RESUMO
A series of novel bichalcone analogs were synthesized and evaluated in lipopolysaccharide (LPS)-activated microglial cells as inhibitors of nitric oxide (NO) and for in vitro anticancer activity using a limited panel of four human cancer cell lines. All analogs inhibited NO production. Compounds 4 and 11 exhibited optimal activity with IC(50) values of 0.3 and 0.5 µM, respectively, and were at least 38-fold better than the positive control. A mechanism of action study showed that both compounds significantly blocked the nuclear translocation of NF-κB p65 and up-regulation of iNOS at 1.0 µM. Compound 4 and three other analogs (3, 20, and 23) exerted significant in vitro anticancer activity GI(50) values ranging from 0.70 to 13.10 µM. A mode of action study using HT-29 colon cancer cells showed that 23 acts by inducing apoptosis signaling.
Assuntos
Antineoplásicos/química , Apoptose , Chalconas/química , Piridinas/química , Fator de Transcrição RelA/antagonistas & inibidores , Receptor fas/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Piridinas/síntese química , Piridinas/toxicidade , Fator de Transcrição RelA/metabolismoRESUMO
Some chalcones exert potent anti-inflammatory activities. Mannich bases of heterocyclic chalcones inhibited nitric oxide (NO) production in lipopolysaccharide and interferon-γ stimulated RAW 264.7 macrophages. Also Formyl-Met-Leu-Phe and cytochalasin B induced superoxide anion generation (O2·-) and elastase release in human neutrophils. Mannich bases of heterocyclic chalcone analogs exhibited potent inhibitory effects on NO production with IC(50) values ranges between 10.5 and 0.018 µM, O2·- generation (IC(50) 39.87-0.68 µM) and elastase release (IC(50) 39.74-0.95 µM). Compound 29 (IC(50) 0.055 µM) and 34 (IC(50) 0.018 µM) were showed excellent inhibition on NO production. On the other hand, compounds 2 and 8 showed potent inhibition on O2·- generation and elastase release. Therefore, these four compounds may be new leads for development of anti-inflammatory activities. The structure-activity relationships are also discussed.
Assuntos
Chalconas/farmacologia , Macrófagos/metabolismo , Neutrófilos/metabolismo , Óxido Nítrico/biossíntese , Elastase Pancreática/metabolismo , Superóxidos/metabolismo , Animais , Anti-Inflamatórios , Chalconas/química , Compostos Heterocíclicos , Humanos , Ativação de Macrófagos , Camundongos , Relação Estrutura-AtividadeRESUMO
The chalcone skeleton (1,3-diphenyl-2-propen-1-one) is a unique template that is associated with various biological activities. We synthesized Mannich bases of heterocyclic chalcones (9-47) using a one-step Claisen-Schmidt condensation of heterocyclic aldehydes with Mannich bases of acetophenones, and tested the target compounds for cytotoxicity against three human cancer cell lines (prostate, PC-3; breast, MCF-7; nasopharynx, KB) and a multi-drug resistant subline (KB-VIN). Out of the 39 chalcones synthesized, 31 compounds showed potent activity against at least one cell line with IC(50) values ranging from 0.03 to 3.80 microg/mL. Structure-activity relationships (SAR) are also discussed.