase and sucrase were examined and compared with those of the parent alpha-glycosidase inhibitor, salacinol (1a). Compounds 10a and 10b showed a potent inhibitory activity equal to that of 1a against both enzymes, although 12a was a weak inhibitor against sucrase and maltase. These results indicated that the O-sulfonate anion moiety of 1a is not essential for the inhibitory activity.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors , Sugar Alcohols/chemistry , Sulfates/chemistry , Animals , Anions/chemistry , Enzyme Inhibitors/chemical synthesis , Rats , Structure-Activity RelationshipABSTRACT
Three analogs (5, 6, and 7) lacking polar substituents in the side chain of a naturally occurring alpha-glucosidase inhibitor, salacinol (1a), were synthesized by the coupling reaction of a thiosugar, 1,4-dideoxy-1,4-epithio-D-arabinitol (3), with cyclic sulfates (8, 9, and 10), and their alpha-glucosidase inhibitory activities were examined. All these simpler analogs (5, 6, and 7) showed less inhibitory activity compared to 1a, and proved the importance of cooperative role of the polar substituents for the alpha-glucosidase inhibitory activity. A practical synthetic route to 3 starting from D-xylose is also described.
Subject(s)
Enzyme Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors , Sugar Alcohols/chemical synthesis , Sugar Alcohols/pharmacology , Sulfates/chemical synthesis , Sulfates/pharmacology , Animals , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Mass Spectrometry , Microvilli/drug effects , Microvilli/enzymology , Spectrophotometry, Infrared , Sugar Alcohols/chemistry , Sulfates/chemistryABSTRACT
<p><b>AIM</b>To investigate more efficient synthetic method of the nitrogen analogue 4 of salacinol (1) for searching new antidiabetic agents.</p><p><b>METHODS</b>The synthesis of the key intermediate 2, 4-O-isopropylidene-L-erythritol 1,3-cyclic sulfate (2a) was accomplished by modification of reports from D-glucose via seven steps in much more less expensive. Using this method, an efficient synthesis of 4 was carried out. The glycosidase inhibitory activity of 4 was tested for the intestinal alpha-glucosidase in vitro and compared with that of salacinol.</p><p><b>RESULTS</b>A nitrogen analogue 4 of salacinol (1) was synthesized by the coupling reaction between the cyclic sulfate 2a and an azasugar 3b.</p><p><b>CONCLUSION</b>Substitution of the sulfur atom in 1 with a nitrogen reduced the activity considerably.</p>
Subject(s)
Animals , Rats , Enzyme Inhibitors , Chemistry , Pharmacology , Glycoside Hydrolase Inhibitors , Intestinal Mucosa , Molecular Structure , Nitrogen Compounds , Pharmacology , Structure-Activity Relationship , Sugar Alcohols , Chemistry , Pharmacology , Sulfates , Chemistry , Pharmacology , alpha-Glucosidases , MetabolismABSTRACT
Aim To investigate more efficient synthetic method of the nitrogen analogue 4 of salacinol (1) for searching new antidiabetic agents. Methods The synthesis of the key intermediate 2,4-O-isopropylidene-L-erythritol 1,3-cyclic sulfate (2a) was accomplished by modification of reports from Dglucose via seven steps in much more less expensive. Using this method, an efficient synthesis of 4 was carried out. The glycosidase inhibitory activity of 4 was tested for the intestinal α-glucosidase in vitro and compared with that of salacinol. Results A nitrogen analogue 4 of salacinol (1) was synthesized by the coupling reaction between the cyclic sulfate 2a and an azasugar 3b. Conclusion Substitution of the sulfur atom in 1 with a nitrogen reduced the activity considerably.
