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1.
RSC Med Chem ; 15(3): 963-980, 2024 Mar 20.
Article in English | MEDLINE | ID: mdl-38516603

ABSTRACT

Based on a multitarget approach implementing rivastigmine-INDY hybrids 1, we identified a set of pseudo-irreversible carbamate-type inhibitors of eqBuChE that, after carbamate transfer at the active site serine residue, released the corresponding INDY analogues 2 endowed with hDYRK1A/hCLK1 kinases inhibitory properties. A SAR study and molecular docking investigation of both series of compounds 1 and 2 revealed that appropriate structural modifications at the carbamate moiety and at the N-appendage of the benzothiazole core led to potent and selective eqBuChE inhibitors with IC50 up to 27 nM and potent hDYRK1A and hCLK1 inhibitors with IC50 up to 106 nM and 17 nM respectively. Pleasingly, identification of the matched pair of compounds 1b/2b with a good balance between inhibition of eqBuChE and hDYRK1A/hCLK1 kinases (IC50 = 68 nM and IC50 = 529/54 nM, respectively) further validated our multitarget approach based on a sequential mechanism of action. In addition, target compound 1b exhibited a suitable ADMET profile, including good brain permeability and high stability in PBS, encouraging further biological investigation as a drug candidate.

2.
Molecules ; 28(1)2022 Dec 21.
Article in English | MEDLINE | ID: mdl-36615235

ABSTRACT

The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer's disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article.


Subject(s)
Protein Kinase Inhibitors , Quinones , Humans , Alzheimer Disease/drug therapy , Down Syndrome/drug therapy , Glycogen Synthase Kinase 3/metabolism , Molecular Docking Simulation , Phosphorylation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Quinones/chemistry , Quinones/pharmacology , Quinones/therapeutic use , Dyrk Kinases
3.
Molecules ; 24(7)2019 Apr 01.
Article in English | MEDLINE | ID: mdl-30939771

ABSTRACT

Despite their side effects, cholinesterase (ChE) inhibitors remain the only approved drugs to treat Alzheimer's disease patients, along with the N-methyl-d-aspartate (NMDA) receptor antagonist memantine. In the last few years, the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has also been studied as a promising target for the development of new drugs for this pathology. In this context, and based on our previous characterization of bio-oxidizable prodrugs of potent acetylcholinesterase (AChE) inhibitors, we envisioned a strategy involving the synthesis of a bio-oxidizable prodrug of both ChE and DYRK1A inhibitors. To this end, we fixed our interest on a known potent inhibitor of DYRK1A, namely INDY. The designed prodrug of both ChE and DYRK1A inhibitors was successfully synthesized, connecting both inhibitors by a carbonate link. This prodrug and its corresponding drug were then evaluated as ChEs and DYRK1A inhibitors. Remarkably, in vitro results were in accordance with the starting hypothesis, showing a relative inactivity of the prodrug against DYRK1A and ChEs and a potent inhibition of ChEs by the oxidized form. Molecular docking and kinetic studies of ChE inhibition by the active compound are also discussed in this report.


Subject(s)
Acetylcholinesterase/chemistry , Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Drug Design , Prodrugs/chemistry , Prodrugs/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Cholinesterase Inhibitors/chemistry , Humans , In Vitro Techniques , Kinetics , Molecular Docking Simulation , Molecular Structure , Protein Conformation , Dyrk Kinases
4.
ACS Med Chem Lett ; 10(3): 352-357, 2019 Mar 14.
Article in English | MEDLINE | ID: mdl-30891139

ABSTRACT

The norepinephrine transporter (NET) plays an important role in neurotransmission and is involved in a multitude of psychiatric and neurodegenerative diseases. [123I/131I]meta-iodobenzylguanidine (MIBG) is a widely used radiotracer in the diagnosis and follow-up of peripheral neuroendocrine tumors overexpressing the norepinephrine transporter. MIBG does not cross the blood-brain barrier (BBB), and we have demonstrated the "proof-of-concept" that 1,4-dihydroquinoline/quinolinium salt as chemical delivery system (CDS) is a promising tool to deliver MIBG to the brain. To improve BBB passage, various substituents on the 1,4-dihydroquinoline moiety and a linker between CDS and MIBG were added. A series of CDS-MIBG 1a-d was synthesized, labeled with carbon-11, and evaluated in vivo into rats. The in vivo results demonstrated that, although adding substituents on CDS in 1a-c is of no benefit for brain delivery of MIBG, the presence of a linker in CDS-MIBG 1d greatly improved both brain penetration and the release rate of MIBG in the central nervous system.

5.
J Org Chem ; 83(17): 10231-10240, 2018 09 07.
Article in English | MEDLINE | ID: mdl-30004228

ABSTRACT

This work aims at exploiting both the enantioselective Tsuji allylation of allyl carbonate 6 and an organocatalytic aza-ene-type domino reaction between enal 3a and ß-enaminone 4a to develop a straightforward access to all of the four possible stereoisomers of a donepezil-like 1,4-dihydropyridine 1a (er up to 99.5:0.5; overall yield up 64%), an anti-Alzheimer's prodrug candidate. This strategy was extended to the preparation of other enantioenriched 1,4-dihydropyridines 1b-i (eight examples), highlighting its potential in the development of these chiral AChE inhibitors.


Subject(s)
Alzheimer Disease/drug therapy , Dihydropyridines/chemistry , Dihydropyridines/pharmacology , Donepezil/chemistry , Prodrugs/metabolism , Catalysis , Cyclization , Dihydropyridines/metabolism , Dihydropyridines/therapeutic use , Stereoisomerism
6.
Eur J Med Chem ; 155: 171-182, 2018 Jul 15.
Article in English | MEDLINE | ID: mdl-29886321

ABSTRACT

Herein, we report a new class of dual binding site AChE inhibitor 4 designed to exert a central cholinergic activation thanks to a redox-activation step of a prodrug precursor 3. Starting from potent pseudo-irreversible quinolinium salts AChE inhibitors 2 previously reported, a new set of diversely substituted quinolinium salts 2a-p was prepared and assayed for their inhibitory activity against AChE. Structure-activity relationship (SAR) analysis of 2a-p coupled with molecular docking studies allowed us to determine which position of the quinolinium scaffold may be considered to anchor the phtalimide fragment presumed to interact with the peripheral anionic site (PAS). In addition, molecular docking provided insight on the linker length required to connect both quinolinium and phatlimide moieties without disrupting the crucial role of quinolinium salt moiety within the catalytic active site (CAS); namely placing the carbamate in the correct position to trigger carbamylation of the active-site serine hydroxyl. Based on this rational design, the putative dual binding site inhibitor 4 and its prodrug 3 were synthesized and subsequently evaluated in vitro against AChE. Pleasingly, whereas compound 4 showed to be a highly potent inhibitor of AChE (IC50 = 6 nM) and binds to AChE-PAS to the same extent as donepezil, its prodrug 3 revealed to be inactive (IC50 > 10 µM). These preliminary results constitute one of the few examples of carbamate-based dual binding site AChE inhibitors.


Subject(s)
Acetylcholinesterase/metabolism , Carbamates/pharmacology , Cholinesterase Inhibitors/pharmacology , Drug Design , Prodrugs/pharmacology , Quinolinium Compounds/pharmacology , Amyloid beta-Peptides/antagonists & inhibitors , Binding Sites/drug effects , Caco-2 Cells , Carbamates/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Peptide Fragments/antagonists & inhibitors , Prodrugs/chemical synthesis , Prodrugs/chemistry , Protein Aggregates/drug effects , Quinolinium Compounds/chemical synthesis , Quinolinium Compounds/chemistry , Structure-Activity Relationship
7.
Eur J Med Chem ; 145: 165-190, 2018 Feb 10.
Article in English | MEDLINE | ID: mdl-29324339

ABSTRACT

As an extension of our previous work on donepezil-based "bio-oxidizable" prodrug approach, two new classes of N-benzylpyridinium donepezil analogues in tetralone B2 and acetophenone B3 series and a new set of indanone derivatives B1 were investigated along with the corresponding dihydropyridine prodrugs A1-3. A total of fifty one N-benzylpyridinium quaternary donepezil analogues B1-3 and twenty two prodrugs A1-3 were synthesized and evaluated for their inhibitory activities against hAChE and eqBuChE. While most prodrugs A1-3 were demonstrated to be inactive against AChE (IC50 > 10 µM), a large number of the corresponding N-benzylpyridinium salt B1-3 exhibited appealing three-to-one-digit nanomolar hAChE inhibitory activities and even reaching subnanomolar activity (IC50 = 0.36 nM). In addition, in silico docking studies were conducted for several compounds to explain the more relevant in vitro results. Lastly, the influence of the two stereogenic centers in prodrugs A was also evaluated, highlighting not only marked differences in residual AChE inhibitory activity of the four separated isomers of prodrug 23h (IC50 ranging from 173 nM to 10 µM) but also significant variations of the oxidation rate between two separated diastereoisomers of prodrug 24a. This work provides useful information in the search of a preclinical candidate to conduct further development of this attractive "bio-oxidizable" prodrug strategy.


Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Dihydropyridines/pharmacology , Prodrugs/pharmacology , Pyridinium Compounds/pharmacology , Animals , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dihydropyridines/chemistry , Dose-Response Relationship, Drug , Electrophorus , Horses , Molecular Docking Simulation , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/chemistry , Pyridinium Compounds/chemical synthesis , Pyridinium Compounds/chemistry , Salts/chemical synthesis , Salts/chemistry , Salts/pharmacology , Structure-Activity Relationship
8.
ACS Chem Neurosci ; 8(11): 2457-2467, 2017 11 15.
Article in English | MEDLINE | ID: mdl-28787127

ABSTRACT

The development of delivery systems to transport some specific radiotracers across the blood-brain barrier (BBB) needs to be investigated for brain imaging. [18F]FLT (3'-deoxy-3'-18F-fluoro-l-thymidine), an analogue substrate of the nucleoside thymidine, has been developed as a proliferation tracer for oncological PET studies. Unfortunately, low-grade brain tumors are poorly visualized due to the low uptake of [18F]FLT in brain tissue, preventing its use in PET imaging to detect brain tumors at an early stage. Based on our previous work, a redox chemical delivery system (CDS) related to Bodor's strategy was developed to enable the penetration of FLT into the brain. To this end, FLT was covalently linked to a series of lipophilic carriers based on a 1,4-dihydroquinoline structure. To determine the best carrier, various sets of [11C]CDS-FLT were prepared and injected into rats. Pleasingly, in vivo results let us suggest that this CDS is a promising approach to overcome the BBB to target low-grade brain tumors for PET imaging.


Subject(s)
Dideoxynucleosides/administration & dosage , Animals , Blood-Brain Barrier , Brain Chemistry , Carbon Radioisotopes , Chromatography, High Pressure Liquid , Dideoxynucleosides/analysis , Dideoxynucleosides/pharmacokinetics , Diffusion , Drug Delivery Systems , Fluorine Radioisotopes , Hydrophobic and Hydrophilic Interactions , Isotope Labeling , Nuclear Magnetic Resonance, Biomolecular , Oxidation-Reduction , Quinolines , Rats , Rats, Sprague-Dawley
9.
J Med Chem ; 60(13): 5909-5926, 2017 07 13.
Article in English | MEDLINE | ID: mdl-28613859

ABSTRACT

With the aim of reducing side effects of acetylcholinesterase inhibitors (AChEIs) during symptomatic treatment of Alzheimer's disease, we report herein a new class of donepezil-based "bio-oxidizable" prodrugs 1 designed to be converted into dual binding site AChEIs 2. While most of indanone-derived N-benzylpyridinium salts 2 revealed to be highly potent dual binding site hAChEIs (IC50 up to 3 nM), outperforming the standard drug donepezil (IC50 = 11 nM), most of the corresponding 1,4-dihydropyridines 1 were found to be inactive. Promisingly, whereas the selected prodrug 1r showed good permeability in the PAMPA-BBB model and high in vitro antioxidant activity, its conversion to AChEI 2r could be easily achieved under mild conditions when incubated in various oxidizing media. Lastly, both compounds 1r and 2r did not show genotoxicity in vitro and displayed high LD50 values in mice, making this prodrug 1r/drug 2r couple a good candidate for further in vivo biological experiments.


Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Indans/chemistry , Indans/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Prodrugs/chemistry , Prodrugs/pharmacology , Alzheimer Disease/drug therapy , Amyloid/antagonists & inhibitors , Amyloid/metabolism , Animals , Cholinesterase Inhibitors/pharmacokinetics , Donepezil , Drug Design , Female , Humans , Indans/pharmacokinetics , Mice , Molecular Docking Simulation , Piperidines/pharmacokinetics , Prodrugs/pharmacokinetics
10.
J Org Chem ; 80(13): 6537-44, 2015 Jul 02.
Article in English | MEDLINE | ID: mdl-26098725

ABSTRACT

An efficient Pd-catalyzed carbonylation protocol is described for the coupling of a large panel of aryl, heteroaryl, benzyl, vinyl and allyl halides 2 with the unusual N-hydroxysuccinimidyl (NHS) formate 1 as a CO surrogate to afford the corresponding valuable NHS esters 3. High conversion to the coupling products was achieved with up to 98% yield by means of Pd(OAc)2/Xantphos catalyst system.


Subject(s)
Alkenes/chemistry , Carbon Monoxide/chemistry , Formates/chemistry , Hydrocarbons, Halogenated/chemistry , Catalysis , Molecular Structure , Palladium/chemistry
11.
ACS Chem Neurosci ; 6(5): 737-44, 2015 May 20.
Article in English | MEDLINE | ID: mdl-25695305

ABSTRACT

With the aim of improving the efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer's disease, plagued by adverse effects arising from peripheral cholinergic activation, this work reports a biological evaluation of new central AChE inhibitors based on an original "bio-oxidizable" prodrug strategy. After peripheral injection of the prodrug 1a [IC50 > 1 mM (hAChE)] in mice, monitoring markers of central and peripheral cholinergic activation provided in vivo proof-of-concept for brain delivery of the drug 2a [IC50 = 20 nM (hAChE)] through central redox activation of 1a. Interestingly, peripheral cholinergic activation has been shown to be limited in time, likely due to the presence of a permanent positive charge in 2a promoting rapid elimination of the AChE inhibitor from the circulation of mice. To support these assumptions, the radiosynthesis with carbon-11 of prodrug 1a was developed for additional ex vivo studies in rats. Whole-body biodistribution of radioactivity revealed high accumulation in excretory organs along with moderate but rapid brain uptake. Radio-HPLC analyses of brain samples confirm rapid CNS penetration of [(11)C]1a, while identification of [(11)C]2a and [(11)C]3a both accounts for central redox activation of 1a and pseudoirreversible inhibition of AChE, respectively. Finally, Caco-2 permeability assays predicted metabolite 3a as a substrate for efflux transporters (P-gp inter alia), suggesting that metabolite 3a might possibly be actively transported out of the brain. Overall, a large body of evidence from in vivo and ex vivo studies on small animals has been collected to validate this "bio-oxidizable" prodrug approach, emerging as a very promising strategy in the rational design of selective central AChE inhibitors.


Subject(s)
Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Animals , Carbamates/chemical synthesis , Carbamates/pharmacology , Carbon Radioisotopes/pharmacology , Chromatography, High Pressure Liquid , Male , Mice , Rats , Rats, Sprague-Dawley
12.
Eur J Med Chem ; 81: 218-26, 2014 Jun 23.
Article in English | MEDLINE | ID: mdl-24852273

ABSTRACT

The therapeutic efficiency of palliative treatments of AD, mostly based on acetylcholinesterase (AChE) inhibitors, is marred by serious adverse effects due to peripheral activity of these AChE inhibitors. In the literature, a redox-based chemical delivery system (CDS) has been developed to enhance drugs distribution to the brain while reducing peripheral side effects. Herein, we disclose two new synthetic strategies for the preparation of 1,4-dihydroquinoline/quinolinium salt redox-based systems particularly well designed for brain delivery of drugs sensitive to alkylation reactions. These strategies have been applied in the present case to the AChE inhibitor galantamine with the aim of alleviating adverse effects observed with cholinergic AD treatment. The first strategy is based on an intramolecular alkylation reaction as key step, whilst the second strategy relies on a useful coupling between galantamine and quinolinium salt key intermediate. In the course of this work, polymer-supported reagents and a solid-phase synthesis approach revealed to be highly helpful to develop this redox-based galantamine CDS.


Subject(s)
Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Brain/metabolism , Cholinesterase Inhibitors/administration & dosage , Drug Delivery Systems , Galantamine/administration & dosage , Quinolines/chemistry , Alzheimer Disease/enzymology , Brain/drug effects , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/therapeutic use , Galantamine/chemistry , Galantamine/metabolism , Galantamine/therapeutic use , Humans , Molecular Structure , Oxidation-Reduction , Quinolines/chemical synthesis , Quinolines/metabolism
13.
Bioorg Med Chem Lett ; 23(13): 3704-8, 2013 Jul 01.
Article in English | MEDLINE | ID: mdl-23726027

ABSTRACT

Tumor hypoxia plays a major role in reducing the efficacy of therapeutic modalities like chemotherapy and radiation therapy in combating cancer. In order to target hypoxic tissues, a tripeptide ligand having a 2-nitroimidazole moiety, as a bioreductive species, was synthesized. The latter was radiolabeled with (99m)Tc for imaging hypoxic regions of tumors and was characterized by means of its rhenium analogue. The biodistribution and scintigraphic image of the corresponding (99m)Tc-complex showed accumulation in tumor and these results suggest that it could be a marker for imaging tumor hypoxia.


Subject(s)
Cell Hypoxia , Glioblastoma , Imidazoles , Organotechnetium Compounds , Animals , Cell Line, Tumor , Glioblastoma/diagnostic imaging , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Mice , Mice, Nude , Molecular Structure , Organotechnetium Compounds/chemistry , Organotechnetium Compounds/pharmacokinetics , Radionuclide Imaging , Tissue Distribution
14.
Bioorg Med Chem ; 21(13): 3680-8, 2013 Jul 01.
Article in English | MEDLINE | ID: mdl-23665140

ABSTRACT

The syntheses of new nitroimidazole compounds using silicon-[(18)F]fluorine chemistry for the potential detection of tumor hypoxia are described. [(18)F]silicon-based compounds were synthesized by coupling 2-nitroimidazole with silyldinaphtyl or silylphenyldi-tert-butyl groups and labeled by fluorolysis or isotopic exchange. Dinaphtyl compounds (6, 10) were labeled in 56-71% yield with a specific activity of 45 GBq/µmol, however these compounds ([(18)F]7 and [(18)F]11) were not stable in plasma. Phenyldi-tert-butyl compounds were labeled in 70% yield with a specific activity of 3 GBq/µmol by isotopic exchange, or in 81% yield by fluorolysis of siloxanes with a specific activity of 45 GBq/µmol. The labeled compound [(18)F]18 was stable in plasma and excreted by the liver and kidneys in vivo. In conclusion, the fluorosilylphenyldi-tert-butyl (SiFA) group is more stable in plasma than fluorosilyldiphenyl moiety. Thus, compound [(18)F]18 is suitable for further in vivo assessments.


Subject(s)
Fluorine Radioisotopes/chemistry , Nitroimidazoles/chemistry , Silicon/chemistry , Animals , Fluorine Radioisotopes/metabolism , Humans , Hypoxia/diagnosis , Nitroimidazoles/chemical synthesis , Nitroimidazoles/metabolism , Positron-Emission Tomography/methods , Rats , Rats, Wistar , Silicon/metabolism , Tissue Distribution
15.
Org Lett ; 15(9): 2294-7, 2013 May 03.
Article in English | MEDLINE | ID: mdl-23639081

ABSTRACT

Starting from alkyl halides or Michael acceptors, thioacetates were prepared in situ and further treated with t-BuOCl, affording the corresponding sulfonyl chlorides which were trapped with nucleophiles such as water, alcohol, or amines. The three steps can be achieved in a one-pot procedure. Oxidative deprotection also proved to be efficient with S-trityl and S-tert-butyl groups, making it a convenient route toward cysteic acid derivatives.


Subject(s)
Butanes/chemistry , Hypochlorous Acid/chemistry , Sulfhydryl Compounds/chemistry , Sulfonic Acids/chemical synthesis , Molecular Structure , Sulfonic Acids/chemistry
16.
Org Biomol Chem ; 7(12): 2612-8, 2009 Jun 21.
Article in English | MEDLINE | ID: mdl-19503937

ABSTRACT

This work deals with the design of a bio-oxidisable prodrug strategy for the development of new central selective acetylcholinesterase inhibitors. This prodrug approach is expected to reduce peripheral anticholinesterase activity responsible for various side effects observed with presently marketed AChE inhibitors. The design of these new AChE inhibitors in quinoline series is roughly based on cyclic analogues of rivastigmine. The key activation step of the prodrug involves an oxidation of an N-alkyl-1,4-dihydroquinoline 1 to the corresponding quinolinium salt 2 unmasking the positive charge required for binding to the catalytic anionic site of the enzyme. The synthesis of a set of 1,4-dihydroquinolines 1 and their corresponding quinolinium salts 2 is presented. An in vitro biological evaluation revealed that while all reduced forms 1 were unable to exhibit any anticholinesterase activity (IC50 > 10(6) nM), most of the quinolinium salts 2 displayed high AChE inhibitory activity (IC50 ranging from 6 microM to 7 nM). These preliminary in vitro assays validate the use of these cyclic analogues of rivastigmine in quinoline series as appealing chemical tools for further in vivo development of this bio-oxidisable prodrug approach.


Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Drug Design , Prodrugs/metabolism , Blood-Brain Barrier/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/metabolism , Humans , Inhibitory Concentration 50 , Oxidation-Reduction , Phenylcarbamates/chemistry , Prodrugs/chemistry , Quinolines/chemistry , Rivastigmine , Substrate Specificity
17.
Org Biomol Chem ; 6(13): 2282-94, 2008 Jul 07.
Article in English | MEDLINE | ID: mdl-18563261

ABSTRACT

The development of broad-spectrum metallo-beta-lactamase (MBL) inhibitors is challenging due to structural diversity and differences in metal utilisation by these enzymes. Analysis of structural data, followed by non-denturing mass spectrometric analyses, identified thiols proposed to inhibit representative MBLs from all three sub-classes: B1, B2 and B3. Solution analyses led to the identification of broad spectrum inhibitors, including potent inhibitors of the CphA MBL (Aeromonas hydrophila). Structural studies revealed that, as observed for other B1 and B3 MBLs, inhibition of the L1 MBL thiols involves metal chelation. Evidence is reported that this is not the case for inhibition of the CphA enzyme by some thiols; the crystal structure of the CphA-Zn-inhibitor complex reveals a binding mode in which the thiol does not interact with the zinc. The structural data enabled the design and the production of further more potent inhibitors. Overall the results suggest that the development of reasonably broad-spectrum MBL inhibitors should be possible.


Subject(s)
Drug Evaluation, Preclinical/methods , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacology , beta-Lactamase Inhibitors , beta-Lactamases/chemistry , Bacteria/drug effects , Bacteria/enzymology , Binding Sites , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Molecular Conformation
18.
Org Biomol Chem ; 5(9): 1397-404, 2007 May 07.
Article in English | MEDLINE | ID: mdl-17464409

ABSTRACT

This work reports the synthesis of new axially chiral bridged 2,2'-bipyridines 1 and pyridylmonooxazolines (pymox) 2. The potential of these new axially chiral N,N-ligands was evaluated in asymmetric catalytic cyclopropanation of styrene derivatives 22a-c with diazoesters 21a,b. While 2,2'-bipyridines 1a-c afforded the corresponding cyclopropanes 23a-f in up to 65% ee, pymoxs 2a-e gave somewhat lower enantioselectivities (up to 53% ee). Both classes of ligands produced trans-cyclopropanes 23a-f as the major isomer, although with modest diasteroselectivities (56 : 44 to 78 : 22). A structure-stereoselectivity relationship study of ligands 1 and 2 identified the chiral biaryl axis as being mostly responsible for the enantioselective performances of these ligands.

19.
Org Biomol Chem ; 4(5): 817-25, 2006 Mar 07.
Article in English | MEDLINE | ID: mdl-16493464

ABSTRACT

A solid phase approach for the preparation of peptides attached to a redox chemical delivery system derived from stable annulated NADH models is reported. The synthesis starts with the grafting on a Merrifield resin of quinoline 4b, precursor of the redox carrier. From the resulting quinoline supported resin 4d, the stepwise SPPS of both octapeptide OP (RPGLLDLK) and octadecaneuropeptide ODN (QATVGDVNTDRPGLLDLK), two neuropeptides exhibiting anorexigenic effects, was successfully achieved by conventional methods. Quaternization of the quinoline moiety prior to cleavage of the modified OP and ODN peptides from the resin, led to the expected quinolinium salt 8a and 8b respectively linked to OP or ODN peptides. Finally, the reduction with NaBH4 monitored by UV-vis, provided the desired annulated NADH models as peptides carriers with either the OP (11a,b) or ODN (12a,b) moiety.


Subject(s)
Biochemistry/methods , Drug Delivery Systems , Neuropeptides/chemical synthesis , Amino Acid Sequence , Borohydrides/chemistry , Brain/drug effects , Dihydropyridines/chemistry , Humans , Molecular Sequence Data , NAD/metabolism , Neuropeptides/administration & dosage , Neuropeptides/metabolism , Oxidation-Reduction , Quinolines/chemistry , Quinolinium Compounds/chemistry , Spectrophotometry, Ultraviolet
20.
J Am Chem Soc ; 127(45): 15668-9, 2005 Nov 16.
Article in English | MEDLINE | ID: mdl-16277485

ABSTRACT

A new and unprecedented exploitation of quinolinium thioester salts 2 in peptide bond formation is reported. These synthetic tools were assessed during the preparation of a number of dipeptides 3a-f obtained in good yields with complete stereochemical integrity. A sequential mechanism related to a prior amine capture strategy is well-established. Additionally, a tripeptide 3g was prepared according to a "safety-catch" approach, thus demonstrating the important potential of these new synthetic tools in the design of new safety-catch linkers exploitable in Solid-Phase Peptide Synthesis (SPPS).


Subject(s)
Amines/chemistry , Peptides/chemical synthesis , Quinolinium Compounds/chemistry , Sulfuric Acid Esters/chemistry , Salts/chemistry
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