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

Abstract

Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer’s disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as curcumin analogues and incorporating the key structural fragment of piperlongumine, a natural neuroinflammation inhibitor, were synthesized by a two-step route that combines a three-component reaction between primary amines, β-ketoesters and α-haloesters and a base-promoted acylation with cinnamoyl chlorides. These compounds were predicted to have good oral absorption and CNS permeation, had good scavenging properties in the in vitro DPPH experiment and in a cellular assay based on the oxidation of dichlorofluorescin to a fluorescent species. The compounds showed low toxicity in two cellular models, were potent inductors of the Nrf2-ARE phase II antioxidant response, inhibited PHF6 peptide aggregation, closely related to Tau protein aggregation and were active against the LPS-induced inflammatory response. They also afforded neuroprotection against an oxidative insult induced by inhibition of the mitochondrial respiratory chain with the rotenone-oligomycin A combination and against Tau hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. This multitarget pharmacological profile is highly promising in the development of treatments for AD and provides a good hit structure for future optimization efforts.

Curcumin-Piperlongumine Hybrid Molecule Increases Cell Cycle Arrest and Apoptosis in Lung Cancer through JNK/c-Jun Signaling Pathway

“…Cores et al aimed to develop curcumin analogues with a heterocyclic core to enhance stability while retaining the pharmacological profile of curcumin. However, the length and conformation of the new curcumin-piperlongumine hybrids differ significantly from those of curcumin, suggesting that their pharmacological activity and mechanism may also differ …”

“…However, the length and conformation of the new curcumin-piperlongumine hybrids differ significantly from those of curcumin, suggesting that their pharmacological activity and mechanism may also differ. 30 The chemical stability of curcumin, piperlongumine, and CP was detected and measured by UV/vis absorption in phosphate buffer (pH 7.4). As shown in Figure S1, curcumin displayed an intense optical absorption region with an absorption at maximum of close to 425 nm.…”

Integrating a quinone substructure into histone deacetylase inhibitors to cope with Alzheimer's disease and cancer

“…Obtained 0.093 g (75% yield). 1 (12). To a solution of acid 9 (1.20 g, 4.80 mmol) in anhydrous DMF (10 ml) under a stream of nitrogen, IBCF (0.68 ml, 0.716 g, 5.26 mmol) and NMM (0.58 ml, 0.533 g, 5.26 mmol) were added and the mixture was stirred at 0 °C for 30 min.…”

“…In an intriguing and similar manner, quinone-based molecules have been proven to exert beneficial effects as both antiproliferative 10,11 and neuroprotective agents. 12 Quinones have traditionally represented a major source of anticancer compounds. These agents are unique among cancer therapeutics because of their capability to generate toxic free radical species following catalyzed bioreduction of the quinone moiety.…”

“…More recently, quinone-based compounds have shown interesting activities also in the context of neurodegenerative diseases (NDs). 12 For instance, Bolognesi and coworkers reported that quinone-based compounds (e.g., memoquin in Fig. 1), being reduced to hydroquinones, can act as radical scavengers and exhibit neuroprotective effects.…”