ABSTRACT
Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays. Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes.
Subject(s)
Diabetes Mellitus, Experimental/enzymology , Drug Design , Enzyme Activators/pharmacology , Glucokinase/metabolism , Hypoglycemic Agents/pharmacology , Pyridones/pharmacology , Animals , Crystallography, X-Ray , Diabetes Mellitus, Experimental/drug therapy , Disease Models, Animal , Enzyme Activation/drug effects , Enzyme Activators/administration & dosage , Enzyme Activators/chemistry , Glucose Tolerance Test , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Mice , Mice, Inbred C57BL , Mice, Obese , Models, Molecular , Molecular Structure , Pyridones/administration & dosage , Pyridones/chemistry , Structure-Activity RelationshipABSTRACT
A general strategy for the total synthesis of the antitumor agent apoptolidin (1) is proposed, and the chemical synthesis of the defined key building blocks (4, 5, 6, 8, and 9) in their enantiomerically pure forms is described. The projected total synthesis calls for a dithiane coupling reaction to construct the C(20)-C(21) bond, a Stille coupling reaction to form the C(11)-C(12) bond, and a Yamaguchi macrolactonization to assemble the macrolide ring, as well as two glycosidation reactions to fuse the carbohydrate units onto the molecule. First and second generation syntheses to the required fragments for apoptolidin (1) are described.
Subject(s)
Macrolides/chemical synthesis , StereoisomerismABSTRACT
The total synthesis of apoptolidin (1) is reported together with the design, synthesis, and biological evaluation of a number of analogues. The assembly of key fragments 6 and 7 to vinyl iodide 3 via dithiane coupling technology was supplemented by a second generation route to this advanced intermediate involving a Horner-Wadsworth-Emmons coupling of fragments 22 and 25. The final stages of the synthesis featured a Stille coupling between vinyl iodide 3 and vinylstannane 2, a Yamaguchi lactonization, a number of glycosidations, and final deprotection. The developed synthetic technology was applied to the construction of several analogues including 74, 75, and 77 which exhibit significant bioactivity against tumor cells.
