- Synthesis and biological evaluation of 3-phenyl-3-aryl carboxamido propanoic acid derivatives as small molecule inhibitors of retinoic acid 4-hydroxylase (CYP26A1)
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All-trans-retinoic acid (ATRA), the biologically active metabolite of vitamin A, is used medicinally for the treatment of hyperproliferative diseases and cancers. However, it is easily metabolized. In this study, the leading compound S8 was found based on virtual screening. To improve the activity of the leading compound S8, a series of novel S8 derivatives were designed, synthesized and evaluated for their in vitro biological activities. All of the prepared compounds showed that substituting the 5-chloro-3-methyl-1-phenyl-1H-pyrazole group for the 2-tertbutyl-5-methylfuran scaffold led to a clear increase in the biological activity. The most promising compound 32, with a CYP26A1 IC50 value of 1.36 μM (compared to liarozole (IC50 = 2.45 μM) and S8 (IC50 = 3.21 μM)) displayed strong inhibitory and differentiation activity against HL60 cells. In addition, the study focused on the effect of β-phenylalanine, which forms the coordination bond with the heme of CYP26A1. These studies suggest that the compound 32 can be used as an appropriate candidate for future development.
- Zhao, Dongmei,Sun, Bin,Ren, Jinhong,Li, Fengrong,Song, Shuai,Lv, Xuejiao,Hao, Chenzhou,Cheng, Maosheng
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p. 1356 - 1365
(2015/03/04)
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- The bacterial ammonia lyase EncP: A tunable biocatalyst for the synthesis of unnatural amino acids
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Enzymes of the class I lyase-like family catalyze the asymmetric addition of ammonia to arylacrylates, yielding high value amino acids as products. Recent examples include the use of phenylalanine ammonia lyases (PALs), either alone or as a gateway to deracemization cascades (giving (S)- or (R)-α-phenylalanine derivatives, respectively), and also eukaryotic phenylalanine aminomutases (PAMs) for the synthesis of the (R)-β-products. Herein, we present the investigation of another family member, EncP from Streptomyces maritimus, thereby expanding the biocatalytic toolbox and enabling the production of the missing (S)-β-isomer. EncP was found to convert a range of arylacrylates to a mixture of (S)-α- and (S)-β-arylalanines, with regioselectivity correlating to the strength of electron-withdrawing/-donating groups on the ring of each substrate. The low regioselectivity of the wild-type enzyme was addressed via structure-based rational design to generate three variants with altered preference for either α- or β-products. By examining various biocatalyst/substrate combinations, it was demonstrated that the amination pattern of the reaction could be tuned to achieve selectivities between 99:1 and 1:99 for β:α-product ratios as desired.
- Weise, Nicholas J.,Parmeggiani, Fabio,Ahmed, Syed T.,Turner, Nicholas J.
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supporting information
p. 12977 - 12983
(2015/10/28)
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- Carica papaya lipase catalysed resolution of β-amino esters for the highly enantioselective synthesis of (S)-dapoxetine
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An efficient synthesis of the (S)-3-amino-3-phenylpropanoic acid enantiomer has been achieved by Carica papaya lipase (CPL) catalysed enantioselective alcoholysis of the corresponding racemic N-protected 2,2,2-trifluoroethyl esters in an organic solvent. A high enantioselectivity (E > 200) was achieved by two strategies that involved engineering of the substrates and optimization of the reaction conditions. Based on the resolution of a series of amino acids, it was found that the structure of the substrate has a profound effect on the CPL-catalysed resolution. The enantioselectivity and reaction rate were significantly enhanced by switching the conventional methyl ester to an activated trifluoroethyl ester. When considering steric effects, the substituted phenyl and amino groups should not both be large for the CPL-catalysed resolution. The mechanism of the CPL-catalysed enantioselective alcoholoysis of the amino acids is discussed to delineate the substrate requirements for CPL-catalysed resolution. Finally, the reaction was scaled up, and the products were separated and obtained in good yields (≥ 80 %). The (S)-3-amino-3- phenylpropanoic acid obtained was used as a key chiral intermediate in the synthesis of (S)-dapoxetine with very high enantiomeric excess (> 99 %). A carica papaya lipase catalysed resolution of N-protected β-phenylalanine esters has been developed. High enantioselectivity was achieved by two strategies that involved engineering of the substrates and optimization of the reaction conditions. After 50 % conversion, the products were separated and used as key chiral intermediates for the synthesis of (S)-dapoxetine with > 99 % ee. Copyright
- You, Pengyong,Qiu, Jian,Su, Erzheng,Wei, Dongzhi
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p. 557 - 565
(2013/03/13)
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- Synthesis of novel 7-oxo and 7-hydroxy trifluoroallocolchicinoids with cytotoxic effect
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The synthesis of 7-oxo and 7-hydroxy trifluoroallocolchicinoids was achieved through the intramolecular cyclization of o-phenyl-β- phenylalanines. The resulting compounds were evaluated for their cytotoxic activity against KB cells and their inhibitory ef
- Chosson, Elizabeth,Santoro, Francesca,Rochais, Christophe,Santos, Jana Sopkova-De Oliveira,Legay, Rémi,Thoret, Sylviane,Cresteil, Thierry,Sinicropi, Maria Stefania,Besson, Thierry,Dallemagne, Patrick
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experimental part
p. 2614 - 2623
(2012/06/01)
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- Phenylalanine aminomutase-catalyzed addition of ammonia to substituted cinnamic acids: A route to enantiopure α- and β-amino acids
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(Chemical Equation Presented) An approach is described for the synthesis of aromatic α- and β-amino acids that uses phenylalanine aminomutase to catalyze a highly enantioselective addition of ammonia to substituted cinnamic acids. The reaction has a broad scope and yields substituted α- and β-phenylalanines with excellent enantiomeric excess. The regioselectivity of the conversion is determined by substituents present at the aromatic ring. A box model for the enzyme active site is proposed, derived from the influence of the hydrophobicity of substituents on the enzyme affinity toward various substrates.
- Szymanski, Wiktor,Wu, Bian,Weiner, Barbara,De Wildeman, Stefaan,Feringa, Ben L.,Janssen, Dick B.
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supporting information; experimental part
p. 9152 - 9157
(2010/03/01)
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- Preparation of enantiomerically enriched aromatic β-amino acids via enzymatic resolution
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A range of enantiomerically enriched aromatic β-amino acids with high e.e. have been prepared via enzymatic resolution of ethyl ester derivatives. (C) 2000 Elsevier Science Ltd.
- Faulconbridge, Susan J.,Holt, Karen E.,Garcia Sevillano, Luis,Lock, Christopher J.,Tiffin, Peter D.,Tremayne, Neil,Winter, Stephen
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p. 2679 - 2681
(2007/10/03)
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- Une synthese simple des premieres amino-3 indanones-1
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The synthesis of various substituted 3-amino-1-indanones was achieved in five steps starting from corresponding benzaldehydes.
- Rault, Sylvain,Dallemagne, Patrick,Robba, Max
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p. 1079 - 1083
(2007/10/02)
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