ABSTRACT
α-Isocyanoacetamide derivatives were first converted to oxazolines under newly developed conditions. These oxazolines were used as precursors of α-isocyanoacrylamides, which could lead to various 2-arylated imidazolones. In addition, it was shown that both oxazolines and their precursors could efficiently lead to imidazolones unsubstituted at C2 in a very rapid, one-pot transformation, thus paving the way toward unprecedented routes to imidazolones, having a good tolerance to different substitution patterns.
Subject(s)
Aldehydes , Cyanides , ImidazolesABSTRACT
An unprecedented enantioselective conjugate addition reaction of sodium bisulfite to various nitrostyrenes occurred upon the influence of a bifunctional amino-thiourea organocatalyst; a strategy that opens a straightforward route to unprotected chiral taurine derivatives thanks to the reduction of the obtained ß-nitroethanesulfonic acids into the corresponding amino derivatives.
ABSTRACT
A series of hydroxamic acids linked by different lengths to a chiral imidazo-ketopiperazine scaffold were synthesized. The compounds with linker lengths of 6 and 7 carbon atoms were the most potent in histone deacetylase (HDAC) inhibition, and were specific submicromolar inhibitors of the HDAC1, HDAC6 and HDAC8 isoforms. A docking model for the binding mode predicts binding of the hydroxamic acid to the active site zinc cation and additional interactions between the imidazo-ketopiperazine and the enzyme rim. The compounds were micromolar inhibitors of the MV4-11, THP-1 and U937 cancer cell lines. Increased levels of histone H3 and tubulin acetylation support a cellular mechanism of action through HDAC inhibition.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.
Subject(s)
Histone Deacetylase 1/antagonists & inhibitors , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Repressor Proteins/antagonists & inhibitors , Acetylation , Histone Deacetylase 1/chemistry , Histone Deacetylase 6/chemistry , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylases/chemistry , Humans , Hydroxamic Acids/chemistry , Molecular Docking Simulation , Protein Isoforms , Repressor Proteins/chemistry , Stereoisomerism , Structure-Activity Relationship , THP-1 Cells , U937 CellsABSTRACT
The first one-pot synthesis of N-substituted 2-H-4-benzylidene imidazolones and their subsequent palladium-catalyzed and copper-assisted direct C2-H arylation and alkenylation with aryl- and alkenylhalides are described. This innovative synthesis is step-economical, azide-free, high yielding, highly flexible in the introduction of a variety of electronically different groups, and can be operated on large-scale. Moreover, the method allows direct access to C2-arylated or alkenylated imidazolone-based green fluorescent protein (GFP) and Kaede protein fluorophores, including ortho-hydroxylated models.
Subject(s)
Benzylidene Compounds/chemistry , Green Fluorescent Proteins/chemistry , Green Fluorescent Proteins/chemical synthesis , Imidazoles/chemistry , Catalysis , Copper/chemistry , Molecular Structure , Palladium/chemistryABSTRACT
A microwave-assisted method for the palladium-catalyzed direct arylation of quinazolin-4-one has been developed under copper-assistance. This method is applicable to a wide range of aryl iodides and substituted (2H)-quinazolin-4-ones. This protocol provides a simple and efficient way to synthesize biologically relevant 2-arylquinazolin-4-one backbones.
Subject(s)
Copper/chemistry , Iodides/chemistry , Palladium/chemistry , Quinazolinones/chemistry , Catalysis , Hydrogen Bonding , Microwaves , Molecular StructureABSTRACT
Direct C-H arylation and alkenylation of 4,4'-dialkylimidazolones with a broad range of halides under palladium and copper catalysis have been developed. This methodology is applied to the preparation of recently discovered fatty acid synthetase (FAS) inhibitors.
Subject(s)
Alkenes/chemistry , Hydrocarbons, Aromatic/chemistry , Imidazoles/chemistry , Palladium/chemistry , Catalysis , Enzyme Inhibitors/chemistry , Fatty Acid Synthases/antagonists & inhibitors , Halogens/chemistry , HumansABSTRACT
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 DistributionABSTRACT
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/chemistryABSTRACT
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 DistributionABSTRACT
Starting from amino acid esters, new peptidomimetics based on the imidazole scaffold were prepared. An efficient and rapid sequence consisting of two subsequent one-pot procedures was developed and applied to various aminoacids. As they provide more substitution patterns, these heterocyclic mimics are promising tools for structural and biological studies.
Subject(s)
Imidazoles/chemistry , Peptidomimetics/chemistry , Amides/chemistry , Aza Compounds/chemistry , Molecular StructureABSTRACT
INTRODUCTION: Development of new (18)F-labeled tracers for positron emission tomography (PET) imaging is increasingly important. Herein, we described the synthesis of silicon analogues of [(18)F]fluoromisonidazole in order to develop new radiolabelled compounds for the detection of tumour hypoxic domain. Their stabilities and their in vivo biodistribution were evaluated. METHODS: (18)F-labeled silicon-based misonidazole analogues were synthesized by alkylating 2-nitroimidazole with alkyloxy-(3-chloropropyl)dialkyl or diarylsilane. These intermediates were labeled with [(18)F]F(-) with a mixture of K(18)F and Kryptofix (K222) in acetonitrile as standard condition. PET imaging was performed using a dedicated small animal PET scanner. RESULTS: (18)F-labeled silicon-based misonidazole analogues were easily synthesized in three steps. The hydrolytic and radiolytic stability of these new fluorosilanes depend on the steric hindrance at the silicon center. Indeed, partial uptake of dimethylfluorosilane [(18)F]2a(1-(3-(Fluorodimethylsilyl)propyl)-2-nitro-1H-imidazole) in tumor hypoxic area was observed but defluorination also appeared. Moreover, PET studies indicated that, owing to its high lipophilicity, the most stable dinaphtylfluorosilane [(18)F]2d is retained mainly by the lungs. CONCLUSION: We have described an efficient and versatile approach for the synthesis of (18)F-labeled, silicon-based misonidazole analogues. PET imaging of one of these compounds revealed that hypoxia could be detected. Controlling the biodistribution of (18)F-labeled silicon-based misonidazole analogues will require additional studies.
Subject(s)
Fibrosarcoma/diagnostic imaging , Fibrosarcoma/metabolism , Misonidazole/chemistry , Misonidazole/pharmacokinetics , Animals , Cell Line, Tumor , Fluorine Radioisotopes/chemistry , Fluorine Radioisotopes/pharmacokinetics , Isotope Labeling/methods , Male , Metabolic Clearance Rate , Mice , Mice, Inbred C3H , Organ Specificity , Radionuclide Imaging , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Silicon/chemistry , Silicon/pharmacokinetics , Tissue DistributionABSTRACT
Starting from suitably protected amino acids, mercaptoimidazoles were synthesized either from the acid or including the amine nitrogen itself. A preliminary optimisation study led to efficient conditions for the obtention of the imidazole ring. These conditions are compatible with the presence of amino acid or dipeptide scaffolds.
Subject(s)
Acids/chemistry , Amino Acids/chemistry , Chemistry, Organic/methods , Imidazoles/chemistry , Imidazoles/chemical synthesis , Amino Acid Motifs , Disulfides/chemistry , Hydrolysis , Metals/chemistry , Models, Chemical , Peptide Hydrolases/chemistry , Peptides/chemistry , Protein Structure, TertiaryABSTRACT
A four-step synthesis of (-)-lentiginosine and its epimers is described starting from 2-bromopyridine. The key step consisted of a quaternarization of a fully unprotected pyridinium-polyol unit using Mitsunobu methodology. Subsequent PtO(2)-catalyzed diastereoselective hydrogenation of the pyridinium ring proceeded smoothly and led to the expected dihydroxyindolizidines with excellent yields. This stereochemically flexible strategy has been illustrated by the concise total synthesis of non-natural products derivatives such as (-)-lentiginosine and its stereoisomers in high yields.
Subject(s)
Alkaloids/chemical synthesis , Alkaloids/chemistry , Molecular Structure , Pyrimidines/chemistry , StereoisomerismABSTRACT
A very simple, safe and powerful method for the in situ generation of formaldehyde at low temperature in anhydrous conditions is described. This new tool avoids the use of gaseous formaldehyde and is suitable for basic carbon nucleophiles which cannot be generated in aqueous reaction media. Various substrates, including organolithium reagents and enolates, underwent smooth hydroxymethylation showing the versatility of this process. A Wittig reaction was also carried out in high yield. [reaction: see text]
ABSTRACT
A novel one-pot methodology is described for the synthesis of functionalized pyrrolopyridinones using in situ generated formimines and an ortho-lithiated pyridinecarboxamide species. Depending on the reaction conditions, this procedure allows versatile access to aminomethylated pyridinecarboxamides, 2,3-dihydro-pyrrolopyridinones, or 1,1-dialkylated 2,3-dihydro-pyrrolopyridinone derivatives. [reaction: see text]
ABSTRACT
The first deprotonations of oxazole and benzoxazole using lithium magnesates are described. The reactions occurred in tetrahydrofuran at room temperature using 1/3 equiv of lithium tributylmagnesate. As 2-lithiooxazole and 2-lithiobenzoxazole, lithium tri(2-oxazolyl)magnesate and lithium tri(2-benzoxazolyl)magnesate very rapidly and completely isomerized to the more stable 2-(isocyano)enolate and 2-(isocyano)phenolate type structures, respectively, a result shown by NMR analysis. The isolation of 2-substituted oxazoles and benzoxazoles in medium to good yields after electrophilic trapping was interpreted in two ways: (1) the equilibration between the open and closed structures is faster than the trapping of the open isomers, and the closed isomers are more reactive than the open ones, or (2) the open isomers react with electrophiles in a intramolecular Passerini type reaction. The nonreactivity of the 2-(isocyano)enolate type structure toward anisaldehyde in the absence of lithium bromide makes the intramolecular Passerini type reaction more plausible.