RESUMO
A several series of low molecular weight 5-HT(2A) leads were identified from an analysis of HTS data, the exploration of SAR and optimization of one series using parallel synthesis are described, affording compound 22 (5-HT(2A) IC(50) 1.1 nM).
Assuntos
Azepinas/química , Azepinas/metabolismo , Hidrogênio/química , Receptor 5-HT2A de Serotonina/metabolismo , Aminação , Azepinas/síntese química , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The chemokine receptor, CCR2, is predominantly expressed on monocytes/macrophages, and on a subset of memory T cells. It binds to several CC type chemokines of the monocyte chemoattractant protein (MCP) family of which MCP-1 exhibits the highest affinity. CCR2/MCP-1 expression/association in monocyte/macrophage/T cells has been associated with inflammatory processes such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. Neutralization of CCR2 with either a peptide or receptor antagonist results in the prevention of joint swelling in rodent models of arthritis. In this paper, bioassay-guided discovery of CCR2 receptor antagonists derived from natural product extracts are reported. These antagonists belong to two main classes exemplified by bisthiodiketopiperazines and cytochalasins. Six compounds, including emestrin, two new emestrin analogs, and chaetomin represent the first group of compounds. These compounds inhibited the binding of MCP-1 to CCR2 (CHO membrane) with IC50 values of 0.8 to 9 microM and exhibited good activity in a whole cell assay using MCP-1 and human monocytes with IC50's ranging from 4-9 microM. Cytochalasins A and B represented the second group and inhibited the binding activity with IC50 values of 5 and 188 microM, respectively. This is the first report of natural product antagonists of the CCR2 receptor.
Assuntos
Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Fungos/química , Receptores de Quimiocinas/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/química , Membrana Celular/metabolismo , Células Cultivadas , Quimiocina CCL2/metabolismo , Citocalasinas/química , Citocalasinas/isolamento & purificação , Citocalasinas/farmacologia , Dissulfetos/química , Dissulfetos/isolamento & purificação , Dissulfetos/farmacologia , Fungos/metabolismo , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Estrutura Molecular , Monócitos/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Piperazinas/química , Piperazinas/isolamento & purificação , Piperazinas/farmacologia , Receptores CCR2 , Receptores de Quimiocinas/metabolismoRESUMO
Extracts from 44 species of seaweed from Gran Canaria (Canary Islands, Spain) were screened for the production of antibacterial and antifungal compounds against a panel of gram-negative and gram-positive bacteria, mycobacteria, yeasts and fungi. A total of 28 species displayed antibacterial activity, of which six also showed antifungal activity. Asparagopsis taxiformis and Cymopolia barbata were the species with the strongest activities against the broadest spectrum of target microorganisms. All the species with antibacterial activity were active against gram-positive bacteria, whereas only two species, A. taxiformis and Osmundea hybrida, were active against mycobacteria. The production of secondary metabolites with antimicrobial activities by the macroalgae was also studied under different conditions, although no common trend for bioactivity was observed (AU)
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