RESUMEN
Tsitsikammamines are marine alkaloids whose structure is based on the pyrroloiminoquinone scaffold. These and related compounds have attracted attention due to various interesting biological properties, including cytotoxicity, topoisomerase inhibition, antimicrobial, antifungal and antimalarial activity. Indoleamine 2,3-dioxygenase (IDO1) is a well-established therapeutic target as an important factor in the tumor immune evasion mechanism. In this preliminary communication, we report the inhibitory activity of tsitsikammamine derivatives against IDO1. Tsitsikammamine A analogue 11b displays submicromolar potency in an enzymatic assay. A number of derivatives are also active in a cellular assay while showing little or no activity towards tryptophan 2,3-dioxygenase (TDO), a functionally related enzyme. This IDO1 inhibitory activity is rationalized by molecular modeling studies. An interest is thus established in this class of compounds as a potential source of lead compounds for the development of new pharmaceutically useful IDO1 inhibitors.
Asunto(s)
Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Pirroles/química , Quinolinas/química , Alcaloides/síntesis química , Alcaloides/química , Alcaloides/toxicidad , Sitios de Unión , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Pirroles/síntesis química , Pirroles/toxicidad , Quinolinas/síntesis química , Quinolinas/toxicidad , Relación Estructura-ActividadRESUMEN
Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC(50) values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results.
Asunto(s)
Etano/química , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indoles/química , Indoles/farmacología , Dominio Catalítico , Línea Celular , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Modelos Moleculares , Dominios y Motivos de Interacción de Proteínas , Relación Estructura-ActividadRESUMEN
Indoleamine 2,3-dioxygenase (IDO) is an important new therapeutic target for the treatment of cancer. With the aim of discovering novel IDO inhibitors, a virtual screen was undertaken and led to the discovery of the keto-indole derivative 1a endowed with an inhibitory potency in the micromolar range. Detailed kinetics were performed and revealed an uncompetitive inhibition profile. Preliminary SARs were drawn in this series and corroborated the putative binding orientation as suggested by docking.