Protein arginine N‐methyl transferase 4 (PRMT4) asymmetrically dimethylates the arginine residues of histone H3 and nonhistone proteins. The overexpression of PRMT4 in several cancers has stimulated interest in the discovery of inhibitors as biological tools and, potentially, therapeutics. Although several PRMT4 inhibitors have been reported, most display poor selectivity against other members of the PRMT family of methyl transferases. Herein, we report the structure‐based design of a new class of alanine‐containing 3‐arylindoles as potent and selective PRMT4 inhibitors, and describe key structure–activity relationships for this class of compounds.
The Ni salen complex N,N′-bis(2,3,4-trimethoxysalicylidene)-1,2-cyclohexane-(1R,2R)-diamine nickel(II) (1), containing ortho-, meta-, and para-methoxy-substituted phenolate moieties, was prepared. Electrochemical studies revealed that the first oxidation of 1 occurs at a similar potential to a previously reported Ni salen complex NiSal tBu,OMe , employing an ortho-tBu and para-methoxy substitution pattern (M. Orio et al., Angew. Chem. Int. Ed. 2010, 49, 4989), demonstrating the counteracting effects of the methoxy substituent depending on ring location (ortho/para vs. meta). The second oxidation occurred at a much lower potential (E 1/2 2 -E 1/2 1 = 0.11 V) for 1, in comparison to NiSal tBu,OMe , suggesting significant localization of the [a]
A series of octahedral CoIII salen complexes (where salen represents a N2O2 bis-Schiff-base bis-phenolate framework) were prepared with axial imidazole ligating groups. When using 1-methylimidazole (1-MeIm) axial ligands, the CoIII/CoII reduction potential could be altered by 220 mV via variation of the electron-donating ability of the para-ring substituents (R = H (1), OMe (2), tBu (3), Br (4), NO2 (5), and CF3 (6)). In addition, the irreversibility of the reduction process suggested substantial geometrical changes and axial ligand exchange upon reduction to the more labile CoII oxidation state. Installing an imidazole-coumarin conjugate as the axial ligands resulted in fluorescence quenching when bound to the CoIII centre (R = H (7), OMe (8), and CF3 (9)). The redox properties and fluorescence increase upon ligand release for 7–9 were studied under reducing conditions and in the presence of excess competing ligand (1-MeIm). It was determined that the Lewis acidity of the CoIII centre was the dominant factor in controlling axial ligand exchange for this series of complexes.
A short enantioselective total synthesis of 1-deoxygalactonojirimycin (migalastat) has been achieved that does not rely on chiral pool starting materials or biocatalysis. Instead, this synthesis exploits a one-pot proline-catalyzed α-chlorination and aldol reaction of a commercially available aldehyde to assemble the entire carbon skeleton in a single step. The key role played by a nitrogen protecting group in the final epoxide opening reaction is highlighted as is the amenability to access structural analogues using this route.
Protein arginine N-methyl transferase 4 (PRMT4) asymmetrically dimethylates arginine residues of histone H3 and non-histone proteins. The overexpression of PRMT4 in several cancers has stimulated interest in the discovery of inhibitors as biological tools and potentially therapeutics. While several PRMT4 inhibitors have been reported, most display poor selectivity against other members of the PRMT family of methyl transferases. Here, we report the structure-based design of a new class of alanine containing 3-arylindoles as potent and selective PRMT4 inhibitors and describe key structure activity relationships for this class of compounds.
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