RESUMEN
A small library of antiplasmodial methoxy-thiazinoquinones, rationally designed on the model of the previously identified hit 1, has been prepared by a simple and inexpensive procedure. The synthetic derivatives have been subjected to in vitro pharmacological screening, including antiplasmodial and toxicity assays. These studies afforded a new lead candidate, compound 9, endowed with higher antiplasmodial potency compared to 1, a good selectivity index when tested against a panel of mammalian cells, no toxicity against RBCs, a synergistic antiplasmodial action in combination with dihydroartemisinin, and a promising inhibitory activity on stage V gametocyte growth. Computational studies provided useful insights into the structural requirements needed for the antiplasmodial activity of thiazinoquinone compounds and on their putative mechanism of action.
Asunto(s)
Antimaláricos/farmacología , Quinonas/farmacología , Tiazinas/farmacología , Animales , Antimaláricos/síntesis química , Antimaláricos/toxicidad , Artemisininas/farmacología , Línea Celular Tumoral , Células Cultivadas , Teoría Funcional de la Densidad , Sinergismo Farmacológico , Eritrocitos/efectos de los fármacos , Humanos , Ratones Endogámicos C57BL , Modelos Químicos , Simulación de Dinámica Molecular , Estructura Molecular , Plasmodium falciparum/efectos de los fármacos , Quinonas/síntesis química , Quinonas/toxicidad , Relación Estructura-Actividad , Tiazinas/síntesis química , Tiazinas/toxicidadRESUMEN
The full absolute configuration assignment of phosphoeleganin (1), a recently discovered marine-derived phosphorylated polyketide with protein tyrosine phosphatase 1B inhibitory activity, was achieved. It was based on the synthesis of model diasteroisomeric compounds of the C-8-C-12 segment portion of phosphoeleganin, chiral derivatization methods, and application of the universal NMR database concept.
Asunto(s)
Policétidos/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Bases de Datos Factuales , Biología Marina , Modelos Químicos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Policétidos/síntesis química , Policétidos/farmacología , EstereoisomerismoRESUMEN
The electrochemical response of four natural cytotoxic thiazinoquinones isolated from the Aplidium species was studied using conventional solution-phase and solid-state techniques, based on the voltammetry of immobilized particles methodology. The interaction with O2 and electrochemically generated reactive oxygen species (ROS) was electrochemically monitored. At the same time, a molecular modeling study including density functional theory (DFT) calculations was performed in order to analyze the conformational and electronic properties of the natural thiazinoquinones, as well as those of their reduced intermediates. The obtained electrochemical and computational results were analyzed and correlated to cytotoxic activity of these compounds, highlighting some features possibly related to their mechanism of action.
Asunto(s)
Organismos Acuáticos , Quinonas/química , Especies Reactivas de Oxígeno/química , Urocordados , Animales , ElectroquímicaRESUMEN
A new sulfated sterol, phallusiasterol C (1), has been isolated from the Mediterranean ascidian Phallusia fumigata and its structure has been determined on the basis of extensive spectroscopic (mainly 2D NMR) analysis. The possible role in regulating the pregnane X receptor (PXR) activity of phallusiasterol C has been investigated; although the new sterol resulted inactive, this study adds more items to the knowledge of the structure-PXR regulating activity relationships in the case of sulfated steroids.
Asunto(s)
Esteroides/química , Urocordados/química , Animales , Línea Celular Tumoral , Células Hep G2 , Humanos , Espectroscopía de Resonancia Magnética/métodos , Receptor X de Pregnano , Receptores de Esteroides/metabolismo , Esteroides/farmacología , Esteroles/química , Esteroles/farmacologíaRESUMEN
The present review describes research on novel natural antitumor alkaloids isolated from marine invertebrates. The structure, origin, and confirmed cytotoxic activity of more than 130 novel alkaloids belonging to several structural families (indoles, pyrroles, pyrazines, quinolines, and pyridoacridines), together with some of their synthetic analogs, are illustrated. Recent discoveries concerning the current state of the potential and/or development of some of them as new drugs, as well as the current knowledge regarding their modes of action, are also summarized. A special emphasis is given to the role of marine invertebrate alkaloids as an important source of leads for anticancer drug discovery.