RESUMEN
In the present study we synthesized new methoxy derivatives of trans 2,3-diaryl-2,3-dihydrobenzofurans, starting from suitable trans 2,3-diaryloxiranes, using regio- and stereoselective nucleophilic oxiranyl ring-opening reactions. The compounds were tested as anti-inflammatories in U937 cells. All compounds showed a significant role in inhibiting the NF-κB pathway and were able to restore normal ROS and NO level upon LPS activation. Moreover, regarding inhibition of ACLY, enantioenriched (50% ee) 7a50 showed more potency than the racemic counterpart 7arac, together with a higher reduction of prostaglandin E2 production, thus suggesting a stereoselective interaction in this pathway.
Asunto(s)
Antiinflamatorios/farmacología , Benzofuranos/farmacología , ATP Citrato (pro-S)-Liasa/antagonistas & inhibidores , Antiinflamatorios/síntesis química , Benzofuranos/síntesis química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Estructura Molecular , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Transcripción ReIA/metabolismo , Células U937RESUMEN
Myricanol 1, a constituent of Myrica species, has been reported to lower the levels of the microtubule-associated protein tau (MAPT), whose accumulation plays an important role in some neurodegenerative diseases, such as Alzheimer's disease (AD). Herein we described a new synthetic route to prepare myricanol in 9 steps and 4.9% overall yield starting from commercially available 2,3-dimethoxyphenol and methyl 3-(4-benzyloxyphenyl)propanoate. The key steps are a cross-metathesis to obtain a linear diarylheptanoid intermediate and a Suzuki-Miyaura domino reaction to generate the challenging macrocycle.
RESUMEN
New heteroaryl HIV-protease inhibitors bearing a carboxyamide spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core modifying the type of heteroarene and the central core, with the presence of either H or benzyl group. Their in vitro inhibition activity against recombinant protease showed a general beneficial effect of carboxyamide moiety, the IC50 values ranging between 1 and 15nM. In particular benzofuryl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such benzofuryl derivatives in terms of number of interactions in the active site, supporting the experimental results on activity. The inhibition activity of such molecules has been also evaluated in HEK293 cells expressing the protease fused to green fluorescent protein, by western blotting analysis, fluorescence microscopy and cytofluorimetry.
Asunto(s)
Amidas/química , Inhibidores de la Proteasa del VIH/síntesis química , Proteasa del VIH/metabolismo , Amidas/síntesis química , Amidas/farmacología , Sitios de Unión , Supervivencia Celular/efectos de los fármacos , Células HEK293 , VIH/efectos de los fármacos , VIH/enzimología , Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , Humanos , Concentración 50 Inhibidora , Microscopía Fluorescente , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Relación Estructura-Actividad , TransfecciónRESUMEN
New structurally simple indolic non peptidic HIV Protease inhibitors were synthesized from (S)-glycidol by regioselective methods. Following the concept of targeting the protein backbone, different substitution patterns were introduced onto the common stereodefined isopropanolamine core modifying the type of functional group on the indole, the position of the functional group on the indole and the type of the nitrogen containing group (sulfonamides or perhydroisoquinoline), alternatively. The systematic study on in vitro inhibition activity of such compounds confirmed the general beneficial effect of the 5-indolyl substituents in presence of arylsulfonamide moieties, which furnished activities in the micromolar range. Preliminary docking analysis allowed to identify several key features of the binding mode of such compounds to the protease.