RESUMO
A series of O-substituted analogues of the B,C-ring truncated scaffold of deguelin were designed as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antiproliferative agents against HER2-positive breast cancer. Among the synthesized compounds, compound 80 exhibited significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells, whereas compound 80 did not show any cytotoxicity in normal cells. Compound 80 markedly downregulated the expression of the major client proteins of HSP90 in both cell types, indicating that the cytotoxicity of 80 in breast cancer cells is attributed to the destabilization and inactivation of HSP90 client proteins and that HSP90 inhibition represents a promising strategy to overcome trastuzumab resistance. A molecular docking study of 80 with the homology model of a HSP90 homodimer showed that 80 fit nicely in the C-terminal domain with a higher electrostatic complementary score than that of ATP.
Assuntos
Antineoplásicos/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Rotenona/análogos & derivados , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Simulação de Acoplamento Molecular , Rotenona/química , Rotenona/metabolismo , Rotenona/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of indane-type acetamide and propanamide analogues were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that indane A-region analogues exhibited better antagonism than did the corresponding 2,3-dihydrobenzofuran and 1,3-benzodioxole surrogates. Among them, antagonist 36 exhibited potent and selective antagonism toward capsaicin for hTRPV1 and mTRPV1. Further, in vivo studies indicated that antagonist 36 showed excellent analgesic activity in both phases of the formalin mouse pain model and inhibited the pain behavior completely at a dose of 1 mg/kg in the 2nd phase.
Assuntos
Amidas/química , Indanos/química , Canais de Cátion TRPV/antagonistas & inibidores , Acetamidas/química , Acetamidas/metabolismo , Acetamidas/uso terapêutico , Amidas/metabolismo , Amidas/uso terapêutico , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Capsaicina/química , Capsaicina/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Piridinas/química , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
Paradoxically, some TRPV1 agonists are, at the organismal level, both nonpungent and clinically useful as topical analgesics. Here, we describe the scaled-up synthesis and characterization in mouse models of a novel, nonpungent vanilloid. Potent analgesic activity was observed in models of neuropathic pain, and the compound blocked capsaicin induced allodynia, showing dermal accumulation with little transdermal absorption. Finally, it displayed much weaker systemic toxicity compared to capsaicin and was negative in assays of genotoxicity.