ABSTRACT
The viridiofungin analogue NA808 was synthesized by the stereoselective Ireland-Claisen rearrangement of dienylmethyl ester, regioselective bromolactonization of ß-divinylpropanoic acid and retro-bromolactonization.
Subject(s)
Antiviral Agents/chemical synthesis , Carboxylic Acids/chemistry , Citrates/chemistry , Citrates/chemical synthesis , Furans/chemistry , Tyrosine/analogs & derivatives , Antiviral Agents/chemistry , Carboxylic Acids/chemical synthesis , Furans/chemical synthesis , Halogenation , Lactones/chemical synthesis , Lactones/chemistry , Stereoisomerism , Tyrosine/chemical synthesis , Tyrosine/chemistryABSTRACT
An efficient and scalable synthesis of an antidiabetic drug, tofogliflozin (1), which was identified as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor, is described. A key factor in the synthesis of 1 was the selection of the purpose-designed protecting group, which plays a strategic role in protection, chemoselective activation, and crystalline purification. The developed and optimized method made it possible to prepare 1 on a multidecagram scale without any column chromatography.
Subject(s)
Benzhydryl Compounds/chemical synthesis , Glucose/chemistry , Glucosides/chemical synthesis , Sodium-Glucose Transporter 2 Inhibitors , Sodium-Glucose Transporter 2/chemistry , Benzhydryl Compounds/chemistry , Glucosides/chemistry , Molecular StructureABSTRACT
C-Aryl 5a-carba-ß-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes.
Subject(s)
Cyclohexanols/chemistry , Diabetes Mellitus, Type 2/drug therapy , Glucose/analogs & derivatives , Hypoglycemic Agents/chemistry , Sodium-Glucose Transporter 2 Inhibitors , Administration, Oral , Animals , Area Under Curve , Blood Glucose/analysis , Cyclohexanols/pharmacokinetics , Cyclohexanols/therapeutic use , Glucose/pharmacokinetics , Glucose/therapeutic use , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Mice , Mice, Obese , Sodium-Glucose Transporter 2/metabolism , Structure-Activity RelationshipABSTRACT
5a-Carba-ß-D-glucopyranose derivatives were synthesized and identified as novel SGLT2-selective inhibitors. These inhibitors exhibited potent SGLT2 inhibition with high selectivity over SGLT1. Among the tested compounds, 6f indicated the most potent hSGLT2 inhibition and the highest selectivity over hSGLT1. Moreover, the pharmacokinetics data also showed that 6h, which had the same aglycon structure as sergliflozin-active (3-active), had a threefold longer half-life time (T(1/2)) than sergliflozin (3) with a high distribution volume in db/db mice. Subsequently, 6h lowered blood glucose levels as much as 3 and showed longer hypoglycemic action than 3 in db/db mice.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Glucose/analogs & derivatives , Sodium-Glucose Transporter 2 Inhibitors , Animals , Glucose/chemical synthesis , Glucose/chemistry , Glucose/pharmacology , Male , Mice , Mice, Obese , Molecular Conformation , Molecular Sequence Data , Sodium-Glucose Transporter 2/metabolism , Stereoisomerism , Structure-Activity Relationship , Tissue DistributionABSTRACT
A new method for the synthesis of enantiomerically enriched cyclohexadienone spiroisoxazoline (-)-2a has been described. Asymmetric intramolecular oxidative cyclization of the o-phenolic oxime-ester 1c using a novel optically active tertiary alcohol (-)-3 as a chiral auxiliary proceeded smoothly to afford cyclohexadienone spiroisoxazoline 2c in 83% yield. Opitcally active tertiary alcohol (-)-3 was synthesizied from racemic (1S,8R,9R,10R)-8-phenyl-1-decalol (4) by optical resolution. Removal of the chiral auxiliary in 2c with CF(3)COOH followed by methylation gave methyl ester (-)-2a in 74% ee (71% chemical yield) having S-configuration. The absolute configuration of 2awas determined by the synthesis of the marine natural product (+)-aerothionin.