ABSTRACT
IgG1 monoclonal antibodies with reduced glycan fucosylation have been shown to improve antibody-dependent cellular cytotoxicity (ADCC) by allowing more effective binding of the Fc region of these proteins to T cells receptors. Increased in vivo efficacy in animal models and oncology clinical trials has been associated with the enhanced ADCC provided by these engineered mAbs. 6,6,6-Trifluorofucose (1) is a new inhibitor of fucosylation that has been demonstrated to allow the preparation of IgG1 monoclonal antibodies with lower fucosylation levels and thus improve the ADCC of these proteins. A new process has been developed to support the preparation of 1 on large-scale for wide mAb manufacture applications. The target fucosylation inhibitor (1) was synthesized from readily available d-arabinose in 11% overall yield and >99.5/0.5 dr (diastereomeric ratio). The heavily telescoped process includes seven steps, two crystallizations as purification handles, and no chromatography. The key transformation of the sequence involves the diastereoselective preparation of the desired trifluoromethyl-bearing alcohol in >9/1 dr from a trimethylsilylketal intermediate via a ruthenium-catalyzed tandem ketal hydrolysis-transfer hydrogenation process.
Subject(s)
Antibodies, Monoclonal/chemistry , Fucose/analogs & derivatives , Fucose/chemistry , Antibody-Dependent Cell Cytotoxicity , Catalysis , Crystallization , Hydrogenation , Immunoglobulin G/chemistry , Oxidation-Reduction , Ruthenium , StereoisomerismABSTRACT
A new convenient and scalable synthesis of phenylacetic acids has been developed via the iodide catalyzed reduction of mandelic acids. The procedure relies on in situ generation of hydroiodic acid from catalytic sodium iodide, employing phosphorus acid as the stoichiometric reductant.
Subject(s)
Iodides/chemistry , Phenylacetates/chemical synthesis , Acids/chemistry , Catalysis , Iodine Compounds/chemistry , Mandelic Acids/chemistry , Molecular Structure , Oxidation-Reduction , Phenylacetates/chemistry , StereoisomerismABSTRACT
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC(50) of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
Subject(s)
Acetamides/therapeutic use , Bradykinin B1 Receptor Antagonists , Inflammation/drug therapy , Pain/drug therapy , Piperazines/therapeutic use , Acetamides/chemical synthesis , Acetamides/chemistry , Animals , Dogs , Inhibitory Concentration 50 , Mice , Models, Animal , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Rabbits , Rats , Receptor, Bradykinin B1/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A variety of N-tert-butanesulfinyl imines were reduced with NaBH4 in THF containing 2% water to provide the corresponding secondary sulfinamides in high yield and diastereoselectivity. By using the same sulfinyl imine starting materials and changing the reductant to L-Selectride, the stereoselectivity could be efficiently reversed to afford the opposite product diastereomer in high yield and selectivity.
Subject(s)
Imines/chemistry , Sulfonium Compounds/chemistry , Borohydrides/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
Homo-ligated dirhodium(II) carboxamidates provide well-defined structural frameworks with which to investigate catalyst-controlled multiple asymmetric induction ("match/mismatch" effects). Diastereomeric pairs of methyl 2-oxoimidazolidine-4(S)-carboxylate ligands containing 2-phenylcyclopropane (4S,2'S,3'S-HMCPIM and 4S,2'R,3'R-HMCPIM) and N-benzenesulfonylproline (4S,2'S-HBSPIM and 4S,2'R-HBSPIM) attachments at the 1-N-acyl site have been prepared; the resulting (cis-2,2)-Rh(2)L(4) compounds have been produced in good yields, and the X-ray crystal structure of each dirhodium(II) compound has been obtained. The incorporation of additional stereocenters into the dirhodium(II) ligands leads to recognizable levels of double asymmetric induction for C-H insertion, cyclopropanation, and hetero-Diels-Alder cycloaddition applications. The configurationally "matched" cases provide modest increases in enantioselectivity for intramolecular C-H insertion reactions relative to the model catalyst Rh(2)(MPPIM)(4), but applications of the configurationally mismatched catalysts result in significant lowering of enantioselectivity. The Rh(2)(BSPIM)(4) catalysts show the highest degree of differential selectivity. Hetero-Diels-Alder reactions show inverse behavior from the configurationally matched and mismatched Rh(2)L(4) catalysts to that found in the metal carbene transformations.
