RESUMEN
A group of 4-(benzyloxy)-1-phenylbut-2-yn-1-ol derivatives were designed using Site point connection method, synthesized and evaluated for their 5-Lipoxygenase (5-LOX) inhibitory activity. Hydrophobic site points in 5-LOX were considered for the study and substitutions were planned such that 4k will have strong hydrophobic group in the corresponding site point. Biological results supported the in silico prediction with compound 4k exhibiting good inhibition with IC(50) value of 8 µM against 5-LOX. The compounds 4j and 4k showed potent cytotoxic effects against various cancer cell lines (COLO-205, MDA-MB-231 and HepG2) but with no effect on normal cell line (HaCaT). The overall trend showed 4k as the most potent compound. Further studies demonstrated the protective effect of 4k in mouse Acute Lung Injury (ALI) model induced by lipopolysaccharide (LPS).
Asunto(s)
Araquidonato 5-Lipooxigenasa/metabolismo , Compuestos de Bencilo/química , Compuestos de Bencilo/farmacología , Butanoles/química , Butanoles/farmacología , Diseño de Fármacos , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/prevención & control , Animales , Araquidonato 5-Lipooxigenasa/química , Compuestos de Bencilo/síntesis química , Butanoles/síntesis química , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Lipopolisacáridos/farmacología , Inhibidores de la Lipooxigenasa/síntesis química , Ratones , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Ten novel mono- and di-O-prenylated chalcone derivatives were designed on the basis of a homology derived molecular model of 5-lipoxygenase (5-LOX). The compounds were docked into 5-LOX active site and the binding characteristics were quantified using LUDI. To verify our theoretical assumption, the molecules were synthesized and tested for their 5-LOX inhibitory activities. The synthesis was carried out by Claisen-Schmidt condensation reaction of mono- and di-O-prenylated acetophenones with appropriate aldehydes. 5-LOX in vitro inhibition assay showed higher potency of di-O-prenylated chalcones than their mono-O-prenylated chalcone analogs. Compound 5e exhibited good inhibition with an IC(50) at 4 microM. The overall trend for the binding energies calculated and LUDI score was in good qualitative agreement with the experimental data. Further, the compound 5e showed potent anti-proliferative effects (GI(50) at 9 microM) on breast cancer cell line, MCF-7.
Asunto(s)
Araquidonato 5-Lipooxigenasa/metabolismo , Proliferación Celular/efectos de los fármacos , Chalconas/química , Chalconas/farmacología , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacología , Araquidonato 5-Lipooxigenasa/química , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Chalconas/síntesis química , Neoplasias del Colon/tratamiento farmacológico , Humanos , Inhibidores de la Lipooxigenasa/síntesis química , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Two flavonoids, (2S)-5,7,3',4'-tetramethoxyflavanone (1) and 5,7,2',5'-tetramethoxyflavone (2) together with three known flavonoids, 7-O-methylwogonin (3), skullcapflavone I (4) and 5-hydroxy-7,2'-dimethoxyflavone (5) were isolated from the whole plant of Limnophila indica. The structures of compounds 1-5 were elucidated on the basis of spectral and chemical studies.
