RESUMO
A series of novel aza vinyl sulfones were designed, synthesized in good yields and evaluated as antiplasmodial agents. Tested compounds did not show activity against papain or the Plasmodium falciparum cysteine protease falcipain-2. However, a number of the new compounds effectively inhibited the in vitro development of P. falciparum. Compounds containing a squaramide group were the most active, with IC(50) values between 0.95 and 4.5 µM, suggesting that these are potential lead compounds for the development of new antimalarial agents.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Sulfonas/química , Sulfonas/farmacologia , Antimaláricos/síntese química , Cisteína Endopeptidases/metabolismo , Eritrócitos/parasitologia , Humanos , Concentração Inibidora 50 , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/enzimologia , Sulfonas/síntese químicaRESUMO
On thermolysis appropriately substituted N-silyloxy-N-allyl enamines undergo smooth 3,3-sigmatropic rearrangments to the corresponding N-silyloxy imino ethers.
RESUMO
In this article we describe an expanded structure-activity relationship study for vinyl sulfones as caspase-3 inhibitors, a topic virtually unexplored in the existing literature. Most remarkably, and to our surprise, tripeptidyl vinyl sulfones were not active for caspase-3, opposite to other examples described in literature for peptidyl vinyl sulfones as potent cysteine protease inhibitors of clan CA. Moreover, the caspase-3 inhibitory activity of vinyl sulfones using an in vitro assay was then confirmed using a yeast cell-based assay. The results show that Fmoc-protected vinyl sulfones containing only the Asp moiety are inhibitors of a caspase-3-dependent pathway and the IC50 values obtained in the yeast assay are in the same order of magnitude of that obtained with the caspase-3 inhibitor tetrapeptidyl chloromethyl ketone, Ac-DEVD-CMK. This observation is consistent with appropriate cell permeability properties displayed by the vinyl sulfone inhibitors, as reflected by logP values ranging from 1.1 to 3.4. Overall, these results suggest that vinyl sulfones containing Asp at P1 should be considered for further optimization as caspase inhibitors and modulators of caspase-3-dependent pathways.
Assuntos
Ácido Aspártico/farmacologia , Inibidores de Caspase , Inibidores de Cisteína Proteinase/farmacologia , Sulfonas/farmacologia , Compostos de Vinila/farmacologia , Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Caspase 3/metabolismo , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Humanos , Conformação Molecular , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Compostos de Vinila/síntese química , Compostos de Vinila/químicaRESUMO
The first structure-activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp at P(1), as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CH=CH-SO(2)Me was the most potent inhibitor of caspase-3 in the series, with a IC(50) of 29 microM and a second-order rate constant of inactivation, k(inact)/K(i), of 1.5 M(-1) s(-1). Computational studies suggest that the second amino acid occupies position S(3) of the enzyme. In addition, Fmoc-Val-Asp-trans-CH=CH-SO(2)Ph was inactive for caspase-7 for the tested concentrations.
Assuntos
Inibidores de Caspase , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Caspase 3/química , Inibidores Enzimáticos/síntese química , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade , Sulfonas/síntese químicaRESUMO
Apoptosis is now recognized as a normal feature in the development of the nervous system and may also play a role in neurodegenerative disorders, such as Alzheimer's disease. Cell surface receptors, caspases, mitochondrial factors or p53 participate in the modulation and execution of cell death. Therefore, the ability to understand and manipulate the cell death machinery is an obvious goal of medical research. Potential therapeutic approaches to modulate disease by regulating apoptosis are being tested, and include the traditional use of small molecules to target specific players in the apoptosis cascade. As our understanding of apoptosis increases, further opportunities will arise for more specific therapies that will result in improved efficacy. This review focuses on molecular mechanisms of apoptosis in Alzheimer's disease and highlights the potential use of small molecule modulators to treat neurodegenerative disorders.