ABSTRACT
A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-ß (TGF-ß) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-ß-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC(50) = 5.5 nM) as well as inhibitory activity against TGF-ß-induced Smad2/3 phosphorylation at a cellular level (IC(50) = 36 nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals).
Subject(s)
Imidazoles/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Animals , Female , Mice , Mice, Inbred C57BL , Mice, Transgenic , Protein Serine-Threonine Kinases/chemistry , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/chemistryABSTRACT
We have described the synthesis, enzyme inhibitory activity, structure-activity relationships, and proposed binding mode of a novel series of pyrrole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s <10nM) for Lck kinase inhibition.
Subject(s)
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrroles/chemical synthesis , Adenosine Triphosphate/chemistry , Binding Sites , Computer Simulation , Crystallography, X-Ray , Hydrogen Bonding , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism , Lymphocytes/drug effects , Lymphocytes/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
A total synthesis of the macquarimicins A-C (1-3), novel natural products with intriguing tetra- or pentacyclic frameworks, has been achieved. The synthesis features an extensive investigation of the biosynthesis-based intramolecular Diels-Alder (IMDA) reactions of (E,Z,E)-1,6,8-nonatrienes. Considering possible biosynthetic sequences, four types of substrates were synthesized, and their IMDA reactions were examined. From one of the four substrates, the total synthesis was achieved via a transannular Diels-Alder reaction, which led to the stereoselective construction of the unique molecular framework. The convergent and efficient synthetic pathway afforded (+)-1 in 27 linear steps with 4.3% and 9.9% overall yields from readily available ethyl (2E,4S)-4,5-(isopropylidene)dioxy-2-pentenoate (22) and (R)-epichlorohydrin (30), respectively. Furthermore, efficient syntheses of 2, 3, and the 9-epi-cochleamycins A (57) and B (58) were accomplished. Additionally, the present work established the absolute stereochemistry of macquarimicins and revised the C(2)--C(3) geometry of 1.
Subject(s)
Macrolides/chemical synthesis , Biomimetics , Cyclization , Macrolides/chemistry , Macrolides/metabolism , Models, Molecular , StereoisomerismABSTRACT
The first total synthesis of (+)-macquarimicin A (1), a novel inhibitor of neutral sphingomyelinase (N-SMase) with antiinflammatory activity, has been accomplished. The present work determined the absolute configuration of (+)-1 and revised the C(2)-C(3) geometry to be Z. The synthesis features a transannular Diels-Alder reaction, which constructed the tetracyclic framework stereoselectively, and a convergent and efficient synthetic pathway, which afforded (+)-macquarimicin A (1) in 27 steps (longest linear sequence) with 9.9% overall yield.
