ABSTRACT 4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) are a new class of constrained he... more ABSTRACT 4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) are a new class of constrained heterocyclic γ-amino acids built around a thiazole ring; these compounds are valuable as design mimics of the secondary structures of proteins such as helices, β-sheets, turns, and β-hairpins. We report herein a short and versatile chemical route to orthogonally protected ATCs. The synthesis is centered on cross-Claisen condensations between N-Fmoc-amino acids and sterically hindered 1,1-dimethylallyl acetate. The optimized conditions are compatible with aliphatic, aromatic, acidic, and basic amino acids. The resulting N-Fmoc-β-keto ester intermediates were engaged in a two-step process to give ATCs in 45–90 % yields. The synthetic protocol provides a highly flexible method for the introduction of a wide variety of lateral chains either on the γ-carbon atom or on the thiazole core of the γ-amino acids.
Journal of The American Society for Mass Spectrometry, 2009
Mass spectrometry, and especially electrospray ionization, is now an efficient tool to study nonc... more Mass spectrometry, and especially electrospray ionization, is now an efficient tool to study noncovalent interactions between proteins and inhibitors. It is used here to study the interaction of some weak inhibitors with the NCoA-1/STAT6 protein with K D values in the µM range. High signal intensities corresponding to some nonspecific electrostatic interactions between NCoA-1 and the oppositely charged inhibitors were
Template-fixed β-hairpin peptidomimetics of the general formula (I) wherein Z is a template-fixed... more Template-fixed β-hairpin peptidomimetics of the general formula (I) wherein Z is a template-fixed chain of 8 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid), are GIy or Pro or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have agonizing or antagonizing activity against urotensin II or show inhibition of the STAT6/NCoA-1 interaction and can be used for preventing or treating diseases or disorders related to urotensin II, STAT6 and NCoA-1. These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.
A tandem aza-Friedel–Crafts reaction/Hantzsch cyclization is described to access various polysubs... more A tandem aza-Friedel–Crafts reaction/Hantzsch cyclization is described to access various polysubstituted 2-amino-1,3-thiazoles from electron-rich (hetero)-aromatic rings, aldehydes, thiourea and α-chloroketones.
The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrei... more The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrein family. KLK7 is involved in skin homeostasis and inflammation. Excess of KLK7 activity is also associated with tumor metastasis processes, especially in ovarian carcinomas, prostatic and pancreatic cancers. Development of Kallikrein 7 inhibitors is thus of great interest in oncology but also for treating skin diseases. Most of the developed synthetic inhibitors present several drawbacks such as poor selectivity and unsuitable physico-chemical properties for in vivo use. Recently, we described a practical sequence for the synthesis of imidazopyridine-fused [1,3]-diazepines. Here, we report the identification of pyrido-imidazodiazepinone core as a new potential scaffold to develop selective and competitive inhibitors of kallikrein-related peptidase 7. Structure-activity relationships (SAR), inhibition mechanisms and selectivity as well as cytotoxicity against selected cancer cell lines were investigated.
ABSTRACT 4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) are a new class of constrained he... more ABSTRACT 4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) are a new class of constrained heterocyclic γ-amino acids built around a thiazole ring; these compounds are valuable as design mimics of the secondary structures of proteins such as helices, β-sheets, turns, and β-hairpins. We report herein a short and versatile chemical route to orthogonally protected ATCs. The synthesis is centered on cross-Claisen condensations between N-Fmoc-amino acids and sterically hindered 1,1-dimethylallyl acetate. The optimized conditions are compatible with aliphatic, aromatic, acidic, and basic amino acids. The resulting N-Fmoc-β-keto ester intermediates were engaged in a two-step process to give ATCs in 45–90 % yields. The synthetic protocol provides a highly flexible method for the introduction of a wide variety of lateral chains either on the γ-carbon atom or on the thiazole core of the γ-amino acids.
Journal of The American Society for Mass Spectrometry, 2009
Mass spectrometry, and especially electrospray ionization, is now an efficient tool to study nonc... more Mass spectrometry, and especially electrospray ionization, is now an efficient tool to study noncovalent interactions between proteins and inhibitors. It is used here to study the interaction of some weak inhibitors with the NCoA-1/STAT6 protein with K D values in the µM range. High signal intensities corresponding to some nonspecific electrostatic interactions between NCoA-1 and the oppositely charged inhibitors were
Template-fixed β-hairpin peptidomimetics of the general formula (I) wherein Z is a template-fixed... more Template-fixed β-hairpin peptidomimetics of the general formula (I) wherein Z is a template-fixed chain of 8 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid), are GIy or Pro or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have agonizing or antagonizing activity against urotensin II or show inhibition of the STAT6/NCoA-1 interaction and can be used for preventing or treating diseases or disorders related to urotensin II, STAT6 and NCoA-1. These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.
A tandem aza-Friedel–Crafts reaction/Hantzsch cyclization is described to access various polysubs... more A tandem aza-Friedel–Crafts reaction/Hantzsch cyclization is described to access various polysubstituted 2-amino-1,3-thiazoles from electron-rich (hetero)-aromatic rings, aldehydes, thiourea and α-chloroketones.
The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrei... more The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrein family. KLK7 is involved in skin homeostasis and inflammation. Excess of KLK7 activity is also associated with tumor metastasis processes, especially in ovarian carcinomas, prostatic and pancreatic cancers. Development of Kallikrein 7 inhibitors is thus of great interest in oncology but also for treating skin diseases. Most of the developed synthetic inhibitors present several drawbacks such as poor selectivity and unsuitable physico-chemical properties for in vivo use. Recently, we described a practical sequence for the synthesis of imidazopyridine-fused [1,3]-diazepines. Here, we report the identification of pyrido-imidazodiazepinone core as a new potential scaffold to develop selective and competitive inhibitors of kallikrein-related peptidase 7. Structure-activity relationships (SAR), inhibition mechanisms and selectivity as well as cytotoxicity against selected cancer cell lines were investigated.
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Papers by Ludovic Maillard