RESUMO
Organic chemistry honors Icilio Guareschi (1847-1918) with three eponymic reactions, the best known ones being the Guareschi synthesis of pyridones and the Guareschi-Lustgarten reaction. A third Guareschi reaction, the so-called "Guareschi 1897 reaction", is one of the most unusual reactions in organic chemistry, involving the radical-mediated paradoxical aerobic generation of hydrocarbons in near-neutral water solution. A discussion of the mechanism of this amazing reaction, the only metal-free process that generates hydrocarbons, and the implications of the approach in biology and geosciences mirrors the multifaceted scientific personality of the discoverer. Thus, Guareschi's eclectic range of activities spans a surprising variety of topics, overcoming the boundaries of the traditional partition of chemistry into organic, inorganic, and analytical branches and systematically crosses the divide between pure and applied science as well as between the history of chemistry and the personal contributions to its development.
RESUMO
In recent years, channels that mediate store-operated calcium entry (SOCE, i.e., the ability of cells to sense a decrease in endoplasmic reticulum luminal calcium and induce calcium entry across the plasma membrane) have been associated with a number of disorders, spanning from immune disorders to acute pancreatitis and have been suggested to be druggable targets. In the present contribution, we exploited the click chemistry approach to synthesize a class of SOCE modulators where the arylamide substructure that characterizes most inhibitors so far described is substituted by a 1,4-disubstituted 1,2,3-triazole ring. Within this series, inhibitors of SOCE were identified and the best compound proved effective in an animal model of acute pancreatitis, a disease characterized by a hyperactivation of SOCE. Strikingly, two enhancers of the process were discovered, affording invaluable research tools to further explore the (patho)physiological role of capacitative calcium entry.
Assuntos
Cálcio/metabolismo , Desenho de Fármacos , Pancreatite/tratamento farmacológico , Triazóis/química , Triazóis/farmacologia , Doença Aguda , Animais , Transporte Biológico/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Células HEK293 , Humanos , Camundongos , Triazóis/uso terapêuticoRESUMO
Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and the development of new capsaicinoids is a promising pharmacological approach in the management of skin disorders related to inflammation and pruritus. Here we report the synthesis and the evaluation of capsaicin soft drugs that undergo deactivation by the hydrolyzing activity of skin esterases. The implanting of an ester group in the lipophilic moiety of capsaicinoids by the Passerini multicomponent reaction affords both agonists and antagonists that retain transient receptor potential vanilloid 1 channel (TRPV1) modulating activity and, at the same time, are susceptible to hydrolysis. The most promising antagonist identified shows in vivo anti-nociceptive activity on pruritus and hyperalgesia without producing hyperthermia, thus validating it as novel treatment for dermatological conditions that implicate TRPV1 channel dysfunction.
Assuntos
Capsaicina/administração & dosagem , Capsaicina/química , Descoberta de Drogas , Inflamação/tratamento farmacológico , Queratinócitos/efeitos dos fármacos , Lauratos/farmacologia , Dermatopatias/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Administração Tópica , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/química , Animais , Células Cultivadas , Feminino , Humanos , Inflamação/induzido quimicamente , Lauratos/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Dermatopatias/induzido quimicamenteRESUMO
Indoleamine 2,3-dioxygenase plays a crucial role in immune tolerance and has emerged as an attractive target for cancer immunotherapy. In this study, the Passerini and Ugi multicomponent reactions have been employed to assemble a small library of imidazothiazoles that target IDO1. While the p-bromophenyl and the imidazothiazole moieties have been kept fixed, a full SAR study has been performed on the side-chain, leading to the discovery of nine compounds with sub-micromolar IC50 values in the enzyme-based assay. Compound 7d, displaying a α-acyloxyamide substructure, is the most potent compound, with an IC50 value of 0.20⯵M, but a low activity in a cell-based assay. Compound 6o, containing a α-acylaminoamide moiety, shows an IC50 value of 0.81⯵M in the IDO1-based assay, a full biocompatibility at 10⯵M, together with a modest inhibitory activity in A375 cells. Molecular docking studies show that both 7d and 6o display a unique binding mode in the IDO1 active site, with the side-chain protruding in an additional pocket C, where a crucial hydrogen bond is formed with Lys238. Overall, this work describes an isocyanide based-multicomponent approach as a straightforward and versatile tool to rapidly access IDO1 inhibitors, providing a new direction for their future design and development.
Assuntos
Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Tiazóis/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imidazóis/síntese química , Imidazóis/química , Indolamina-Pirrol 2,3,-Dioxigenase/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Oximas/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Tiazóis/síntese química , Tiazóis/química , Triptofano/análogos & derivados , Triptofano/farmacologiaRESUMO
Activation of the phosphoinositide 3-kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on-target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life-threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so-far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan-PI3K inhibitor.
Assuntos
Ácidos Carboxílicos/química , Inibidores Enzimáticos/química , Inibidores de Fosfoinositídeo-3 Quinase , Pró-Fármacos/química , Animais , Sítios de Ligação , Ácidos Carboxílicos/metabolismo , Ácidos Carboxílicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Camundongos , Microssomos/metabolismo , Simulação de Dinâmica Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Quinolonas/química , Quinolonas/metabolismo , Quinolonas/farmacologia , Relação Estrutura-AtividadeRESUMO
Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme involved in the recycling of nicotinamide to maintain adequate NAD levels inside the cells. It has been postulated to be a pharmacological target, as it is overexpressed in cancer cells as well as in inflammatory diseases. We describe the synthesis and characterization of a novel class of one-digit nanomolar NAMPT inhibitors based on in vitro characterization. The most active compound tested, 30c, displayed activity in xenograft and allograft models, strengthening the potential of NAMPT inhibitors as antitumoral drugs. Furthermore, in the present contribution we describe the ability of 30c to significantly improve the outcome of colitis in mice. Given that this is the first report of an effect of NAMPT inhibitors in colitis, this result paves the way for novel applications for this class of compounds.
Assuntos
Anti-Inflamatórios/farmacologia , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Triazóis/farmacologia , Anti-Inflamatórios/química , Inibidores Enzimáticos/química , Análise Espectral/métodos , Triazóis/químicaRESUMO
A novel series of 4-aryl-3-cyano-2-(3-hydroxyphenyl)-6-morpholino-pyridines have been designed as potential phosphatidylinositol-3-kinase (PI3K) inhibitors. The compounds have been synthesized using the Guareschi reaction to prepare the key 4-aryl-3-cyano-2,6-dihydroxypyridine intermediate. A different selectivity according to the nature of the aryl group has been observed. Compound 9b is a selective inhibitor against the PI3Kα isoform, maintaining a good inhibitory activity. Docking studies were also performed in order to rationalize its profile of selectivity.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores de Fosfoinositídeo-3 Quinase , Piridinas/síntese química , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Células NIH 3T3 , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
In the present manuscript, starting from the 1,4-benzodiazepin-2-one nucleus, a privileged structure in medicinal chemistry, we have synthesized a novel class of cis-locked combretastatins named combreatabenzodiazepines. They show similar cytotoxic and antitubulin activity compared to combretastatin A-4 in neuroblastoma cells, showing a better pharmacokinetic profile. This class of compounds has therefore the potential for further development as antitubulin agents.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzodiazepinonas/farmacologia , Desenho de Fármacos , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Benzodiazepinonas/síntese química , Benzodiazepinonas/química , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Moduladores de Tubulina/química , Células Tumorais CultivadasRESUMO
Over the last decade, 1,2,3-triazoles have received increasing attention in medicinal chemistry thanks to the discovery of the highly useful and widely applicable 1,3-dipolar cycloaddition reaction between azides and alkynes (click chemistry) catalyzed by copper salts and ruthenium complexes. After a decade of medicinal chemistry research on 1,2,3-triazoles, we feel that the time is ripe to demonstrate the real ability of this heterocycle to participate in important and pivotal binding interactions with biological targets while maintaining a good pharmacokinetic profile. In this study, we retrieved and analyzed X-ray crystal structures of complexes between 1,2,3-triazoles and either proteins or DNA to understand the pharmacophoric role of the triazole. Furthermore, the metabolic stability, the capacity to inhibit cytochromes, and the contribution of 1,2,3-triazoles to the overall aqueous solubility of compounds containing them have been analyzed. This information should furnish fresh insight for medicinal chemists in the design of novel bioactive molecules that contain the triazole nucleus.
Assuntos
Proteínas/química , Triazóis/química , Alcinos/química , Azidas/química , Sítios de Ligação , Catálise , Química Click , Cobre/química , Reação de Cicloadição , Bases de Dados de Proteínas , Estrutura Terciária de Proteína , Proteínas/metabolismo , Rutênio/química , Solubilidade , Eletricidade Estática , Triazóis/metabolismo , Água/químicaRESUMO
Since Professors Sharpless, Finn, and Kolb first introduced the concept of "click reactions" in 2001 as powerful tools in drug discovery, 1,4-disubstituted-1,2,3-triazoles have become important in medicinal chemistry due to the simultaneous discovery by Sharpless, Fokin, and Meldal of a perfect click 1,3-dipolar cycloaddition reaction between azides and alkynes catalyzed by copper salts. Because of their chemical features, these triazoles are proposed to be aggressive pharmacophores that participate in drug-receptor interactions while maintaining an excellent chemical and metabolic profile. Surprisingly, no virtual libraries of 1,4-disubstituted-1,2,3-triazoles have been generated for the systematic investigation of the click-chemical space. In this manuscript, a database of triazoles called ZINClick is generated from literature-reported alkynes and azides that can be synthesized within three steps from commercially available products. This combinatorial database contains over 16 million 1,4-disubstituted-1,2,3-triazoles that are easily synthesizable, new, and patentable! The structural diversity of ZINClick ( http://www.symech.it/ZINClick ) will be explored. ZINClick will also be compared to other available databases, and its application during the design of novel bioactive molecules containing triazole nuclei will be discussed.
Assuntos
Química Click , Bases de Dados de Produtos Farmacêuticos , Patentes como Assunto , Triazóis/química , Triazóis/síntese química , Alcinos/química , Azidas/química , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta , Modelos Moleculares , Conformação Molecular , NADP/análogos & derivados , NADP/síntese química , NADP/química , NADP/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Triazóis/farmacologiaRESUMO
Combretastatin A1 (CA1) binds to the ß-subunit at the colchicine binding site of tubulin and inhibits polymerization. As such, it is both an antitumor agent and a vascular disrupting agent. It has been shown to be at least tenfold more potent than combretastatin A4 (CA4) in terms of vascular shutdown, which correlates with its metabolism to reactive ortho-quinone species that are assumed to be directly cytotoxic in tumor cells. A series of 3,4-diarylpyrazoles were concisely synthesized, one of which, 3-methoxy-6-[4-(3,4,5-trimethoxyphenyl)-1H-pyrazol-3-yl]benzene-1,2-diol (27), proved to be a cytotoxic anti-tubulin agent with low nanomolar potency. We also report that combretastatins, including CA1, CA4, and 27, are effective against mesothelioma cell lines and therefore have significant clinical promise. Metabolism experiments demonstrate that 27 retains the ability to form ortho-quinone species, while the pyrazole ring shows high metabolic stability, suggesting that this compound might result in better pharmacokinetic profiles than CA1, with similar pharmacodynamic properties and clinical potential.
Assuntos
Pirazóis/química , Estilbenos/química , Moduladores de Tubulina/síntese química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Pirazóis/síntese química , Pirazóis/toxicidade , Ratos , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/toxicidadeRESUMO
Chikungunya virus (CHIKV) is an Arbovirus that is transmitted to humans primarily by the mosquito species Aedes aegypti. Infection with this pathogen is often associated with fever, rash and arthralgia. Neither a vaccine nor an antiviral drug is available for the prevention or treatment of this disease. Albeit considered a tropical pathogen, adaptation of the virus to the mosquito species Aedes albopictus, which is also very common in temperate zones, has resulted in recent outbreaks in Europe and the US. In the present study, we report on the discovery of a novel series of compounds that inhibit CHIKV replication in the low µM range. In particular, we initially performed a virtual screening simulation of â¼5 million compounds on the CHIKV nsP2, the viral protease, after which we investigated and explored the Structure-Activity Relationships of the hit identified in silico. Overall, a series of 26 compounds, including the original hit, was evaluated in a virus-cell-based CPE reduction assay. The study of such selective inhibitors will contribute to a better understanding of the CHIKV replication cycle and may represents a first step towards the development of a clinical candidate drug for the treatment of this disease.
Assuntos
Infecções por Alphavirus/virologia , Antivirais/química , Antivirais/farmacologia , Vírus Chikungunya/efeitos dos fármacos , Desenho de Fármacos , Infecções por Alphavirus/tratamento farmacológico , Antivirais/síntese química , Linhagem Celular , Febre de Chikungunya , Vírus Chikungunya/fisiologia , Desenho Assistido por Computador , Avaliação Pré-Clínica de Medicamentos , Humanos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
As part of an effort to identify novel selective modulators of sirtuins, we synthesized and tested several isosteres and constrained analogues of nicotinamide. Biological data suggest that compound 2 is selective for Sirt3 over Sirt1 and Sirt2.
Assuntos
Inibidores de Histona Desacetilases/farmacologia , Niacinamida/farmacologia , Sirtuína 1/antagonistas & inibidores , Sirtuína 2/antagonistas & inibidores , Sirtuína 3/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Niacinamida/síntese química , Niacinamida/química , Especificidade por SubstratoRESUMO
Computer-aided drug design techniques have become an integral part of the drug discovery process. In particular, de novo methodologies can be useful to identify putative ligands for a specific target relying only on the structural information of the target itself. Here we discuss the basic de novo approaches available and their application in antiviral drug design.:
RESUMO
Computational approaches have been increasingly applied to drug design over the past three decades and have already provided some useful results in the discovery of anticancer drugs. Given the increased availability of crystal structures in recent years, a growing number of molecular modeling studies on tubulin have been reported. Herein we present a brief overview of the role played by computational methods in anti-tubulin research, specifically in the context of colchicine binding agent research. An overview of current structures is reported, along with a brief discussion on the issues associated with the various tubulin isotypes. Finally, a summary of the most recent and relevant results is presented, highlighting the challenges and opportunities faced by researchers in this field.
Assuntos
Colchicina/química , Colchicina/farmacologia , Desenho de Fármacos , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Humanos , Modelos Moleculares , Estrutura Terciária de Proteína , Tubulina (Proteína)/químicaRESUMO
In a program aimed at discovering novel protein kinase inhibitors, a convenient synthesis of 3,8-diaminoimidazo[1,2-a]pyrazines has been developed exploiting the isocyanide-based multicomponent Blackburn reaction, followed by a nucleophilic aromatic substitution with ammonia or primary and secondary amines. The potential of the reported scaffold is strengthened by the inhibition of STAT5-dependent transcription displayed by four of the synthesized compounds.
Assuntos
Imidazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Pirazinas/síntese química , Imidazóis/química , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Pirazinas/química , EstereoisomerismoRESUMO
In the chalcone scaffold, it is thought that the double bond is an important structural linker but it is likely not essential for the interaction with tubulin. Yet, it may be a potential site of metabolic degradation and interaction with biological nucleophiles. In this letter, we have replaced this olefinic portion of chalcones with two metabolically stable and chemically inert heterocyclic rings, namely triazole or tetrazole. Yet, our biologic data suggest that, unlike in other antitubulinic structures, the olephinic ring might not be merely a structural linker.
Assuntos
Chalconas/química , Chalconas/farmacologia , Tetrazóis/química , Tetrazóis/farmacologia , Triazóis/química , Triazóis/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/síntese química , Humanos , Modelos Moleculares , Neuroblastoma/tratamento farmacológico , Tetrazóis/síntese química , Triazóis/síntese química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese químicaRESUMO
Phosphoinositide 3-kinases (PI3K) are key molecular players in male fertility. However, the specific roles of different p110 PI3K catalytic subunits within the spermatogenic lineage have not been characterized so far. Herein, we report that male mice expressing a catalytically inactive p110beta develop testicular hypotrophy and impaired spermatogenesis, leading to a phenotype of oligo-azoospermia and defective fertility. The examination of testes from p110beta-defective tubules demonstrates a widespread loss in spermatogenic cells, due to defective proliferation and survival of pre- and postmeiotic cells. In particular, p110beta is crucially needed in c-Kit-mediated spermatogonial expansion, as c-Kit-positive cells are lost in the adult testis and activation of Akt by SCF is blocked by a p110beta inhibitor. These data establish that activation of the p110beta PI3K isoform by c-Kit is required during spermatogenesis, thus opening the way to new treatments for c-Kit positive testicular cancers.
Assuntos
Infertilidade Masculina/genética , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Azoospermia , Catálise , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Fertilidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oligospermia , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/fisiologia , Isoformas de Proteínas , Proteínas Proto-Oncogênicas c-kit/metabolismo , Espermatogênese , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologiaRESUMO
The inhibition of NAD synthesis or salvage pathways has been proposed as a novel target for antitumoral drugs. Two molecules with this mechanism of action are at present undergoing clinical trials. In searching for similar novel molecules, we exploited copper-catalyzed [3 + 2] cycloaddition between azides and alkynes (click chemistry) to synthesize 185 novel analogues. The most promising compound displays an IC(50) for cytotoxicity in vitro of 3.8 +/- 0.3 nM and an IC(50) for NAD depletion of 3.0 +/- 0.4 nM. Herein, we strengthen previous data suggesting that this class of compounds induces autophagic cell death. In addition to characterizing this compound and providing a rationale via molecular docking, we reinforce the excellent potential of click chemistry for rapidly generating structure-activity relationships and for drug screening.
Assuntos
Azidas/química , Inibidores Enzimáticos/síntese química , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Alcinos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Autofagia , Azidas/farmacologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
HDAC inhibitors show great promise for the treatment of cancer. As part of a broader effort to explore the SAR of HDAC inhibitors, synthesis, biological evaluation, and molecular docking of novel Ugi products containing a zinc-chelating moiety are presented. One compound shows improved inhibitory potencies compared to SAHA, demonstrating that hindered lipophilic residues grafted on the peptide scaffold of the alpha-aminoacylamides can be favorable in the interaction with the enzyme.