Aza‐CGP37157‐lipoic hybrids designed as novel Nrf2‐inducers and antioxidants exert neuroprotection against oxidative stress and show neuroinflammation inhibitory properties

Abstract

Two multitarget hybrids, derived from an aza-analogue of CGP37157, a mitochondrial Na + /Ca 2+ exchanger antagonist, and lipoic acid were designed in order to combine in a single molecule the antioxidant and Nrf2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The hybrid derivatives showed Nrf2 induction and radical scavenging properties, leading to a good neuroprotective profile against oxidative stress, together with an interesting antineuroinflammatory activity.The results obtained show differences in activity depending on the configuration of the chiral center of LA. K E Y W O R D Santi-inflammatory activity, neuroprotection, Nrf2 induction, radical scavenging

Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease

“…As previously reported, derivatives CGP37157, rac- 3a and ( rac,R )-3b demonstrated NRF2 induction activity at the micromolar range. More importantly, both compounds showed interesting differences depending on the configuration of chiral carbon at LA [ 19 ]. NRF2 has been associated with the LA moiety that has previously demonstrated a capacity to activate the phase II antioxidant response [ 38 , 39 ], but at high concentrations [ 19 ].…”

“…More importantly, both compounds showed interesting differences depending on the configuration of chiral carbon at LA [ 19 ]. NRF2 has been associated with the LA moiety that has previously demonstrated a capacity to activate the phase II antioxidant response [ 38 , 39 ], but at high concentrations [ 19 ]. To evaluate the influence of both stereogenic centers in the NRF2 induction capacity of aza-CGP37157-LA hybrids, we used the AREc32 cell line model [ 26 ] by analyzing luciferase expression upon treatment with NRF2 inducers.…”

“…TBHQ was included as a positive control, and CGP37157, S - and R -LA, rac- 3a and ( rac,R )-3b and precursors derivatives ( R -6 and S -6 ) were included for comparative purposes. Previous results demonstrated an improved NRF2 induction capacity when racemic LA was exchanged by the R -LA moiety (CD = 14.8 ± 1.6 μM and CD = 9.8 ± 1.6 μM, respectively [ 19 ]). In line with these results, enantiopure derivatives 7a–d also showed interesting differences in activity depending on both chiral centers.…”

“…Based on its antioxidant profile, our group synthesized derivatives an aza-CGP37157–lipoic acid hybrid ( Figure 1 ) that showed a promising profile as a neuroprotective agent due to the induction of NRF2 and antioxidant activity [ 19 ]. However, the study of these compounds had an important limitation: they were studied as racemic mixtures, since it was not possible to obtain the aza-CGP-37157 derivative in the form of a single enantiomer.…”

Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation

“…As demonstrated by our previously described studies, compounds 2a – f exert antioxidant capacity, reduce ROS production in cells and induce Nrf2, a combination of activities that should prevent neuronal damage caused by high oxidative stress. Therefore, we set out to evaluate the potential neuroprotective properties of the curcumin/piperlongumine hybrids 2a – f in a model of oxidative stress produced by mitochondrial toxicity, namely the rotenone-oligomycin A (R/O) toxic combination [ 78 , 79 , 80 ]. This combination inhibits complexes I and V of the mitochondrial respiratory chain, increasing the concentration of free radical species in the cytoplasm and inducing cellular death.…”