RESUMEN
3-(3-Pyridyl)-2-hydroxy-2-phosphonopropanoic acid (3-PEHPC, 1) is a phosphonocarboxylate (PC) analogue of 2-(3-pyridyl)-1-hydroxyethylidenebis(phosphonic acid) (risedronic acid, 2), an osteoporosis drug that decreases bone resorption by inhibiting farnesyl pyrophosphate synthase (FPPS) in osteoclasts, preventing protein prenylation. 1 has lower bone affinity than 2 and weakly inhibits Rab geranylgeranyl transferase (RGGT), selectively preventing prenylation of Rab GTPases. We report here the synthesis and biological studies of 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid (3-IPEHPC, 3), the PC analogue of minodronic acid 4. Like 1, 3 selectively inhibited Rab11 vs. Rap 1A prenylation in J774 cells, and decreased cell viability, but was 33-60x more active in these assays. After resolving 3 by chiral HPLC (>98% ee), we found that (+)-3-E1 was much more potent than (-)-3-E2 in an isolated RGGT inhibition assay, approximately 17x more potent (LED 3 microM) than (-)-3-E2 in inhibiting Rab prenylation in J774 cells and >26x more active in the cell viability assay. The enantiomers of 1 exhibited a 4-fold or smaller potency difference in the RGGT and prenylation inhibition assays.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Lactatos/farmacología , Organofosfonatos/farmacología , Compuestos Organofosforados/farmacología , Conservadores de la Densidad Ósea/síntesis química , Conservadores de la Densidad Ósea/farmacología , Resorción Ósea/tratamiento farmacológico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Ácido Etidrónico/análogos & derivados , Ácido Etidrónico/farmacología , Ácido Etidrónico/uso terapéutico , Humanos , Lactatos/síntesis química , Lactatos/uso terapéutico , Organofosfonatos/síntesis química , Organofosfonatos/uso terapéutico , Compuestos Organofosforados/síntesis química , Compuestos Organofosforados/uso terapéutico , Osteoporosis/tratamiento farmacológico , Prenilación de Proteína/efectos de los fármacos , Ácido Risedrónico , Estereoisomerismo , Proteínas de Unión al GTP rabRESUMEN
A new tripod molecule containing an aromatic core bearing three peracetylated cyclodextrins was synthesized via a microwave-assisted Huisgen 1,3-dipolar cycloaddition and was studied by fluorescence spectroscopy. The photoluminescent properties of complexation phenomena with different pesticides were evaluated in acetonitrile. Fluorescence titrations have been performed to calculate binding constants, sensitivity factors, and limit of detection of the resulting complexes. 2D NMR experiments confirmed the inclusion of pesticide in the hydrophobic cavity of the macrocycle and validated the supramolecular association responsible for the quenching of the fluorescence.