Bioinspired Total Synthesis and Human Proteasome Inhibitory Activity of (−)-Salinosporamide A, (−)-Homosalinosporamide A, and Derivatives Obtained via Organonucleophile Promoted Bis-cyclizations

A full account of concise, enantioselective syntheses of the anticancer agent (−)-salinosporamide A and derivatives, including (−)-homosalinosporamide, that was inspired by biosynthetic considerations is described. The brevity of the synthetic strategy stems from a key bis-cyclization of a β-keto tertiary amide, which retains optical purity enabled by A1,3-strain rendering slow epimerization relative to the rate of bis-cyclization. Optimization studies of the key bis-cyclization, enabled through byproduct isolation and characterization, are described that ultimately allowed for a gram scale synthesis of a versatile bicyclic core structure with a high degree of stereoretention. An optimized procedure for zincate generation by the method of Knochel, generally useful for the synthesis of salino A derivatives, led to dramatic improvements in side-chain attachment and a novel diastereomer of salino A. The versatility of the described strategy is demonstrated by the synthesis of designed derivatives including (−)-homosalinosporamide A. Inhibition of the human 20S and 26S proteasome by these derivatives using an enzymatic assay are also reported. The described total synthesis of salino A raises interesting questions regarding how biosynthetic enzymes leading to the salinosporamides proceeding via optically active β-keto secondary amides, are able to maintain the stereochemical integrity at the labile C2 stereocenter or if a dynamic kinetic resolution is operative

Bioinspired Total Synthesis and Human Proteasome Inhibitory Activity of (−)-Salinosporamide A, (−)-Homosalinosporamide A, and Derivatives Obtained via Organonucleophile Promoted Bis-cyclizations

A full account of concise, enantioselective syntheses of the anticancer agent (−)-salinosporamide A and derivatives, including (−)-homosalinosporamide, that was inspired by biosynthetic considerations is described. The brevity of the synthetic strategy stems from a key bis-cyclization of a β-keto tertiary amide, which retains optical purity enabled by A1,3-strain rendering slow epimerization relative to the rate of bis-cyclization. Optimization studies of the key bis-cyclization, enabled through byproduct isolation and characterization, are described that ultimately allowed for a gram scale synthesis of a versatile bicyclic core structure with a high degree of stereoretention. An optimized procedure for zincate generation by the method of Knochel, generally useful for the synthesis of salino A derivatives, led to dramatic improvements in side-chain attachment and a novel diastereomer of salino A. The versatility of the described strategy is demonstrated by the synthesis of designed derivatives including (−)-homosalinosporamide A. Inhibition of the human 20S and 26S proteasome by these derivatives using an enzymatic assay are also reported. The described total synthesis of salino A raises interesting questions regarding how biosynthetic enzymes leading to the salinosporamides proceeding via optically active β-keto secondary amides, are able to maintain the stereochemical integrity at the labile C2 stereocenter or if a dynamic kinetic resolution is operative

Bioinspired Total Synthesis and Human Proteasome Inhibitory Activity of (−)-Salinosporamide A, (−)-Homosalinosporamide A, and Derivatives Obtained via Organonucleophile Promoted Bis-cyclizations

A full account of concise, enantioselective syntheses of the anticancer agent (−)-salinosporamide A and derivatives, including (−)-homosalinosporamide, that was inspired by biosynthetic considerations is described. The brevity of the synthetic strategy stems from a key bis-cyclization of a β-keto tertiary amide, which retains optical purity enabled by A1,3-strain rendering slow epimerization relative to the rate of bis-cyclization. Optimization studies of the key bis-cyclization, enabled through byproduct isolation and characterization, are described that ultimately allowed for a gram scale synthesis of a versatile bicyclic core structure with a high degree of stereoretention. An optimized procedure for zincate generation by the method of Knochel, generally useful for the synthesis of salino A derivatives, led to dramatic improvements in side-chain attachment and a novel diastereomer of salino A. The versatility of the described strategy is demonstrated by the synthesis of designed derivatives including (−)-homosalinosporamide A. Inhibition of the human 20S and 26S proteasome by these derivatives using an enzymatic assay are also reported. The described total synthesis of salino A raises interesting questions regarding how biosynthetic enzymes leading to the salinosporamides proceeding via optically active β-keto secondary amides, are able to maintain the stereochemical integrity at the labile C2 stereocenter or if a dynamic kinetic resolution is operative

Secondary Structure and Fold Homology of the ArsC Protein from the <i>Escherichia coli</i> Arsenic Resistance Plasmid R773^†

Resistance to several toxic anions in Escherichia coli is conferred by the ars operon carried on plasmid R773. The gene products of this operon catalyze extrusion of antimonials and arsenicals from cells. In this paper, we report the determination of the overall fold for ArsC, a 16 kDa protein of the ars operon involved in the reduction of arsenate to arsenite, using multidimensional, multinuclear NMR. The protein is found to contain large regions of extensive mobility, particularly in the active site. A model fold, computed on the basis of a preliminary set of NOEs, was found to be structurally homologous to E. coli glutaredoxin, thiol transferases, and glutathione S-transferase. Some kinship to the structure of low molecular weight tyrosine phosphatases, based on rough topological similarity but more so on the basis of a common anion-binding-loop motif H−CXnR, was also detected. Although functional, secondary, and tertiary structural homology is observed with these molecules, no significant homology in primary structure was detected. The mobilities of the active site of ArsC and of other enzymes are discussed

Implications of Promiscuous Pim-1 Kinase Fragment Inhibitor Hydrophobic Interactions for Fragment-Based Drug Design

We have studied the subtleties of fragment docking and binding using data generated in a Pim-1 kinase inhibitor program. Crystallographic and docking data analyses have been undertaken using inhibitor complexes derived from an in-house surface plasmon resonance (SPR) fragment screen, a virtual needle screen, and a de novo designed fragment inhibitor hybrid. These investigations highlight that fragments that do not fill their binding pocket can exhibit promiscuous hydrophobic interactions due to the lack of steric constraints imposed on them by the boundaries of said pocket. As a result, docking modes that disagree with an observed crystal structure but maintain key crystallographically observed hydrogen bonds still have potential value in ligand design and optimization. This observation runs counter to the lore in fragment-based drug design that all fragment elaboration must be based on the parent crystal structure alone

Identification of Selective Imidazopyridine CSF1R Inhibitors

Colony stimulating factor-1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase expressed on members of the mononuclear phagocyte system (MPS), plays a key role in the proper functioning of macrophages, microglia, and related cells. Aberrant signaling through CSF1R has been associated with a variety of disease states, including cancer, inflammation, and neurodegeneration. In this Letter, we detail our efforts to develop novel CSF1R inhibitors. Drawing on previously described compounds, including GW2580 (4), we have discovered a novel series of compounds based on the imidazo­[4,5-b]­pyridine scaffold. Initial structure–activity relationship studies culminated in the identification of 36, a lead compound with potent CSF1R biochemical and cellular activity, acceptable in vitro ADME properties, and oral exposure in rat