Synthesis of 3- and 21-monosulfates of [2,2,3β,4,4-²H₅]-tetrahydrocorticosteroids in the 5β-series as internal standards for mass spectrometry.

The 3- and 21-monosulfates of pentadeuterated 5β-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-5β-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.

Biological evaluation of 3'-O-alkylated analogs of salacinol, the role of hydrophobic alkyl group at 3' position in the side chain on the α-glucosidase inhibitory activity.

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.

Role of the side chain stereochemistry in the α-glucosidase inhibitory activity of kotalanol, a potent natural α-glucosidase inhibitor.

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.

Isolation, structure identification and SAR studies on thiosugar sulfonium salts, neosalaprinol and neoponkoranol, as potent α-glucosidase inhibitors.

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.

Facile synthesis of de-O-sulfated salacinols: revision of the structure of neosalacinol, a potent alpha-glucosidase inhibitor.

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.

A unique chair-shaped hexanuclear Cu(I) metallamacrocyclic C2H4 adduct encapsulating a BF4- anion.

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.

The role of Arg114 at subsites E and F in reactions catalyzed by hen egg-white lysozyme.

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.

Bowl-shaped Cu(I) metallamacrocyclic ethylene and carbonyl adducts as structural analogues of organic calixarenes.

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.

Biological evaluation of de-O-sulfonated analogs of salacinol, the role of sulfate anion in the side chain on the alpha-glucosidase inhibitory activity.

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.

Synthesis of a salacinol analogue and its alpha-glucosidase inhibitory activity.

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 D-glucose via seven steps in much more less expensive. Using this method, an efficient synthesis of 4 was carried out.

Synthesis and biological evaluation of deoxy salacinols, the role of polar substituents in the side chain on the alpha-glucosidase inhibitory activity.

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.