I19-Small Molecule Single Crystal Diffraction
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Abstract: Mannich-type reaction of methyl phenylacetate with the N-tert-butylsulfinyl imine derived from (R)-tert-butylsulfinamide and (Z)-14-(pyridin-3′-yl)tetradec-11-enal has been used as the key step in the first asymmetric synthesis of (−)-nakinadine A. Both the 2,3-syn- and 2,3-anti-diastereoisomers were prepared; comparison of spectroscopic and specific rotation data facilitated assignment of the absolute (2S,3R,Z)-configuration within the natural product. (−)-(2S,3R,Z)-Nakinadine A was prepared in 10 steps from 11-bromoundecan-1-ol, in 10% overall yield, 97:3 dr [(Z):(E) ratio], and >98% ee.
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Mar 2014
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I04-Macromolecular Crystallography
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Alice
Legru
,
Federica
Verdirosa
,
Jean-François
Hernandez
,
Giusi
Tassone
,
Filomena
Sannio
,
Manuela
Benvenuti
,
Pierre-Alexis
Conde
,
Guillaume
Bossis
,
Caitlyn A.
Thomas
,
Michael W.
Crowder
,
Melissa
Dillenberger
,
Katja
Becker
,
Cecilia
Pozzi
,
Stefano
Mangani
,
Jean-Denis
Docquier
,
Laurent
Gavara
Diamond Proposal Number(s):
[21741]
Abstract: Metallo-β-lactamases (MBLs) are important contributors of Gram-negative bacteria resistance to β-lactam antibiotics. MBLs are highly worrying because of their carbapenemase activity, their rapid spread in major human opportunistic pathogens while no clinically useful inhibitor is available yet. In this context, we are exploring the potential of compounds based on the 1,2,4-triazole-3-thione scaffold as an original ligand of the di-zinc active sites of MBLs, and diversely substituted at its positions 4 and 5. Here, we present a new series of compounds substituted at the 4-position by a thioether-containing alkyl chain with a carboxylic and/or an aryl group at its extremity. Several compounds showed broad-spectrum inhibition with Ki values in the μM to sub-μM range against VIM-type enzymes, NDM-1 and IMP-1. The presence of the sulfur and of the aryl group was important for the inhibitory activity and the binding mode of a few compounds in VIM-2 was revealed by X-ray crystallography. Importantly, in vitro antibacterial susceptibility assays showed that several inhibitors were able to potentiate the activity of meropenem on Klebsiella pneumoniae clinical isolates producing VIM-1 or VIM-4, with a potentiation effect of up to 16-fold. Finally, a selected compound was found to only moderately inhibit the di-zinc human glyoxalase II, and several showed no or only moderate toxicity toward several human cells, thus favourably completing a promising behaviour.
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Oct 2021
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I04-Macromolecular Crystallography
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Federica
Verdirosa
,
Laurent
Gavara
,
Laurent
Sevaille
,
Giusy
Tassone
,
Giuseppina
Corsica
,
Alice
Legru
,
Georges
Feller
,
Giulia
Chelini
,
Paola S.
Mercuri
,
Silvia
Tanfoni
,
Filomena
Sannio
,
Manuela
Benvenuti
,
Giulia
Cerboni
,
Filomena
De Luca
,
Ezeddine
Bouajila
,
Yen
Vo Hoang
,
Patricia
Licznar-Fajardo
,
Moreno
Galleni
,
Cecilia
Pozzi
,
Stefano
Mangani
,
Jean-Denis
Docquier
,
Jean-François
Hernandez
Diamond Proposal Number(s):
[21741]
Abstract: Metallo-β-lactamases (MBLs) are increasingly involved as a major mechanism of resistance to carbapenems in relevant opportunistic Gram-negative pathogens. Unfortunately, clinically efficient MBL inhibitors still represent an unmet medical need . We previously reported several series of compounds based on the 1,2,4-triazole-3-thione scaffold. In particular, Schiff bases formed between diversely 5-substituted-4-amino compounds and 2-carboxybenzaldehyde were broad-spectrum inhibitors of VIM-type, NDM-1 and IMP-1 MBLs. Unfortunately, they were unable to restore antibiotic susceptibility of MBL-producing bacteria, probably because of poor penetration and/or susceptibility to hydrolysis. To improve their microbiological activity, we developed compounds where the hydrazone-like bond of the Schiff bases was replaced by a stable ethyl link. This small change resulted in a narrower inhibition spectrum, as all compounds were poorly or not inhibiting NDM-1 and IMP-1, but some showed a significantly better activity on VIM-type enzymes, with K i values in the μM to sub-μM range. The resolution of the crystallographic structure of VIM-2 in complex with one inhibitor yielded valuable information about their binding mode. Interestingly, several compounds were shown to restore the β-lactam susceptibility of K. pneumoniae clinical isolates. In addition, selected compounds were found to be devoid of toxicity toward human cells at high concentration, thus showing promising safety.
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Jan 2022
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I03-Macromolecular Crystallography
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Christopher
Asquith
,
Paulo
Godoi
,
Rafael M.
Counago
,
Tuomo
Laitinen
,
John W.
Scott
,
Christopher
Langendorf
,
Jonathan S.
Oakhill
,
David
Drewry
,
William
Zuercher
,
Panayiotis
Koutentis
,
Timothy
Willson
,
Andreas
Kalogirou
Diamond Proposal Number(s):
[14664]
Open Access
Abstract: We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors.
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May 2018
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I03-Macromolecular Crystallography
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Emmanuel H.
Demont
,
Paul
Bamborough
,
Chun-Wa
Chung
,
Peter D.
Craggs
,
David
Fallon
,
Laurie J.
Gordon
,
Paola
Grandi
,
Clare I.
Hobbs
,
Jameed
Hussain
,
Emma J.
Jones
,
Armelle
Le Gall
,
Anne-Marie
Michon
,
Darren J.
Mitchell
,
Rab K.
Prinjha
,
Andy D.
Roberts
,
Robert J.
Sheppard
,
Robert J.
Watson
Abstract: The BRPF (bromodomain and PHD finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Here, we report the discovery, binding mode, and structure–activity relationship (SAR) of the first potent, selective series of inhibitors of the BRPF1 bromodomain.
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Nov 2014
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I02-Macromolecular Crystallography
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Aleksandra
Twarda-Clapa
,
Sylwia
Krzanik
,
Katarzyna
Kubica
,
Katarzyna
Guzik
,
Beata
Labuzek
,
Constantinos G.
Neochoritis
,
Kareem
Khoury
,
Kaja
Kowalska
,
Miroslawa
Czub
,
Grzegorz
Dubin
,
Alexander
Dömling
,
Lukasz
Skalniak
,
Tad A.
Holak
Abstract: The tumor suppressor protein p53, the “guardian of the genome”, is inactivated in nearly all cancer types by mutations in the TP53 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53–MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53–MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers. The compounds have favorable properties at both biochemical and cellular levels. The most effective compound 19 is a tight binder of MDM2 and activates p53 in cancer cells that express the wild-type p53, leading to cell cycle arrest and growth inhibition. Crystal structures reveal that compound 19 induces MDM2 dimerization via the aliphatic linker. This unique dimerization-binding mode opens new prospects for the optimization of the p53–MDM2/MDMX inhibitors and conjugation with bioactive carriers.
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May 2017
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I02-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Marta
Artola
,
Liang
Wu
,
Maria J.
Ferraz
,
Chi-Lin
Kuo
,
Lluís
Raich
,
Imogen Z.
Breen
,
Wendy A.
Offen
,
Jeroen D. C.
Codée
,
Gijsbert A.
Van Der Marel
,
Carme
Rovira
,
Johannes M. F. G.
Aerts
,
Gideon J.
Davies
,
Herman S.
Overkleeft
Diamond Proposal Number(s):
[13587]
Open Access
Abstract: The essential biological roles played by glycosidases, coupled to the diverse therapeutic benefits of pharmacologically targeting these enzymes, provide considerable motivation for the development of new inhibitor classes. Cyclophellitol epoxides and aziridines are recently established covalent glycosidase inactivators. Inspired by the application of cyclic sulfates as electrophilic equivalents of epoxides in organic synthesis, we sought to test whether cyclophellitol cyclosulfates would similarly act as irreversible glycosidase inhibitors. Here we present the synthesis, conformational analysis, and application of novel 1,6-cyclophellitol cyclosulfates. We show that 1,6-epi-cyclophellitol cyclosulfate (α-cyclosulfate) is a rapidly reacting α-glucosidase inhibitor whose 4C1 chair conformation matches that adopted by α-glucosidase Michaelis complexes. The 1,6-cyclophellitol cyclosulfate (β-cyclosulfate) reacts more slowly, likely reflecting its conformational restrictions. Selective glycosidase inhibitors are invaluable as mechanistic probes and therapeutic agents, and we propose cyclophellitol cyclosulfates as a valuable new class of carbohydrate mimetics for application in these directions.
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Jul 2017
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I04-Macromolecular Crystallography
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Ken
Kok
,
Chi-Lin
Kuo
,
Rebecca E.
Katzy
,
Lindsey T.
Lelieveld
,
Liang
Wu
,
Véronique
Roig-Zamboni
,
Gijsbert A.
Van Der Marel
,
Jeroen D. C.
Codée
,
Gerlind
Sulzenbacher
,
Gideon J.
Davies
,
Herman S.
Overkleeft
,
Johannes M. F. G.
Aerts
,
Marta
Artola
Open Access
Abstract: α-Glucosidase inhibitors are potential therapeutics for the treatment of diabetes, viral infections, and Pompe disease. Herein, we report a 1,6-epi-cyclophellitol cyclosulfamidate as a new class of reversible α-glucosidase inhibitors that displays enzyme inhibitory activity by virtue of its conformational mimicry of the substrate when bound in the Michaelis complex. The α-d-glc-configured cyclophellitol cyclosulfamidate 4 binds in a competitive manner the human lysosomal acid α-glucosidase (GAA), ER α-glucosidases, and, at higher concentrations, intestinal α-glucosidases, displaying an excellent selectivity over the human β-glucosidases GBA and GBA2 and glucosylceramide synthase (GCS). Cyclosulfamidate 4 stabilizes recombinant human GAA (rhGAA, alglucosidase alfa, Myozyme) in cell medium and plasma and facilitates enzyme trafficking to lysosomes. It stabilizes rhGAA more effectively than existing small-molecule chaperones and does so in vitro, in cellulo, and in vivo in zebrafish, thus representing a promising therapeutic alternative to Miglustat for Pompe disease.
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Aug 2022
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I04-Macromolecular Crystallography
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Diamond Proposal Number(s):
[12342]
Open Access
Abstract: MCR-2 confers resistance to colistin, a `last-line' antibiotic against extensively resistant Gram-negative pathogens. It is a plasmid-encoded phosphoethanolamine transferase that is closely related to MCR-1. To understand the diversity in the MCR family, the 1.12 Å resolution crystal structure of the catalytic domain of MCR-2 was determined. Variable amino acids are located distant from both the di-zinc active site and the membrane-proximal face. The exceptionally high resolution will provide an accurate starting model for further mechanistic studies.
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Aug 2017
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I04-1-Macromolecular Crystallography (fixed wavelength)
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Open Access
Abstract: The 1.25 Å resolution H32:R crystal structure of a 20 nt ribonucleotide that binds to the TREX-2 complex with high affinity shows a double-stranded RNA duplex arranged along a crystallographic 31 axis in which the antiparallel chains overlap by 18 nucleotides and are related by a crystallographic twofold axis. The duplex shows C–A, U–U and C–C noncanonical base pairings together with canonical Watson–Crick A–U and G–C pairs and a G–U wobble.
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Oct 2015
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