RESUMO
Chronic kidney disease (CKD) is associated with numerous metabolic and endocrine disturbances, including abnormalities of calcium and phosphate metabolism and an inflammatory syndrome. The latter occurs early in the course of CKD and contributes to the development and progression of vascular calcification. A few therapeutic strategies are today contemplated to target vascular calcification in patients with CKD: vitamin K2, calcimimetics and phosphate binders. However, none has provided complete prevention of vascular calcification and there is an urgent need for alternate efficient treatments. Recent findings indicate that tissue-nonspecific alkaline phosphatase (TNAP) may represent a very promising drug target due to its participation in mineralization by vascular smooth muscle cells. We report the synthesis of four levamisole derivatives having better inhibition property on TNAP than levamisole. Their IC50, Ki and water solubility have been determined. We found that the four inhibitors bind to TNAP in an uncompetitive manner and are selective to TNAP. Indeed, they do not inhibit intestinal and placental alkaline phosphatases. Survival MTT tests on human MG-63 and Saos-2 osteoblast-like cells have been performed in the presence of inhibitors. All the inhibitors are not toxic at concentrations that block TNAP activity. Moreover, they are able to significantly reduce mineralization in MG63 and Saos-2 osteoblast-like cells, indicating that they are promising molecules to prevent vascular calcification.
Assuntos
Fosfatase Alcalina/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Levamisol/farmacologia , Tiofenos/farmacologia , Fosfatase Alcalina/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Cinética , Levamisol/síntese química , Levamisol/química , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/químicaRESUMO
A small library of heterocycle-fused quinazolin-4-ones was prepared and evaluated as kinase inhibitors. The key step of the two-step process involves the environmental friendly thermolysis of N-ethoxycarbonyl-N'-(hetero) arylguanidines at 130 °C in water. The cyclization is fully regioselective. The most active molecules, 7-(2-hydroxyethylamino)- and 7-(3-hydroxypropylamino)-pyrazolo[4,3-f]quinazolin-9-ones, inhibit DYRK1A and CLK1 at submicromolar concentrations, indicating the potential interest of this new heterocycle in drug design.
Assuntos
Inibidores Enzimáticos/síntese química , Guanidinas/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinonas/síntese química , Animais , Catálise , Ciclização , Desenho de Fármacos , Escherichia coli , Temperatura Alta , Humanos , Camundongos , Estrutura Molecular , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ratos , Proteínas Recombinantes/metabolismo , Suínos , Temperatura de Transição , Quinases DyrkRESUMO
An original route to 2-alkyamino-4-phenylquinazolines in three steps from simple (hetero)aromatic amines is reported here. The key step involves the intramolecular cyclization of benzoyl arylguanidines performed in [OMIm]Cl ionic liquid. The basic (hetero)aromatic guanidines deprotonate the imidazolium-based ionic liquid, thus triggering the cascade process ultimately leading to the intramolecular cyclization. This reaction is the first example of a Friedel-Crafts-type reaction in which an N-heterocyclic carbene is involved in the formation of the electrophilic intermediate.
Assuntos
Compostos Heterocíclicos/química , Metano/análogos & derivados , Quinazolinas/síntese química , Ciclização , Guanidina/síntese química , Guanidina/química , Metano/química , Estrutura Molecular , Quinazolinas/químicaRESUMO
Two new heterocycles, pyrimido[4,5-c]carbazole and pyrimido[5,4-b]indole, were prepared in three steps from 3-aminocarbazole and 3-aminoindole, respectively. The key Friedel-Crafts intramolecular cyclization was realized under microwave irradiation using montmorillonite K-10 clay as a catalyst. The pyrimido[4,5-c]carbazole derivative shows significant micromolar IC(50) against cancer cell lines. Unlike similar carbazole and indolocarbazole compounds, the molecule does not interfere with topoisomerase activity.
Assuntos
Bentonita/química , Carbazóis/química , Guanidinas/química , Indóis/química , Catálise , Linhagem Celular Tumoral , Ciclização , HumanosRESUMO
In an effort to increase the structural diversity of pyrido[4,3,2-kl]acridines, compounds containing amino substituents on the A ring were synthesized. The key-reactions involve regioselective electrophilic aromatic substitutions. The methodology was applied to the synthesis of the extended angular octacycle 8, which conjugates the physicochemical and spectroscopic properties of the pyridoacridine skeleton with the ability of [1,10]phenanthroline ring for metal complexation. The 9-aminopyridoacridine 4 displays significant cytostatic activities against two cancer cell lines, and may be considered as a new lead in the search of active derivatives.
Assuntos
Acridinas/química , Citostáticos/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Fenantrolinas/química , Acridinas/síntese química , Linhagem Celular Tumoral , Citostáticos/química , Citostáticos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Fenantrolinas/síntese química , Fenantrolinas/farmacologia , EstereoisomerismoRESUMO
The present article reports on the design and the synthesis of a series of mono- and bis-pyrimidinoacridines and their evaluation as a novel family of quadruplex-binders. It is shown that bispyrimidinoacridines represent an interesting compromise between easy synthetic access and efficiency in terms of quadruplex interaction (both affinic and selective), as judged by G4-FID assay and molecular modelling. The present study also highlights that control of the pi-stacking interactions taking place between the ligand and the accessible G-tetrad of a quadruplex-DNA is indeed essential for good recognition but not exclusively (key role of direct and water-mediated H-bonds). The introduction of additional amino side chains, valuable in the acridine series, results here in steric perturbations of the ligand/quadruplex recognition and lowers the quadruplex/duplex selectivity.
Assuntos
Acridinas/síntese química , Quadruplex G , Pirimidinas/síntese química , Acridinas/química , Ligantes , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Transformation of aminoacridines into N-acridinyl-N'-alkylguanidines is described. The chosen procedure allows introduction of pendent substituents (exemplified by N,N-dimethylaminopropyl chain) into key acridinyl thioureas, thus opening the way to structural diversity. Spectroscopic study and pK(a) determination show that the presence of the strongly basic guanidine has a dramatic influence on the ionization of the acridine nucleus by lowering the pk(a) value down to 4.49.
Assuntos
Aminas/química , Aminoacridinas/química , Físico-Química , Guanidinas/química , Guanidinas/síntese química , Fenômenos Químicos , Desenho de Fármacos , Concentração de Íons de Hidrogênio , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade , TermodinâmicaRESUMO
A novel and simple method of preparation of 2-alkylaminoquinazolin-4-ones with fused heteroaromatic rings from easily accessible (hetero)aromatic amines is described. The method is very efficient, and the 2-alkylaminoquinazolinone derivatives are obtained in three steps without chromatographic purification. The key step is the ring closure of the N-protected guanidine intermediates by intramolecular Friedel-Craft's type substitution.