RESUMO
Porphyrins are a group of tetrapyrrole pigments. Physical and chemical properties of porphyrins are often related to their compositions and structures. We conducted 1H solution NMR and UV-visible spectral analysis to characterize the structural feature of a water-soluble, synthetic porphyrin i.e. tetrakis (p-sulfonatophenyl) porphyrin, TPPS4, and its interaction with different metal ions in aqueous solutions. The results indicate that tetrapyrrole and tetraphenyl rings in TPPS4 molecule form a co-planar electron conjugation system; transition-metal ions show stronger binding capacity than alkali and alkali-earth metal ions; the relative stabilities of TPPS4-metal ion complexes can be well assessed by NMR and UV-visible spectral data.
RESUMO
A series of 4-alkynyloxy phenyl sulfanyl, sulfinyl and sulfony alkyl and piperidine-4-carboxylic acid hydroxamides were synthesized. Their structure-activity relationships, against tumor necrosis factor-alpha (TACE) and matrix metalloproteinase (MMP) inhibitor activities, are presented by investigating the oxidation state on sulfur and altering the P1' substituent. The sulfonyl derivatives 20-24 carrying a 4-butynyloxy moiety were selective TACE inhibitors over the MMPs tested. The sulfinyl derivatives showed a preference for a specific oxidation on sulfur as in compounds 25-28. The selectivity over MMPs was also demonstrated in the sulfonyl series. The enhanced cellular activity was achieved upon incorporating a butynyloxy substituent in the piperidene series. Compounds 64 and 65 were potent inhibitors of TNF-alpha release in the mouse at 100 mg/kg po.
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Sulfetos/síntese química , Sulfonas/síntese química , Sulfóxidos/síntese química , Proteínas ADAM , Proteína ADAM17 , Animais , Cristalografia por Raios X , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Técnicas In Vitro , Camundongos , Modelos Moleculares , Estrutura Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Oxirredução , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Relação Estrutura-Atividade , Sulfetos/química , Sulfetos/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Sulfóxidos/química , Sulfóxidos/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and alpha(2)-macroglobulins. Overexpression of these enzymes has been implicated in various pathological disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis. Developing effective small-molecule inhibitors to modulate MMP activity is one approach to treat these degenerative diseases. The present work focuses on the discovery and SAR of novel N-hydroxy-alpha-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/síntese química , Sulfonas/síntese química , Proteínas ADAM , Proteína ADAM17 , Administração Oral , Animais , Bioensaio , Cartilagem/efeitos dos fármacos , Cartilagem/enzimologia , Bovinos , Diálise , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Metaloproteinase 13 da Matriz , Metaloendopeptidases/antagonistas & inibidores , Camundongos , Osteoartrite/tratamento farmacológico , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologiaRESUMO
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.