Publications (27) View all
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Article: Helical Oligomers of Thiazole-Based γ-Amino Acids: Synthesis and Structural Studies.
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ABSTRACT: 9-Helix: 4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) were synthesized as new γ-amino acid building blocks. The structures of various ATC oligomers were analyzed in solution by CD and NMR spectroscopy and in the solid state by X-ray crystallography. The ATC sequences adopted a well-defined 9-helix structure in the solid state and in aprotic and protic organic solvents as well as in aqueous solution.Angewandte Chemie International Edition 04/2013; · 13.45 Impact Factor -
Article: An efficient synthesis of pyrido-imidazodiazepinediones
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ABSTRACT: We herein report the synthesis of a series of 12 optically pure 3,4-dihydro-1H-pyrido-[1 0 ,2 0 :1,2]-imi-dazo[4,5-d][1,3]diazepine-2,5-diones, which form a new family of azaheterocycle-fused [1,3]diazepines. The key step of the synthesis consists in a selective C-acylation of 2-amino-imidazo[1,2-a]pyridine by various natural amino-acids, followed by an intracarbonylation reaction. The diazepine scaffold is one of the classical examples of privi-leged structures, which has proved its effectiveness in a number of pharmaceutical drugs and still continues to attract much interest today in medicinal chemistry. 1,2 Aryldiazepine ring systems achieved popularity first in the 1960s with diazepam as the first orally active benzo[1,4]diazepinone anxiolytic by interaction with GABA receptor. This scaffold was further shown to interact with multiple receptor types with high affinity 3 and has been used in the design of enzyme inhibitors 4–7 and protein–DNA interaction inhibitors. 8 Beyond benzo[1,4]diazepines, [1,4]diazepines fused with various heterocyclic ring systems such as imidazole, 9–14 in-dole, 15 pyrrole, 16 pyridine, 17 pyrazole, 18,19 thiophene, 20–23 etc. have been investigated. Among the different classes of diazepines, the [1,3]diazepines have been studied to a minor extent although their representatives (benzo-, thiazolo-, and imidazo-fused) exhibit various biological activities including cytotoxic, 24 anti-HIV, 25 AMP deaminase inhibi-tor, 26 anti-HCV, 27 lymphocyte-specific kinase (Lck) inhibitors. 28 The [1,3]diazepin-2-one scaffold can also be found in natural prod-ucts 29 or in synthetic compounds with pharmacological activities, like calcitonin gene-related peptide (CGRP) receptor antagonists, 30 dopamine D2 partial agonists, 31 or HIV protease inhibitors 32 (Fig. 1). Therefore, development of new fused [1,3]diazepin-2-one scaffolds, incorporating an urea moiety in the diazepine core could be of interest to access new bioactive compounds. We recently reported the synthesis of an original series of opti-cally pure imidazopyrido[1,3]diazepin-5-ones. 33 The key step of the synthesis is a Friedel–Crafts acylation at the C-3 position of the easily accessible 2-amino-imidazo[1,2-a]pyridine. 34,35 In con-tinuation of this study, we describe herein the synthesis of imi-dazo[1,2-a]pyridine-based [1,3]diazepin-2,5-diones (target compounds 1, Fig. 1). The synthesis of target compounds 1 was envisioned from 2-amino-imidazo[1,2-a]pyridine 3, according to the strategy de-picted in Scheme 1. Imidazo[1,2-a]pyridine (IP), an aza analog ofTetrahedron Letters 01/2013; 54:1364–1367. · 2.68 Impact Factor -
Article: Further characterization of a putative serine protease contributing to the γ-secretase cleavage of β-amyloid precursor protein.
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ABSTRACT: The 3-alkoxy-7-amino-4-chloro-isocoumarins JLK-6 and JLK-2 have been shown to markedly reduce the production of Amyloid β-peptide (Aβ) by Amyloid-β Precursor Protein (APP) expressing HEK293 cells by affecting the γ-secretase cleavage of APP, with no effect on the cleavage of the Notch receptor. This suggested that these compounds do not directly inhibit the presenilin-dependent γ-secretase complex but more likely interfere with an upstream target involved in γ-secretase-associated pathway. The mechanism of action of these compounds is unknown and there are high fundamental and therapeutical interests to unravel their target. Isocoumarin compounds were previously shown to behave as potent mechanism-based irreversible inhibitors of serine proteases, suggesting that the JLK-directed target could belong to such enzyme family. To get further insight into structure-activity relationships and to develop more potent isocoumarin derivatives, we have synthesized and evaluated a series of isocoumarin analogues with modifications at positions 3, 4 and 7. In particular, the 7-amino group was substituted with either acyl, urethane, alkyl or aryl groups, which could represent additional interaction sites. Altogether, the results highlighted the essential integrity of the 3-alkoxy-7-amino-4-chloro-isocoumarin scaffold for Aβ-lowering activity and supported the involvement of a serine protease, or may be more generally, a serine hydrolase. The newly reported 7-N-alkyl series produced the most active compounds with an IC(50) between 10 and 30μM. Finally, we also explored peptide boronates, a series of reversible serine protease inhibitors, previously shown to also lower cellular Aβ production. The presented data suggested they could act on the same target or interfere with the same pathway as isocoumarins derivatives.Bioorganic & medicinal chemistry 12/2012; · 2.82 Impact Factor -
Article: Selective C-acylation of 2-aminoimidazo[1,2-a]pyridine: application to the synthesis of imidazopyridine-fused [1,3]diazepinones.
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ABSTRACT: A series of 20 optically pure 3,4-dihydro-5H-pyrido[1',2':1,2]imidazo[4,5-d][1,3]diazepin-5-ones which form a new family of azaheterocycle-fused [1,3]diazepines were synthesized in four steps with 17-66% overall yields. The key step consists of a selective C-acylation reaction of easily accessible 2-aminoimidazo[1,2-a]pyridine at C-3.The Journal of Organic Chemistry 03/2012; 77(7):3679-85. · 4.45 Impact Factor -
Article: Chemical optimization of new ligands of the low-density lipoprotein receptor as potential vectors for central nervous system targeting.
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ABSTRACT: Drug delivery to the central nervous system is hindered by the presence of physiological barriers such as the blood-brain barrier. To accomplish the task of nutrient transport, the brain endothelium is endowed with various transport systems, including receptor-mediated transcytosis (RMT). This system can be used to shuttle therapeutics into the central nervous system (CNS) in a noninvasive manner. Therefore, the low-density lipoprotein receptor (LDLR) is a relevant target for delivering drugs. From an initial phage display biopanning, a series of peptide ligands for the LDLR was optimized leading to size reduction and improved receptor binding affinity with the identification of peptide 22 and its analogues. Further real-time biphoton microscopy experiments on living mice demonstrated the ability of peptide 22 to efficiently and quickly cross CNS physiological barriers. This validation of peptide 22 led us to explore its binding on the extracellular LDLR domain from an NMR-oriented structural study and docking experiments.Journal of Medicinal Chemistry 03/2012; 55(5):2227-41. · 4.80 Impact Factor
