RESUMO
BACKGROUND/AIM: Indoleamine 2,3-dioxygenase (IDO) is regarded as an important molecular target for cancer immune therapy. This study aimed to examine the IDO1 inhibitory activity of newly synthesized indomethacin derivatives to develop an IDO1 inhibitor. MATERIALS AND METHODS: The inhibitory effects of indole-containing compounds against recombinant human IDO1 (rhIDO1) were evaluated. RESULTS: While some drugs including those with an indole scaffold could inhibit rhIDO1, simple indole compounds were inactive. A total of 27 indomethacin derivatives, including 18 newly synthesized derivatives, were evaluated. Numerous derivatives showed enhanced IDO1 inhibitory activity. The functional group at the 3-position had a strong effect on IDO1 inhibitory activity. The IDO1 inhibitory activity was not directly correlated with tumor cell cytotoxicity. CONCLUSION: We report the finding of novel IDO1 inhibitors and the structure-activity relationship based on indomethacin derivatives. Our findings will be beneficial for the development of IDO1 inhibitors for cancer immune therapy.
Assuntos
Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indometacina/farmacologia , Relação Estrutura-Atividade , Biocatálise/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indometacina/química , Espectroscopia de Ressonância Magnética/métodos , Estrutura MolecularRESUMO
We designed and synthesized conformationally restricted analogues and regioisomers of the nonsteroidal anti-inflammatory drug indomethacin. Evaluation of the inhibitory effects of these compounds on COX, P-glycoprotein, and multidrug resistance indicated that NSAIDS modulation of multidrug-resistant P-glycoprotein and multidrug-resistant protein-1 is not associated with COX-1 and COX-2 inhibitory activities.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Desenho de Fármacos , Indometacina/síntese química , Indometacina/farmacologia , Anti-Inflamatórios não Esteroides/química , Linhagem Celular Tumoral , Técnicas de Química Sintética , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Indometacina/análogos & derivados , Indometacina/química , Modelos Moleculares , Conformação Molecular , Prostaglandina-Endoperóxido Sintases/metabolismoRESUMO
Conformationally restricted indomethacin analogues were designed and prepared from the corresponding 2-substituted indoles, which were synthesized by a one-pot isomerization/enamide-ene metathesis as the key reaction. Conformational analysis by calculations, NMR studies, and X-ray crystallography suggested that these analogues were conformationally restricted in the s-cis or the s-trans form due to the 2-substituent as expected. Their biological activities on cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, and modulation of MRP-1-mediated multidrug resistance (MDR) are described. Some of these indomethacin analogues enhanced doxorubicin cytotoxicity, although they do not have any COX inhibitory activity, which suggests that the MDR-modulating effect of an NSAID can be unassociated with its COX-inhibitory activity. This may be an entry into the combination chemotherapy of doxorubicin with a MDR modulator.
