Ronco C


Full name : Ronco Cyril

First name : Cyril

Mail : IRCOF\; Universite de Rouen\; rue Tesniere\; 76130 Mont Saint Aignan

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Country : France

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Phone : +33235522416

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References (7)

Title : Reaction site-driven regioselective synthesis of AChE inhibitors - Oueis_2014_Org.Biomol.Chem_12_156
Author(s) : Oueis E , Santoni G , Ronco C , Syzgantseva O , Tognetti V , Joubert L , Romieu A , Weik M , Jean L , Sabot C , Nachon F , Renard PY
Ref : Org Biomol Chem , 12 :156 , 2014
Abstract : The enzyme-directed synthesis is an emerging fragment-based lead discovery approach in which the biological target is able to assemble its own multidentate ligands from a pool of building blocks. Here, we report for the first time the use of the human acetylcholinesterase (AChE) as an enzyme for the design and synthesis of new potent heterodimeric huprine-based inhibitors. Both the specific click chemistry site within the protein and the regioselectivity of the Huisgen cycloaddition observed suggest promising alternatives in the design of efficient mono- and dimeric ligands of AChE. Finally, a detailed computational modelling of the click reaction was conducted to further understand the origin of this TGS selectivity.
ESTHER : Oueis_2014_Org.Biomol.Chem_12_156
PubMedSearch : Oueis_2014_Org.Biomol.Chem_12_156
PubMedID: 24216754

Title : Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase - Nachon_2013_Biochem.J_453_393
Author(s) : Nachon F , Carletti E , Ronco C , Trovaslet M , Nicolet Y , Jean L , Renard PY
Ref : Biochemical Journal , 453 :393 , 2013
Abstract : The multifunctional nature of Alzheimer's disease calls for MTDLs (multitarget-directed ligands) to act on different components of the pathology, like the cholinergic dysfunction and amyloid aggregation. Such MTDLs are usually on the basis of cholinesterase inhibitors (e.g. tacrine or huprine) coupled with another active molecule aimed at a different target. To aid in the design of these MTDLs, we report the crystal structures of hAChE (human acetylcholinesterase) in complex with FAS-2 (fasciculin 2) and a hydroxylated derivative of huprine (huprine W), and of hBChE (human butyrylcholinesterase) in complex with tacrine. Huprine W in hAChE and tacrine in hBChE reside in strikingly similar positions highlighting the conservation of key interactions, namely, pi-pi/cation-pi interactions with Trp86 (Trp82), and hydrogen bonding with the main chain carbonyl of the catalytic histidine residue. Huprine W forms additional interactions with hAChE, which explains its superior affinity: the isoquinoline moiety is associated with a group of aromatic residues (Tyr337, Phe338 and Phe295 not present in hBChE) in addition to Trp86; the hydroxyl group is hydrogen bonded to both the catalytic serine residue and residues in the oxyanion hole; and the chlorine substituent is nested in a hydrophobic pocket interacting strongly with Trp439. There is no pocket in hBChE that is able to accommodate the chlorine substituent.
ESTHER : Nachon_2013_Biochem.J_453_393
PubMedSearch : Nachon_2013_Biochem.J_453_393
PubMedID: 23679855
Gene_locus related to this paper: human-ACHE , human-BCHE

Title : Huprine derivatives as sub-nanomolar human acetylcholinesterase inhibitors: from rational design to validation by X-ray crystallography - Ronco_2012_ChemMedChem_7_400
Author(s) : Ronco C , Carletti E , Colletier JP , Weik M , Nachon F , Jean L , Renard PY
Ref : ChemMedChem , 7 :400 , 2012
Abstract : This complete study - from rational design to validation by X-ray crystallography allowed us to discover two sub-nanomolar hAChE inhibitors (430 and 530 pM) grafted with an easily derivatized linker directed toward the AChE peripheral site. The crystal structure of mouse AChE in complex with compound 4 was solved and confirms the favorable position of the triazole in the active site gorge, paving the way for a new class of bifunctional ligands.
ESTHER : Ronco_2012_ChemMedChem_7_400
PubMedSearch : Ronco_2012_ChemMedChem_7_400
PubMedID: 22052791
Gene_locus related to this paper: mouse-ACHE

Title : Screening of new huprines--inhibitors of acetylcholinesterases by electrospray ionization ion trap mass spectrometry - Ziemianin_2012_J.Pharm.Biomed.Anal_70_1
Author(s) : Ziemianin A , Ronco C , Dole R , Jean L , Renard PY , Lange CM
Ref : J Pharm Biomed Anal , 70 :1 , 2012
Abstract : Acetylcholinesterase inhibitors (AChEI) are one of the drugs families validated for clinical use in the treatment of Alzheimer's disease (AD). For this reason, finding new more potent and more selective AChEIs is always of interest. Since 1961, the inhibitory activity of AChEI is evaluated through the Ellman's method. Herein, we reported a MS-based evaluation of potential new AChEI with the determination of their inhibitory activity (IC(50) and K(I)). Compared to the Ellman's method, that uses the substrate analog acetylthiocholine, the electrospray ionization ion trap mass spectrometry (ESI-IT-MS) consists in monitoring the conversion ratio of a low concentration of the natural substrate - acetylcholine to choline. We present here the inhibition activity of huprine X and six of its derivates (bearing different functional groups at position 9) towards the recombinant human (rhAChE) and Electrophorus electricus acetylcholinesterase (EelAChE). Mechanisms of action of selected inhibitors were evaluated by means of Lineweaver-Burk plot analysis. The Michaelis-Menten constants (K(M)), inhibitory constants (K(I)) were examined as well as the IC(50) to allow classifying a series of huprine derivatives by inhibition potency by a comparison with a reference (huprine X). Our results demonstrate that these drugs are very potent AChE inhibitors, especially (+/-)-huprine 6 with an inhibitory activity on recombinant human AChE (rhAChE) in the picomolar range. This study reveals the interest of huprine compounds in the treatment of AD.
ESTHER : Ziemianin_2012_J.Pharm.Biomed.Anal_70_1
PubMedSearch : Ziemianin_2012_J.Pharm.Biomed.Anal_70_1
PubMedID: 22677656

Title : Human butyrylcholinesterase produced in insect cells: huprine-based affinity purification and crystal structure - Brazzolotto_2012_Febs.J_279_2905
Author(s) : Brazzolotto X , Wandhammer M , Ronco C , Trovaslet M , Jean L , Lockridge O , Renard PY , Nachon F
Ref : Febs J , 279 :2905 , 2012
Abstract : Butyrylcholinesterase is a serine hydrolase present in all mammalian tissues. It can accommodate larger substrates or inhibitors than acetylcholinesterase, the enzyme responsible for hydrolysis of the neurotransmitter acetylcholine in the central nervous system and neuromuscular junctions. AChE is the specific target of organophosphorous pesticides and warfare nerve agents, while BChE is their stoichiometric bioscavenger. Conversion of BChE into a catalytic bioscavenger by rational design or designing reactivators specific to BChE required structural data obtained with a recombinant low-glycosylated human BChE expressed in Chinese hamster ovary cells. This expression system yields about 1 mg of pure enzyme per liter of cell culture. Here, we report an improved expression system with 4-fold higher yield for truncated human BChE with all glycosylation sites present using insect cells. We developed a fast purification protocol of the recombinant protein using a huprine-based affinity chromatography superior to the classical procainamide-based affinity. The purified BChE crystallized in different conditions and space group than those for the recombinant low-glycosylated protein produced in Chinese hamster ovary cells. The crystals diffracted to 2.5 A. The overall monomer structure is similar to the low-glycosylated structure but for the presence of the additional glycans. Remarkably, the carboxylic acid molecule systematically bound to the catalytic serine in the low-glycosylated structure is also present in this new structure, despite the different expression system, purification protocol and crystallization conditions.
ESTHER : Brazzolotto_2012_Febs.J_279_2905
PubMedSearch : Brazzolotto_2012_Febs.J_279_2905
PubMedID: 22726956
Gene_locus related to this paper: human-BCHE

Title : New huprine derivatives functionalized at position 9 as highly potent acetylcholinesterase inhibitors - Ronco_2011_ChemMedChem_6_876
Author(s) : Ronco C , Foucault R , Gillon E , Bohn P , Nachon F , Jean L , Renard PY
Ref : ChemMedChem , 6 :876 , 2011
Abstract : A series of 24 huprine derivatives diversely functionalized at position 9 have been synthesized and evaluated for their inhibitory activity against human recombinant acetylcholinesterase (AChE). These derivatives were prepared in one to five steps from huprine 1 bearing an ester function at position 9. Ten analogues (1, 2, 6-9, 13-15, and 23) are active in the low nanomolar range (IC(50) <5 nM), very close to the parent compound huprine X. Compounds 2, 6, and 7 show a very good selectivity for AChE, with AChE inhibitory activities 700-1160-fold higher than those for butyrylcholinesterase (BChE). The inhibitory potency of these compounds decreases with the steric bulk of the substituents at position 9. According to docking simulations, small substituents fit into the acyl-binding pocket, whereas the larger ones stick out of the active site gorge of AChE. Determination of the kinetic parameters of three of the most potent huprines (2, 6, and 7) showed that most of the difference in K(D) is accounted by a decrease in k(on) , which is correlated to the increase of the substituent size. A first in vivo evaluation has been performed in mice for the most active compound 2 (IC(50) =1.1 nM) and showed a rather weak toxicity (LD(50) =40 mg kg(-1) ) and an ability to cross the blood-brain barrier with doses above 15 mg kg(-1).
ESTHER : Ronco_2011_ChemMedChem_6_876
PubMedSearch : Ronco_2011_ChemMedChem_6_876
PubMedID: 21344648

Title : Synthesis and structure-activity relationship of Huprine derivatives as human acetylcholinesterase inhibitors - Ronco_2009_Bioorg.Med.Chem_17_4523
Author(s) : Ronco C , Sorin G , Nachon F , Foucault R , Jean L , Romieu A , Renard PY
Ref : Bioorganic & Medicinal Chemistry , 17 :4523 , 2009
Abstract : New series of Huprine (12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolines) derivatives have been synthesized and their inhibiting activities toward recombinant human acetylcholinesterase (rh-AChE) are reported. We have synthesized two series of Huprine analogues; in the first one, the benzene ring of the quinoline moiety has been replaced by different heterocycles or electron-withdrawing or electron-donating substituted phenyl group. The second one has been designed in order to evaluate the influence of modification at position 12 where different short linkers have been introduced on the Huprine X, Y skeletons. All these molecules have been prepared from ethyl- or methyl-bicyclo[3.3.1]non-6-en-3-one via Friedlander reaction involving selected o-aminocyano aromatic compounds. The synthesis of two heterodimers based on these Huprines has been also reported. Activities from moderate to same range than the most active Huprines X and Y taken as references have been obtained, the most potent analogue being about three times less active than parent Huprines X and Y. Topologic data have been inferred from molecular dockings and variations of activity between the different linkers suggest future structural modifications for activity improvement.
ESTHER : Ronco_2009_Bioorg.Med.Chem_17_4523
PubMedSearch : Ronco_2009_Bioorg.Med.Chem_17_4523
PubMedID: 19473849