169885-19-2Relevant articles and documents
4-Biphenylalanine- and 3-Phenyltyrosine-Derived Hydroxamic Acids as Inhibitors of the JumonjiC-Domain-Containing Histone Demethylase KDM4A
Morera, Ludovica,Roatsch, Martin,Fürst, Michael C. D.,Hoffmann, Inga,Senger, Johanna,Hau, Mirjam,Franz, Henriette,Schüle, Roland,Heinrich, Markus R.,Jung, Manfred
, p. 2063 - 2083 (2016/10/22)
Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate-based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50value of 25.4 μm. Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low-micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell-permeable derivatives clearly showed a demethylase-inhibition-dependent antiproliferative effect against HL-60 human promyelocytic leukemia cells.
Synthesis and biological evaluation of new active For-Met-Leu-Phe-OMe analogues containing para-substituted Phe residues
Mollica, Adriano,Feliciani, Federica,Stefanucci, Azzurra,Costante, Roberto,Lucente, Gino,Pinnen, Francesco,Notaristefano, Daniela,Spisani, Susanna
experimental part, p. 418 - 426 (2012/08/28)
In the present study, we report synthesis and biological evaluation of the N-Boc-protected tripeptides 4a-l and N-For protected tripeptides 5a-l as new For-Met-Leu-Phe-OMe (fMLF-OMe) analogues. All the new ligands are characterized by the C-terminal Phe residue variously substituted at position 4 of the aromatic ring. The agonism of 5a-l and the antagonism of 4a-l (chemotaxis, superoxide anion production, lysozyme release as well as receptor binding affinity) have been examined on human neutrophils. No synthesized compounds has higher activity than the standard fMLF-OMe tripeptide to stimulate chemotaxis, although compounds 5a and 5c with -CH3 and -C(CH3)3, respectively, in position 4 on the aromatic ring, are better than the standard tripeptide to stimulate the production of superoxide anion, in higher concentration. Compounds 4f and 4i, containing -F and -I in position 4, respectively, on the aromatic ring of phenylalanine, exhibit significant chemotactic antagonism. The influence of the different substitution at the position 4 on the aromatic ring of phenylalanine is discussed.
Pharmaceutical compositions, methods of preparation thereof, and methods of treatment
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Page/Page column 6, (2008/06/13)
The present invention provides compositions, useful as pharmaceuticals, comprising 3-biphenyl-4-yl-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid. Also disclosed are methods for preparing the compositions and methods for using the compositions.
Phosphono/biaryl substituted dipetide derivatives
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, (2008/06/13)
The invention relates to the N-phosphonomethyl-biaryl substituted dipeptide derivatives of formula I STR1 and tetrazole derivatives of the formula Ia STR2 wherein A represents a direct bond, lower alkylene, phenylene or cyclohexylene; m represents 1 or zero, provided that m represents 1 when A is a direct bond; R2 represents hydrogen, hydroxy, lower alkyl, aryl-lower alkyl, C5 -C7 -cycloalkyl-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkylthio-lower alkyl or aryl-lower alkoxy-lower alkyl; biaryl represents phenyl substituted by carbocyclic or heterocyclic aryl; and pharmaceutically acceptable mono-, di- or tri-ester derivatives thereof in which one, two or three of the acidic hydroxy groups of the carboxyl and/or phosphono functional groups are esterified in form of a mono-, di- or tri-pharmaceutically acceptable ester; and pharmaceutically acceptable amide derivatives thereof wherein the carboxyl group is derivatized in form of a pharmaceutically acceptable amide; and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; methods for the preparation of said compounds and for the preparation of intermediates; and methods of treating disorders in mammals which are responsive to the inhibition of neutral endopeptidases by administration of said compounds to mammals in need of such treatment.
Phosphono/biaryl substituted dipeptide derivatives
-
, (2008/06/13)
The invention relates to the N-phosphonomethyl-biaryl substituted dipeptide derivatives of formula I STR1 wherein A represents a direct bond, lower alkylene, phenylene or cyclohexylene; m represents 1 or zero, provided that m represents 1 when A is a direct bond; R2 represents hydrogen, hydroxy, lower alkyl, aryl-lower alkyl, C5 -C7 -cycloalkyl-lower alkyl, amino-lower alkyl, hydroxyl-lower alkyl, lower alkylthio-lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkylthio-lower alkyl or aryl-lower alkoxy-lower alkyl; biaryl represents phenyl substituted by carbocyclic or heterocyclic aryl; and pharmaceutically acceptable mono-, di- or tri-ester derivatives thereof in which one, two or three of the acidic hydroxy groups of the carboxyl and phosphono functional groups are esterified in form of a mono-, di- or tri- pharmaceutically acceptable ester; and pharmaceutically acceptable amide derivatives thereof wherein the carboxyl group is derivatized in form of a pharmaceutically acceptable amide; and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; methods for the preparation of said compounds and for the preparation of intermediates; and methods of treating disorders in mammals which are responsive to the inhibition of neutral endopeptidases by administration of said compounds to mammals in need of such treatment.
