RESUMO
The derivatization of resin-bound aminobenzimidazole toward the parallel solid-phase synthesis of aminobenzimidazole tethered pharmacologically important heterocycles such as quinazoline-2,4-diones, thioxoquinazolin-4-ones, benzodiazepine-2,3,5-triones, isoxazoles and isoxazolines is reported. All the compounds were tested for IKK inhibition. Only one compound elicited significant inhibition of IKKε, TBK-1 and IKK2.
Assuntos
Benzimidazóis/química , Benzodiazepinonas/química , Quinase I-kappa B/antagonistas & inibidores , Isoxazóis/química , Inibidores de Proteínas Quinases/síntese química , Quinazolinonas/química , Benzimidazóis/síntese química , Benzimidazóis/metabolismo , Quinase I-kappa B/metabolismo , Cinética , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Técnicas de Síntese em Fase SólidaRESUMO
An experimental study on the synthesis, tautomerism and acid promoted structural changes of spiro-pyrazolines is described. The target was achieved through a [3+2]-dipolar cycloaddition of an alkene with nitrile imines generated in situ and was isolated in high yield. The synthesized cycloadduct displayed a tendency to exhibit an imine-enamine type of tautomerism as evidenced by X-ray crystal and NMR studies. Furthermore, addition of an acid resulted in the transformation of an imine tautomer to an enamine. The current report constitutes a first formal observation of this kind of tautomerism observed in spiro-indoline pyrazolines.
RESUMO
Mild and environmentally benign Lewis acid promoted 1,3-dipolar cycloaddition reactions of α-hydrazonyl chlorides with alkenes in water are reported. These α-hydrazonyl chlorides, in the presence of Lewis acids, generate nitrile imines in situ which react with dipolarophiles to furnish the corresponding cycloaddition products. In many cases, the required times for the completion of the Lewis acid promoted 1,3-dipolar cycloaddition reactions in water were comparable to the equivalent reactions performed in an organic solvent. Analogous tetrahexylammonium chloride promoted 1,3-dipolar cycloaddition reactions were also performed. The comparison of reaction times and cycloadduct yields for the aforementioned 1,3-dipolar reactions in aqueous and organic media as well as the proposed role of the Lewis acid in the 1,3-dipolar cycloaddition reaction are described.
RESUMO
A solid-phase methodology to construct aminobenzimidazole tethered sultams and benzothiazepinones from commercial amino acids, amines, carboxylic acids and sulfonyl chlorides is described. Coupling of Fmoc-Cys(Trt)-OH to resin-bound aminobenzimidazole scaffold provided an essential precursor for the construction of a variety of seven membered benzofused cyclic sulfonamides and thiazepinones via palladium catalyzed Buchwald-Hartwig type intramolecular cyclization.
RESUMO
An efficient approach for the parallel solid phase synthesis of isoxazole and isoxazoline derivatives has been developed. The isoxazoles and isoxazolines were constructed through a 1,3-dipolar cycloaddition reaction of nitrile oxides, with resin-bound alkynes or alkenes. The cycloaddition reaction conditions performed on solid phase supports was optimized, and an array of resin bound carboxylic acid building blocks were utilized for distinct conversions. This methodology presents a new alternative to the diversity oriented synthesis of disubstituted isoxazoles and isoxazolines different from existing routes which are limited in structural diversity.
RESUMO
Regioisomeric spiropyrazolines were synthesized through a tandem intramolecular cyclization/methylation reaction of a functionalized 5,5-disubstituted pyrazoline in one reaction vessel. The 5,5-pyrazolines were constructed through a 1,3-dipolar cycloaddition reaction of aromatic ring containing nitrile imines and a disubstituted geminal alkene. An evaluation of the relative location of the nucleophilic and electrophilic functional groups on the pyrazoline was performed in order to ascertain the best pyrazoline system for the intramolecular cyclization/methylation reaction. Higher spiropyrazoline isolated yields were realized from pyrazolines with the electrophilic ester located further away from the pyrazoline when compared to pyrazolines with a directly bonded ester.
RESUMO
A multistep approach to construct novel 3-(1H-benzo[d]imidazol-2-yl)imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin-4-ones from commercially available amino acids, amines, and carboxylic acids is described. Coupling of Fmoc-amino acid to resin-bound aminobenzimidazole provided following Fmoc elimination free amine. Treatment of the free amine with 1,1'-carbonyldiimidazole or 1,1'-thiocarbonyldiimidazole furnished the corresponding hydantoins and thiohydantoins via intramolecular cyclization. The desired aminobenzimidazole tethered hydantoin or thiohydantoins were isolated in good yields.
RESUMO
The syntheses of an important class of hitherto unreported novel pyrazoles are described. The regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles was achieved by the Huisgen cyclization of nitrile imines with a trisubstituted bromoalkene. The substituted bromoalkene functions as an alkyne synthon which was used to construct 5,5-disubstituted bromopyrazoline intermediates that undergo aromatization to the analogous pyrazoles through the loss of HBr. The cycloaddition regioselectivity was confirmed through single X-ray crystal data of one of the pyrazoles.
RESUMO
The syntheses of an important class of hitherto unreported 1,3,5-pyrazoles, inspired by an unanticipated eliminatory ring opening are described. The reported pyrazole compounds were constructed through the Huisgen cyclization of 2-methylene-1,3,3-trimethylindoline and an in situ generated nitrile imine. The newly formed spiro-pyrazoline intermediate presumably then undergoes a ring opening/elimination process to afford a pyrazole, as evidenced by single X-ray crystal data. The current report constitutes the first formal observation of this kind of ring opening involving a spiro-pyrazoline intermediate.
RESUMO
The regioselective synthesis of 3,5-disubstituted isoxazoles was achieved through the 1,3-dipolar cycloaddition of nitrile oxides with 1,1-disubstituted bromoalkenes. The substituted bromoalkenes function as alkyne synthons which were used to construct 5,5-disubstituted bromoisoxazoline intermediates that aromatize to the analogous isoxazoles through the loss of HBr.
RESUMO
[(18)F]THK-523 and [(18)F]807 are promising radioligands for imaging neurofibrillary tangles (NFTs) with positron emission tomography (PET) in neurodegenerative diseases, such as Alzheimer's disease (AD) and traumatic brain injury. Although [(18)F]THK-523 and [(18)F]T807 are considered high-affinity selective radioligands for NFTs, uncertainty has existed as to whether PET radioligands for imaging NFTs bind to the same molecular site because in vitro assays for ligands binding to NFTs have been lacking. We labeled THK-523 and T807 with tritium to serve as reference radioligands for in vitro binding assays with AD brain homogenates for newly synthesized ligands. With these radioligands, we identified two distinct binding sites for small molecules, one site with high affinity for THK-523 and the other with high affinity for T807. Moreover, binding assays with [(3)H]PIB confirmed that the two newly identified binding sites are also distinct from the thioflavin-T binding site where all current clinically useful PET radioligands for imaging ß-amyloid plaque bind with high affinity. The two newly identified binding sites are considered to reside on NFTs rather than on ß-amyloid plaques. Furthermore, we applied all three binding assays to a set of newly prepared compounds, based on chain modifications to THK-523. Some compounds with high affinity and selectivity for the THK-523 binding site emerged from this set, including one with amenability to labeling with fluorine-18, namely, ligand 10b.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Emaranhados Neurofibrilares/patologia , Tomografia por Emissão de Pósitrons , Compostos de Anilina/química , Compostos de Anilina/farmacocinética , Autorradiografia , Sítios de Ligação/efeitos dos fármacos , Carbolinas/farmacocinética , Diagnóstico , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Quinolinas/química , Quinolinas/farmacocinética , Ensaio Radioligante , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Tiazóis/química , Tiazóis/farmacocinética , Proteínas tau/efeitos dos fármacos , Proteínas tau/metabolismoRESUMO
Heterocycles with potential bioactive properties are of greater interest to researchers engaged in the areas of natural product synthesis and heterocyclic methodology. Several FDA (Food and Drug Administration) approved pharmaceutical drugs incorporate a heterocyclic motif in their core structure. Spiroisoxazolines and spiropyrazolines belong to the class of five membered heterocycles that have received greater attention over the past four decades. Spiropyrazolines structurally resemble naturally occurring spiroisoxazolines, have extra nitrogen in place of isoxazoline oxygen, and offer the viability to construct useful analogs for the exploration of possible bioactivity. As of today, no reports on the construction of these spiropyrazolines were available and the current review is aimed at providing a comprehensive discussion of the protocols applied in the synthesis of functionalized spiropyrazolines.
Assuntos
Técnicas de Química Sintética/métodos , Reação de Cicloadição/métodos , Pirazóis/química , Pirazóis/síntese química , Modelos Químicos , Estrutura Molecular , EstereoisomerismoRESUMO
Estrogens are a group of steroids that exert important effects on reproductive and many non-reproductive tissues. Selective estrogen receptor modulators (SERM) are a class of therapeutic agents widely prescribed for the treatment and prevention of breast cancer, osteoporosis, and postmenopausal symptoms. Raloxifene, an example of oral SERM is prescribed primarily for the treatment and prevention of postmenopausal disorders in woman. The current review provides an outline of practical methodologies used to access benzothiophenyl scaffolds of raloxifene and relevant structural analogs. The contents are discussed in five sections: (a) synthesis of raloxifene, (b) organometallic analogs, (c) radiolabelled analogs, (d) constrained raloxifene analogs, and (e) other oxygen, sulfur, and nitrogen based raloxifene analogs. In addition to the synthesis, biological activity of a few synthetic analogs has been discussed.
Assuntos
Técnicas de Química Sintética/métodos , Cloridrato de Raloxifeno/síntese química , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/síntese química , Linhagem Celular Tumoral , Humanos , Marcação por Isótopo , Compostos Organometálicos/química , Cloridrato de Raloxifeno/análogos & derivados , Cloridrato de Raloxifeno/química , Moduladores Seletivos de Receptor Estrogênico/químicaRESUMO
Heterocyclic chemistry constitutes an essential branch of organic chemistry and heterocycles are widely known to display an array of biological properties. Pyrazoles represent key structural motifs in heterocyclic chemistry and are present in a large number of biologically active molecules relevant to the pharmaceutical and agrochemical industries. Compounds incorporating the pyrazolyl structural unit are being developed in a wide variety of therapeutic areas including CNS, metabolic diseases, and oncology. The current review summarizes recent advances in the synthesis of tetrasubstituted pyrazoles. The contents are discussed in five sections: (a) 1,3-dipolar cycloadditions, (b) related 1,3-dipolar cycloadditions, (c) condensations, (d) allenylphosphonates, and (e) synthesis of fused pyrazole containing heterocycles.
Assuntos
Técnicas de Química Sintética/métodos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Pirazóis/química , Organofosfonatos/químicaRESUMO
Non-steroidal anti-inflammatory drugs are widely used therapeutic agents in the treatment of inflammation, pain and fever. Cyclooxygenase catalyzes the initial step of biotransformation of arachidonic acid to prostanoids, and exist as three distinct isozymes; COX-I, COX-II and COX-III. Selective COX-II inhibitors are a class of potential anti-inflammatory, analgesic, and antipyretic drugs with reduced gastrointestinal (GI) side effects compared to nonselective inhibitors. 3,4-Diarylisoxazole scaffold is recurrently found in a wide variety of NSAIDs, protein kinase inhibitors, hypertensive agents, and estrogen receptor (ER) modulators. In the present review, we document on the recent synthetic strategies of 3,4-diarylisoxazolyl scaffolds of valdecoxib and its relevant structural analogues.