ABSTRACT
As a result of our continued efforts to pursue Gal-3 inhibitors that could be used to fully evaluate the potential of Gal-3 as a therapeutic target, two novel series of benzothiazole derived monosaccharides as potent (against both human and mouse Gal-3) and orally bioavailable Gal-3 inhibitors, represented by 4 and 5, respectively, were identified. These discoveries were made based on proposals that the benzothiazole sulfur atom could interact with the carbonyl oxygen of G182/G196 in h/mGal-3, and that the anomeric triazole moiety could be modified into an N-methyl carboxamide functionality. The interaction between the benzothiazole sulfur and the carbonyl oxygen of G196 in mGal-3 was confirmed by an X-ray co-crystal structure of early lead 9, providing a rare example of using a S···O binding interaction for drug design. It was found that for both the series, methylation of 3-OH in the monosaccharides caused no loss in h & mGal-3 potencies but significantly improved permeability of the molecules.
Subject(s)
Galectin 3 , Monosaccharides , Animals , Humans , Mice , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Drug Design , Galectin 3/antagonists & inhibitors , Galectins/antagonists & inhibitors , Monosaccharides/chemistry , Monosaccharides/pharmacology , Oxygen , SulfurABSTRACT
Galectin-3 (Gal-3), a member of the ß-galactoside-binding protein family, is implicated in a wide variety of human diseases. Identification of Gal-3 inhibitors with the right combination of potency (against both human and mouse Gal-3) and pharmacokinetic properties to fully evaluate the potential of Gal-3 for therapeutic intervention has been a major challenge due to the characteristics of its binding pocket: high hydrophilicity and key structural differences between human Gal-3 and the mouse ortholog. We report the discovery of a novel series of monosaccharide-based, highly potent, and orally bioavailable inhibitors of human and mouse Gal-3. The novel monosaccharide derivatives proved to be selective for Gal-3, the only member of the chimeric type of galectins, over Gal-1 and Gal-9, representative of the prototype and tandem-repeat type of galectins, respectively. The proposed binding mode for the newly identified ligands was confirmed by an X-ray cocrystal structure of a representative analogue bound to Gal-3 protein.
Subject(s)
Galectin 3 , Monosaccharides , Animals , Galectin 3/metabolism , Galectins , Humans , Ligands , MiceABSTRACT
Design, new synthesis, structure-activity relationship studies and calcium receptor antagonist (calcilytic) properties of novel 3H-pyrimidin-4-ones are described.
Subject(s)
Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Receptors, Calcium-Sensing/drug effects , Pyrimidinones/chemistry , Structure-Activity RelationshipABSTRACT
1-(Alkyl/arylthiocarbamoyl)benzotriazoles 4a-i were synthesized in yields of 91-99% from bis(benzotriazolyl)methanethione (3). Reagents 4a-g were then used as isothiocyanate equivalents for the efficient synthesis of 10 secondary and 14 tertiary thioureas in high-yielding, convenient processes.
Subject(s)
Isothiocyanates/chemistry , Thiocarbamates/chemistry , Thiourea/analogs & derivatives , Triazoles/chemistry , Molecular Structure , Tetrazoles/chemical synthesis , Thiourea/chemical synthesisABSTRACT
One-pot reactions of sulfinic acid salts (produced from organometallic reagents with SO2) with N-chlorobenzotriazole gave the corresponding N-alkane-, N-arene-, and N-heteroenesulfonylbenzotriazoles 3a-j in 41-93% yields. Reagents 3a-j are efficient sulfonylating agents, reacting at 20-80 degrees C with various primary and secondary aliphatic amines to yield the corresponding sulfonamides in 64-100% yields.
ABSTRACT
Enynes 5a-g were prepared in moderate to good yields from 1-(triphenylphosphoranylideneaminoalkyl)benzotriazoles. Ring-closing metathesis of 5a-f afforded functionalized dienes 6a-f, respectively, which were used in a Diels-Alder cycloaddition reaction in the synthesis of the corresponding hexahydroisoquinoline derivatives 7a-f.
ABSTRACT
In a new general indole synthesis, the anion derived from benzotriazolyl derivative 5b underwent regioselective 1,4-addition to various alpha,beta-unsaturated ketones; subsequent acid-catalyzed cyclization formed the corresponding indoles 1a-f.
ABSTRACT
2, 4-Benzodiazepin-1-ones were prepared in moderate to good yields by reaction of bis(benzotriazolylmethyl)amines with ortho-metalated N-substituted benzamides.
Subject(s)
Benzodiazepinones/chemical synthesis , Amines/chemistry , Chemistry, Pharmaceutical , Triazoles/chemistryABSTRACT
N,N-Bis(but-3-enyl)amines 5a-i were prepared in overall 74% yield from 1-(triphenylphosphoroylideneaminoalkyl)benzotriazole using an aza-Wittig reaction with aldehydes followed by a double Grignard reaction with allylmagnesium bromide. Use of vinyl or 1-propynylmagnesium bromide and allylmagnesium bromide in a sequential fashion also formed the expected doubly unsaturated amines 9a,b and 12, respectively.