RESUMO
A phenotypic screening of thienodiazepines derived from a hit compound found through a binding assay targeting co-stimulatory molecules on T cells and antigen presenting cells successfully led to the discovery of a thienotriazolodiazepine compound (7f) possessing potent immunosuppressive activity. A chemical biology approach has succeeded in revealing that 7f is a first inhibitor of epigenetic bromodomain-containing proteins. 7f is expected to become an anti-cancer agent as well as an immunosuppressive agent.
Assuntos
Antineoplásicos/farmacologia , Azepinas/farmacologia , Antígenos CD28/metabolismo , Descoberta de Drogas , Imunossupressores/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Azepinas/síntese química , Azepinas/química , Antígenos CD28/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Histona Acetiltransferases , Chaperonas de Histonas , Humanos , Imunossupressores/síntese química , Imunossupressores/química , Estrutura Molecular , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Fenótipo , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
A method for enantioselective desymmetrization of N-Ac and N-Boc-FTY720 by nonenzymatic asymmetric acylation was developed. Effective enantioselective monobenzoylation using benzoyl chloride in the presence of the tetraphenylbisoxazoline (L2)-CuCl2 complex gave the desired products 3a and 3b in 52-62% yield with 64% ee.
Assuntos
Propilenoglicóis/química , Esfingosina/análogos & derivados , Acilação , Benzoatos/química , Catálise , Complexos de Coordenação/química , Cobre/química , Cloridrato de Fingolimode , Oxazóis/química , Solventes/química , Esfingosina/química , EstereoisomerismoRESUMO
A concise synthesis of a useful intermediate 10 for the preparation of fingolimod (FTY-720) analogs was achieved by utilizing a chemoselective Sonogashira reaction of trihalobenzene 12 with alkyne 13. The reaction proceeded with high selectivity to give alkyne 11 containing the dihalobenzene moiety in good yield. Compound 11 was converted into intermediate 10 by hydrogenation without reduction of the halogen atoms.
Assuntos
Imunossupressores/química , Propilenoglicóis/química , Esfingosina/análogos & derivados , Alcinos/síntese química , Alcinos/química , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Catálise , Cloridrato de Fingolimode , Imunossupressores/síntese química , Paládio/química , Propilenoglicóis/síntese química , Esfingosina/síntese química , Esfingosina/química , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/químicaRESUMO
A series of 2-substituted 2-aminopropane-1,3-diols having a biphenyl moiety and their phosphate esters were synthesized to obtain sphingosine 1-phosphate receptor-1 (S1P(1)) receptor agonists with potent immunomodulatory activity accompanied by little or no effect on heart rate. Many of the synthesized compounds sufficiently decreased the number of peripheral blood lymphocytes. Some of the phosphates had potent agonism at S1P(1) but no agonism at S1P(3), which had been reported to be a receptor responsible for heart rate reduction. Although high S1P(1)/S1P(3) selectivity was considered to be favorable to reduce the effect on heart rate, almost all the phosphates showed a remarkable heart rate lowering effect in vivo. The results suggest that other factors in addition to S1P(3) agonism should be responsible for the heart rate reduction caused by S1P(1) agonists. Only 2-amino-2-[2-[2'-fluoro-4'-(4-methylphenylthio)biphenyl-4-yl]ethyl]propane-1,3-diol (6d) was identified as a desired S1P(1) receptor agonist having both the immunomodulatory activity and an attenuated effect on heart rate by a unique screening flow using in vivo evaluating systems primarily.
