RESUMO
The 14-membered macrolide erythromycin A expresses three distinct biological properties, including antibacterial activity, gastrointestinal motor-stimulating activity and anti-inflammatory and/or immunomodulatory effects. Although low-dose, long-term therapy using 14- and 15-membered macrolides displaying anti-inflammatory and/or immunomodulatory activity effectively treats diffuse panbronchiolitis and chronic sinusitis, bacterial resistance may emerge. To address this issue, we developed the 12-membered non-antibiotic macrolide (8R,9S)-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM900) that promotes monocyte to macrophage differentiation, a marker for anti-inflammatory and/or immunomodulatory effects, without possessing antibacterial activity. In this article, we report that the new macrolide derivative (8R,9S) -de(3'-N-methyl)-3'-N-(p-chlorobenzyl)-de(3-O-cladinosyl)-3-dehydro-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A 12,13-carbonate (EM939) exhibited stronger promotive activity for monocyte to macrophage differentiation than that of the parent compound EM900 in addition to reduced cytotoxicity toward THP-1 cells and antibacterial inactivity. In a cigarette-smoking model used to simulate chronic obstructive pulmonary disease (COPD), the EM900 derivatives significantly attenuated lung and alveolar inflations, functionally and histologically, via oral administration. Because of these marked therapeutic effects, non-antibiotic EM900 derivatives may become central to the treatment of chronic inflammatory diseases such as COPD.
Assuntos
Anti-Inflamatórios/farmacologia , Macrolídeos/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Eritromicina/análogos & derivados , Eritromicina/química , Eritromicina/farmacologia , Eritromicina/uso terapêutico , Cobaias , Pulmão/patologia , Macrolídeos/síntese química , Macrolídeos/uso terapêutico , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Testes de Sensibilidade Microbiana , Monócitos/efeitos dos fármacos , Monócitos/patologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Fumar/efeitos adversosAssuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Fatores Imunológicos/síntese química , Fatores Imunológicos/farmacologia , Macrolídeos/síntese química , Macrolídeos/farmacologia , Animais , Anti-Inflamatórios/química , Linhagem Celular Tumoral , Doença de Crohn/tratamento farmacológico , Relação Dose-Resposta a Droga , Humanos , Fatores Imunológicos/química , Macrolídeos/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Herein, we report the design and synthesis of the novel 12-membered non-antibiotic macrolide (8R,9S)-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM900), which was found to be a potent anti-inflammatory and/or immunomodulatory agent, capable of promoting monocyte to macrophage differentiation. This molecule shows improved acid stability, does not exhibit any anti-bacterial activity and has relatively low cytotoxicity against THP-1 cells. In addition, one of its analogues, (8R,9S)-4â³,13-O-diacetyl-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM911), was found to be twice as effective as EM900.