RESUMO
We report herein on a catalytic system involving palladium and copper to achieve the cyclization of N-arylcyanothioformamides and the synthesis of 2-cyanobenzothiazoles. The C-H functionalization/intramolecular C-S bond formation reaction was achieved in the presence of air, using 2.0 equiv of an inorganic additive (KI). In many cases, the reaction led to a sole product regioselectively obtained in good yields, allowing the synthesis of a wide range of substituted 2-cyanobenzothiazole derivatives, providing valuable building blocks for the design of more complex heterocyclic or molecular labeling systems.
Assuntos
Cobre , Paládio , Paládio/química , Ciclização , Catálise , Cobre/químicaRESUMO
Infantile (fetal and neonatal) megakaryocytes (Mks) have a distinct phenotype consisting of hyperproliferation, limited morphogenesis, and low platelet production capacity. These properties contribute to clinical problems that include thrombocytopenia in neonates, delayed platelet engraftment in recipients of cord blood stem cell transplants, and inefficient ex vivo platelet production from pluripotent stem cell-derived Mks. The infantile phenotype results from deficiency of the actin-regulated coactivator, MKL1, which programs cytoskeletal changes driving morphogenesis. As a strategy to complement this molecular defect, we screened pathways with the potential to affect MKL1 function and found that DYRK1A inhibition dramatically enhanced Mk morphogenesis in vitro and in vivo. Dyrk1 inhibitors rescued enlargement, polyploidization, and thrombopoiesis in human neonatal Mks. Mks derived from induced pluripotent stem cells responded in a similar manner. Progenitors undergoing Dyrk1 inhibition demonstrated filamentous actin assembly, MKL1 nuclear translocation, and modulation of MKL1 target genes. Loss-of-function studies confirmed MKL1 involvement in this morphogenetic pathway. Expression of Ablim2, a stabilizer of filamentous actin, increased with Dyrk1 inhibition, and Ablim2 knockdown abrogated the actin, MKL1, and morphogenetic responses to Dyrk1 inhibition. These results delineate a pharmacologically tractable morphogenetic pathway whose manipulation may alleviate clinical problems associated with the limited thrombopoietic capacity of infantile Mks.
Assuntos
Megacariócitos , Trombocitopenia , Actinas/metabolismo , Plaquetas/metabolismo , Humanos , Recém-Nascido , Megacariócitos/metabolismo , Fenótipo , Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases , Trombocitopenia/genética , Trombopoese/genética , Quinases DyrkRESUMO
Transition-metal-free direct arylation of C-H or N-H bonds is one of the key emerging methodologies that is currently attracting tremendous attention. Diaryliodonium salts serve as a stepping stone on the way to alternative environmentally friendly and straightforward pathways for the construction of C-C and C-heteroatom bonds. In this review, we emphasize the recent synthetic advances of late-stage C(sp2)-N and C(sp2)-C(sp2) bond-forming reactions under metal-free conditions using diaryliodonium salts as arylating reagent and its applications to the synthesis of new arylated bioactive heterocyclic compounds.
RESUMO
This paper reports a convenient sequential one-pot approach for the synthesis of an array of 14 pyrazolo[1,5-a][1,3,5]triazines, substituted in C8 by halogen (Br), various functions (CN and CO2Et) and alkyl or (het)aryl groups. This study confirms the interest of combining the efficient heating obtained under dielectric microwave heating and the achievement of sequential one-pot reactions, avoiding the tedious work-up and purification of intermediate compounds, achieving sustainable synthesis processes. Considering usual conventional methods, this microwave protocol is featured by advantages in terms of yields, reaction times, and convenient gram scale synthesis.
RESUMO
A modular synthetic method, involving a hydrothiolation, silylation, and fluoroalkylation, for the construction of highly functionalized fluoroalkyl sulfides has been developed. The use of aprotic polar solvents enables the additive-free chemoselective hydrothiolation of tetrafluoroethylene, trifluorochloroethylene, and hexafluoropropene with various thiols. The stepwise functionalization reactions convert the hydrothiolated intermediates into the tetrafluoroethyl sulfides in high efficiency. The method avoids the use of the environmental pollutant Halon-2402, which was employed as a building block in a reported synthetic route.
RESUMO
DYRK1A is a serine/threonine kinase encoded on human chromosome 21 (HSA21) that has been implicated in several pathologies of Down syndrome (DS), including cognitive deficits and Alzheimer's disease. Although children with DS are predisposed to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL), the HSA21 genes that contribute to malignancies remain largely undefined. Here, we report that DYRK1A is overexpressed and required for B-ALL. Genetic and pharmacologic inhibition of DYRK1A decreased leukemic cell expansion and suppressed B-ALL development in vitro and in vivo. Furthermore, we found that FOXO1 and STAT3, transcription factors that are indispensable for B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupted DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we reveal a DYRK1A/FOXO1/STAT3 axis that facilitates the development and maintenance of B-ALL.
Assuntos
Proteína Forkhead Box O1/metabolismo , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Feminino , Proteína Forkhead Box O1/genética , Masculino , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Fosforilação/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Fator de Transcrição STAT3/genética , Quinases DyrkRESUMO
Efficient microwave-assisted chemical processes were applied to the synthesis of an array of novel N-(4-methoxyphenylamino)-2-methyl benzo-, pyrido- or pyrazino-thieno[3,2-d]pyrimidin-4-amine derivatives. These heteroaromatic systems were envisioned as potent bioisosteric analogues of MPC-6827, an anticancer agent previously developed until phase II clinical studies. A brief evaluation and comparison of their antiproliferative activity on HT-29 and Caco-2, two human colorectal cancer cell lines, were also reported. At the tested concentrations (5 and 10 µM), thieno[3,2-d]pyrimidin-4-amines 4a and 4c exhibited an inhibitory effect similar to MPC-6827 on human colorectal cancer cell proliferation.
RESUMO
Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) hyperactivity has been linked to the development of a number of human malignancies. DYRK1A is the most studied family member, and the discovery of novel specific inhibitors is attracting considerable interest. The 8-cyclopropyl-2(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one (also called FC162) was found to be a promising inhibitor of DYRK1A and was characterized in biological experiments, by western transfer and flow cytometry on SH-SY5Y and pre-B cells. Here, the results obtained with FC162 are compared to well-characterized known DYRK1A inhibitors (e.g., Leucettine L41 and EHT1610).
RESUMO
Efficient metal catalyzed Câ»H arylation of 8-alkyl-thiazolo[5,4-f]-quinazolin-9-ones was explored for SAR studies. Application of this powerful chemical tool at the last stage of the synthesis of kinase inhibitors allowed the synthesis of arrays of molecules inspired by fragment-growing studies generated by molecular modeling calculations. Among the potentially active compounds designed through this strategy, FC162 (4c) exhibits nanomolar IC50 values against some kinases, and is the best candidate for the development as a DYRK kinase inhibitor.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Quinazolinas/síntese química , Micro-Ondas , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/química , Relação Estrutura-Atividade , Quinases DyrkRESUMO
INTRODUCTION: Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a eukaryotic serine-threonine protein kinase belonging to the CMGC group. DYRK1A hyperactivity appears to contribute to the development of a number of human malignancies and to cognitive deficits observed in Down syndrome and Alzheimer's disease. As a result, the DYRK1A kinase represents an attractive target for the synthesis and optimization of pharmacological inhibitors of potential therapeutic interest. Like most tyrosine kinase inhibitors developed up to the market, DYRK1A inhibitors are essentially acting by competing with ATP for binding at the catalytic site of the kinase. Areas covered: This paper reviews patent activity associated with the discovery of synthetic novel heterocyclic molecules inhibiting the catalytic activity of DYRK1A. Expert opinion: Despite the important role of DYRK1A in biological processes and the growing interest in the design of new therapeutic drugs, there are only few patented synthetic DYRK1A inhibitors and most of them were and are still developed by academic research groups, sometimes with industrial partners.
Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Animais , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/fisiopatologia , Síndrome de Down/tratamento farmacológico , Síndrome de Down/fisiopatologia , Humanos , Patentes como Assunto , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Quinases DyrkRESUMO
A selective functionalization of thiazolo[5,4-f]quinazolin-9(8H)-one has been developed through sequential activation of C-H bonds to furnish diarylated compounds. This strategy allows the regioselective C2 and C7 arylation by a judicious choice of coupling partners and bases, requiring no additional ligands or directing groups. Differently substituted N(8)-benzylated-2,7-diaryl-thiazoloquinazolin-9(8H)-ones were thereby obtained in a facile manner. A one-pot procedure was also performed. These protocols provide a synthetically useful route for late-stage functionalization of this highly valuable scaffold, required in drug discovery.
RESUMO
A library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer's disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Quinazolinonas/química , Doença de Alzheimer/enzimologia , Barbitúricos/química , Catálise , Cobre/química , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/isolamento & purificação , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinonas/síntese química , Quinazolinonas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
A library of thirty novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives belonging to four series designated as 12, 13, 14 and 15 was efficiently prepared, helped by microwave-assisted technology when required. The efficient multistep synthesis of methyl 6-amino-2-cyano- benzo[d]thiazole-7-carboxylate (1) has been reinvestigated and performed on a multigram scale. The inhibitory potency of the final products against five kinases involved in Alzheimer's disease was evaluated. This study demonstrates that some molecules of the 12 and 13 series described in this paper are particularly promising for the development of new multi-target inhibitors of kinases.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Quinazolinonas/síntese química , Tiazóis/síntese química , Animais , Humanos , Ligantes , Estrutura Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Quinazolinonas/metabolismo , Quinazolinonas/uso terapêutico , Suínos , Tiazóis/metabolismo , Tiazóis/uso terapêuticoRESUMO
A straightforward method for direct decarboxylative arylation of 1- and 3-carboxy isoquinaldic acid N-oxides with aryl iodides is reported. The reaction proceeded selectively at the carboxy function site to exclusively give the corresponding C-1 or C-3 arylated product. This methodology tolerates various aryl iodides substituted by electronically different groups. Combined with subsequent Reissert-Henze chlorination and SNAr amination, the decarboxylative arylation provides an efficient access to 1,3-functionalized isoquinoline-based antitumor agent.
Assuntos
Óxidos N-Cíclicos/química , Isoquinolinas/síntese química , Halogenação , Iodetos/química , Isoquinolinas/química , Estrutura MolecularRESUMO
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.
Assuntos
Cobre/química , Iodetos/química , Paládio/química , Quinazolinonas/química , Catálise , Ligação de Hidrogênio , Micro-Ondas , Estrutura MolecularRESUMO
Decarboxylative cross-coupling reactions of substituted 2-carboxyazine N-oxides, with a variety of (hetero)aryl halides, by bimetallic Pd(0)/Cu(I) and Pd(0)/Ag(I) catalysis are reported. Two possible pathways, a conventional bimetallic-catalyzed decarboxylative arylation, as well as a protodecarboxylative/direct C-H arylation sequence have been considered. These methods provide the first general decarboxylative arylation methodology for the 2-carboxyazine series.
RESUMO
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.
Assuntos
Imidazóis/química , Peptidomiméticos/química , Amidas/química , Compostos Aza/química , Estrutura MolecularRESUMO
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.
Assuntos
Fibrossarcoma/diagnóstico por imagem , Fibrossarcoma/metabolismo , Misonidazol/química , Misonidazol/farmacocinética , Animais , Linhagem Celular Tumoral , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Marcação por Isótopo/métodos , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C3H , Especificidade de Órgãos , Cintilografia , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Silício/química , Silício/farmacocinética , Distribuição TecidualRESUMO
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.