- Direct Experimental Evidence for Halogen–Aryl π Interactions in Solution from Molecular Torsion Balances
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We dissected halogen–aryl π interactions experimentally using a bicyclic N-arylimide based molecular torsion balances system, which is based on the influence of the non-bonded interaction on the equilibria between folded and unfolded states. Through comparison of balances modulated by higher halogens with fluorine balances, we determined the magnitude of the halogen–aryl π interactions in our unimolecular systems to be larger than ?5.0 kJ mol?1, which is comparable with the magnitude estimated in the biomolecular systems. Our study provides direct experimental evidence of halogen–aryl π interactions in solution, which until now have only been revealed in the solid state and evaluated theoretically by quantum-mechanical calculations.
- Sun, Han,Horatscheck, André,Martos, Vera,Bartetzko, Max,Uhrig, Ulrike,Lentz, Dieter,Schmieder, Peter,Nazaré, Marc
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supporting information
p. 6454 - 6458
(2017/05/29)
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- Discovery and structural optimization of pyrazole derivatives as novel inhibitors of Cdc25B
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Structural optimization and preliminary structure-activity relationship studies of a series of N-substituted maleimide fused-pyrazole analogues with Cdc25B inhibitory activity, starting from a high-throughput screening hit, are illustrated. A simplified 3,5-diacyl pyrazole analogue was obtained as the most potent compound (118, IC50 = 0.12 μM) with a 270-fold increase in potency.
- Chen, Hai-Jun,Liu, Yong,Wang, Li-Na,Shen, Qiang,Li, Jia,Nan, Fa-Jun
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scheme or table
p. 2876 - 2879
(2010/07/04)
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- Synthesis and in vitro evaluation of N-substituted maleimide derivatives as selective monoglyceride lipase inhibitors
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The endocannabinoid 2-arachidonoylglycerol (2-AG) plays a major role in many physiological processes, and its action is quickly terminated via enzymatic hydrolysis catalyzed by monoglyceride lipase (MGL). Regulating its endogenous level could offer therapeutic opportunities; however, few selective MGL inhibitors have been described so far. Here, we describe the synthesis of N-substituted maleimides and their pharmacological evaluation on the recombinant human fatty acid amide hydrolase (FAAH) and on the purified human MGL. A few N-arylmaleimides were previously described (Saario, S. M.; Salo, O. M.; Nevalainen, T.; Poso, A.; Laitinen, J. T.; Jarvinen, T.; Niemi, R. Characterization of the Sulfhydryl-Sensitive Site in the Enzyme Responsible for Hydrolysis of 2-Arachidonoylglycerol in Rat Cerebellar Membranes. Chem. Biol. 2005, 12, 649-656) as MGL inhibitors, and along these lines, we present a new set of maleimide derivatives that showed low micromolar IC50 and high selectivity toward MGL vs FAAH. Then, structure-activity relationships have been investigated and, for instance, 1-biphenyl-4-ylmethylmaleimide inhibits MGL with an IC50 value of 790 nM. Furthermore, rapid dilution experiments reveal that these compounds act as irreversible inhibitors. In conclusion, N-substituted maleimides constitute a promising class of potent and selective MGL inhibitors.
- Matuszak, Nicolas,Muccioli, Giulio G.,Labar, Geoffray,Lambert, Didier M.
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experimental part
p. 7410 - 7420
(2010/04/30)
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- Evaluation of N-aromatic maleimides as free radical photoinitiators: A photophysical and photopolymerization characterization
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Photopolymerizable compositions were prepared using acrylate monomers in combination with various N-aromatic maleimides. N-aromatic maleimides were segregated into two groups: those that could adopt a planar conformation and those that could not adopt a planar conformation. The maleimides were characterized using single-crystal X-ray diffraction spectroscopy, laser flash photolysis spectroscopy, UV-vis absorption spectroscopy, and photodifferential scanning calorimetry. Planar N-aromatic maleimides were found to have a low relative excited-state triplet yield, showing significant shift of the primary maleimide UV absorption band with changes in solvent polarity, and did not initiate free radial polymerization upon direct UV excitation. Twisted N-aromatic maleimides have a higher relative triplet yield, show negligible shift of the primary maleimide UV absorption band, with solvent polarity, and initiate free radical polymerization upon direct excitation. Addition of benzophenone was found to dramatically increase the initiation efficiency of both planar and twisted N-aromatic maleimides to levels approaching that of conventional cleavage photoinitiators.
- Miller, Chris W.,Sonny J?nsson,Hoyle, Charles E.,Viswanathan, Kalyanaraman,Valente, Edward J.
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p. 2707 - 2717
(2007/10/03)
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- Inter-Ring Torsions in N-Phenylmaleimide and Its o-Halo Derivatives: An Experimental and Computational Study
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Structures of N-phenylmaleimide and its o-halophenyl derivatives have been determined in the solid state and show the angle between the phenyl and pyrolinyl ring planes to vary from 49.5° to 83.9° with increasing values for compounds with the larger ortho halophenyl substituents (H F ≤ Cl ≤ Br I). Experimental torsions and trends in the series are supported by semiempirical AM1 and ab initio SCF, DFT, and MP2 calculations. Calculations (AM1) on N-phenylmaleimide modeling the torsional deformation between the rings show that the barrier to planarity has a lower energy than that through a perpendicular conformation. In its o-halo derivatives, molecular planarity is not possible, and torsional deformation proceeds through the perpendicular conformation with diminishing, possibly vanishing, barriers with increasing halogen size. For chloro, bromo, and iodo derivatives, twisted ground-state molecular conformations reside in broad minima essentially centered around the perpendicular conformations. The unusually strong, longer wavelength electronic bands observed in the solution spectra of the series were modeled by Zindo/S CIS computations at the optimum AM1 molecular geometries. The observed lower energy (285-305 nm) band for the parent through the o-bromo derivative appears to arise from a {n(O,N); π (phenyl)} → π*(maleimide) transition. The next higher energy (250-285 nm) band appears to be essentially a phenyl π Ρ π* transition. In the o-iodo derivative, a phenyl π → * (C-I) transition appears to contribute to the longer wavelength band. Trends in the observed electronic spectra in acetonitrile within the series of compounds accord roughly with the results of the computations.
- Miller, Christopher W.,Hoyle, Charles E.,Valente, Edward J.,Magers, David H.,Joensson, E. Sonny
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p. 6406 - 6412
(2007/10/03)
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