RESUMO
A series of sulfasalazine analogs were synthesized and tested for their ability to block cystine-glutamate antiporter system xcâ» using L-[(14)C]cystine as a substrate. Replacement of sulfasalazine's diazo group with an alkyne group led to an equally potent inhibitor, 2-hydroxy-5-((4-(N-pyridin-2-ylsulfamoyl)phenyl)ethynyl)benzoic acid 6. Our SAR studies also revealed that the carboxylate group of sulfasalazine is essential for its inhibitory activity while the phenolic hydroxyl group is dispensable. Truncated analogs lacking an N-pyridin-2-ylsulfamoyl moiety were less potent than sulfasalazine, but may serve as more tractable templates because of their low molecular weight by applying a variety of fragment growing approaches. Given that sulfasalazine is rapidly metabolized through cleavage of the diazo bond, these analogs may possess a more desirable pharmacological profile as system xc- blockers, in particular, for in vivo studies.
Assuntos
Sistema X-AG de Transporte de Aminoácidos/antagonistas & inibidores , Antiporters/antagonistas & inibidores , Cistina/metabolismo , Sulfassalazina/análogos & derivados , Sulfassalazina/farmacologia , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Antiporters/metabolismo , Linhagem Celular , Humanos , Relação Estrutura-AtividadeRESUMO
A series of N-substituted 3-(2-mercaptoethyl)-1H-indole-2-carboxylic acids were synthesized as inhibitors of glutamate carboxypeptidase II (GCPII). Those containing carboxybenzyl or carboxyphenyl groups at the N-position exhibited potent inhibitory activity against GCPII. These indole-based compounds represent the first example of achiral GCPII inhibitors and demonstrate greater tolerance of the GCPII active site for ligands with significant structural difference from the endogenous substrate, N-acetyl-aspartylglutamate.
Assuntos
Glutamato Carboxipeptidase II/antagonistas & inibidores , Indóis/química , Inibidores de Proteases/química , Ácidos Carboxílicos , Avaliação Pré-Clínica de Medicamentos , Glutamato Carboxipeptidase II/metabolismo , Indóis/síntese química , Indóis/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
Hammett analysis of the palladium-catalyzed allyl-aryl coupling reaction has demonstrated that the rate of the coupling reaction is enhanced by electron-withdrawing groups on the aryl siloxane. The positive slope of the Hammett plot indicated involvement of a charged transition state in which negative charge on the aryl ring is stabilized inductively. This result is consistent with either transmetalation or reductive elimination being the rate-determining step in the coupling process. Furthermore, the influence of ligand on the metal site has been assessed from competition studies as a function of ligand type, cone angle, and electronic effects. From the relative ratios of coupling products produced in the Hammett study, it is possible to gather insight into the role of the electronic as well as the steric effects of ligands on the mechanism of the coupling reaction.
Assuntos
Compostos Alílicos/química , Derivados de Benzeno/química , Silicatos/química , Compostos Alílicos/síntese química , Derivados de Benzeno/síntese química , Cinética , Silicatos/síntese química , Siloxanas/químicaRESUMO
Palladium-catalyzed coupling of an aryl siloxane and an allylic carbonate proceeded in good yield to give an adduct that was converted to an analogue of (+/-)-7-deoxypancratistatin.
Assuntos
Alcaloides de Amaryllidaceae/síntese química , Isoquinolinas/síntese química , Paládio/química , Catálise , Ciclização , EstereoisomerismoRESUMO
Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective allosteric inhibitor of kidney-type glutaminase (GLS) that has served as a molecular probe to determine the therapeutic potential of GLS inhibition. In an attempt to identify more potent GLS inhibitors with improved drug-like molecular properties, a series of BPTES analogs were synthesized and evaluated. Our structure-activity relationship (SAR) studies revealed that some truncated analogs retained the potency of BPTES, presenting an opportunity to improve its aqueous solubility. One of the analogs, N-(5-{2-[2-(5-amino-[1,3,4]thiadiazol-2-yl)-ethylsulfanyl]-ethyl}-[1,3,4]thiadiazol-2-yl)-2-phenyl-acetamide 6, exhibited similar potency and better solubility relative to BPTES and attenuated the growth of P493 human lymphoma B cells in vitro as well as in a mouse xenograft model.