RESUMO
A general directed Ru-catalyzed C(sp(3))-H α-alkylation protocol for piperidines (less-reactive substrates than the corresponding five-membered cyclic amines) has been developed. The use of a hindered alcohol (2,4-dimethyl-3-pentanol) as the solvent and catalyst activator, and a catalytic amount of trans-1,2-cyclohexanedicarboxylic acid is necessary to achieve a high conversion to product. This protocol was used to effectively synthesize a number of 2-hexyl- and 2,6-dihexyl piperidines, as well as the alkaloid (±)-solenopsin A. Kinetic studies have revealed that the carboxylic acid additive has a significant effect on catalyst initiation, catalyst longevity, and reverses the reaction selectivity compared with the acid-free reaction (promotes alkylation versus competing alkene reduction).
Assuntos
1-Propanol/química , Álcoois/química , Aminas/química , Ácidos Carboxílicos/química , Piperidinas/química , Rutênio/química , Alquilação , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome. JNJ-64619178 demonstrated a prolonged inhibition of PRMT5 and potent antiproliferative activity in subsets of cancer cell lines derived from various histologies, including lung, breast, pancreatic, and hematological malignancies. In primary acute myelogenous leukemia samples, the presence of splicing factor mutations correlated with a higher ex vivo sensitivity to JNJ-64619178. Furthermore, the potent and unique mechanism of inhibition of JNJ-64619178, combined with highly optimized pharmacological properties, led to efficient tumor growth inhibition and regression in several xenograft models in vivo, with once-daily or intermittent oral-dosing schedules. An increase in splicing burden was observed upon JNJ-64619178 treatment. Overall, these observations support the continued clinical evaluation of JNJ-64619178 in patients with aberrant PRMT5 activity-driven tumors.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteína-Arginina N-Metiltransferases/efeitos dos fármacos , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Pirimidinas/farmacologia , Pirróis/farmacologiaRESUMO
Microwave irradiation has been used to enhance organic reactions since the mid 80's, its use within the field of medicinal chemistry is not so widely evident in the literature. The present review highlights the use of microwave chemistry as an important tool for the fast development of structure activity relationship in several programs related to various therapeutic areas.
Assuntos
Química Farmacêutica , Micro-Ondas , Preparações Farmacêuticas/classificação , Relação Estrutura-AtividadeRESUMO
Clinical doses of available H(1) antihistamines are limited mainly by sedative side effects. However, higher doses are often required to obtain optimal therapeutic activity, especially in dermatology. We report the synthesis of three norpiperidine imidazoazepines representative of a new class of selective and nonsedating H(1) antihistamines. The compounds were at least as potent as cetirizine and loratadine as measured by H(1) receptor binding affinity, by protection against compound 48/80- and histamine-induced lethality in rats and guinea pigs, respectively, and by skin reaction tests in rats, guinea pigs, and dogs. The compounds, in particular 3a, were less prone than the reference compounds to penetrate the brain and to occupy central H(1) receptors, suggesting absence of sedative side effects. In vitro and in vivo cardiovascular safety tests showed that 3a had no intrinsic potential to prolong ventricular repolarization or induce cardiac arrhythmias. Compound 3a has been selected for further clinical development, mainly for application in dermatology.
Assuntos
Benzazepinas/síntese química , Fármacos Dermatológicos/síntese química , Antagonistas não Sedativos dos Receptores H1 da Histamina/síntese química , Imidazóis/síntese química , Piperidinas/síntese química , Compostos de Espiro/síntese química , Anafilaxia/induzido quimicamente , Anafilaxia/tratamento farmacológico , Animais , Arritmias Cardíacas/induzido quimicamente , Benzazepinas/farmacologia , Benzazepinas/toxicidade , Barreira Hematoencefálica/metabolismo , Células CHO , Cricetinae , Cricetulus , Dermatite/tratamento farmacológico , Dermatite/imunologia , Fármacos Dermatológicos/farmacologia , Fármacos Dermatológicos/toxicidade , Cães , Estabilidade de Medicamentos , Feminino , Cobaias , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacologia , Antagonistas não Sedativos dos Receptores H1 da Histamina/toxicidade , Concentração de Íons de Hidrogênio , Imidazóis/farmacologia , Imidazóis/toxicidade , Técnicas In Vitro , Masculino , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Piperidinas/farmacologia , Piperidinas/toxicidade , Ensaio Radioligante , Ratos , Ratos Wistar , Solubilidade , Compostos de Espiro/farmacologia , Compostos de Espiro/toxicidade , Relação Estrutura-Atividade , Função Ventricular/efeitos dos fármacosRESUMO
In 1991, WHO recognized the resurgence of tuberculosis as a global health problem. Although modern chemotherapy is effective against the causative pathogen Mycobacterium tuberculosis, the current drug regimens have failed to eradicate the disease. The success of the pathogen, partially attributed to drug resistance, necessitates the development of novel anti-tuberculosis drugs. Benzo[j]phenanthridine-7,12-diones, tetracyclic derivatives of the natural product benz[g]isoquinoline-5,10-dione, were conveniently synthesized via palladium-catalyzed intramolecular cyclization of N-methanesulfonyl-3-bromo-2-(arylamino)methyl-1,4-naphthoquinones. Here we report on the bioactivity of eight benzo[j]phenanthridine-7,12-dione derivatives as candidate drug molecules against M. tuberculosis and on their cytotoxicity on C3A human hepatocytes. The strongest antimicrobial activity (as detected by growth inhibition of bacteria, using luminometry and BACTEC 460-TB) and lowest cytotoxicity was found for 3-methylbenzo[j]phenanthridine-7,12-dione 5e, which was also effective in targeting intracellular M. tuberculosis (in murine J774 macrophages) and was not genotoxic for C3A hepatocytes.
Assuntos
Antituberculosos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Paládio/química , Fenantridinas/síntese química , Animais , Antituberculosos/química , Antituberculosos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Hepatócitos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/crescimento & desenvolvimento , Fenantridinas/química , Fenantridinas/farmacologia , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
This communication describes the synthesis and in vitro PDE4 inhibitory activity of a novel series of imidazol-2-one and 2-cyanoiminoimidazole derivatives. The compounds described were also tested in in vivo models to evaluate their anti-inflammatory activity after topical administration as well as their gastro-intestinal side effects. Several compounds proved to be potent PDE4 inhibitors and some 2-cyanoiminoimidazoles showed less pronounced gastro-intestinal side effects than reference compounds but maintained anti-inflammatory activity after topical administration.