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Article

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

1
Unidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
2
Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), 28006 Madrid, Spain
3
Instituto Teófilo Hernando y Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas ‘Alberto Sols’ UAM-CSIC, Universidad Autónoma de Madrid, 28029 Madrid, Spain
4
Departamento de Farmacología, Farmacognosia y Botánica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Academic Editor: Domenico Nuzzo
Antioxidants 2022, 11(1), 28; https://doi.org/10.3390/antiox11010028
Received: 21 November 2021 / Revised: 17 December 2021 / Accepted: 21 December 2021 / Published: 24 December 2021
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. View Full-Text
Keywords: oxidative stress; Tau aggregation; neuroinflammation; neuroprotection oxidative stress; Tau aggregation; neuroinflammation; neuroprotection
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MDPI and ACS Style

Cores, Á.; Carmona-Zafra, N.; Martín-Cámara, O.; Sánchez, J.D.; Duarte, P.; Villacampa, M.; Bermejo-Bescós, P.; Martín-Aragón, S.; León, R.; Menéndez, J.C. Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation. Antioxidants 2022, 11, 28. https://doi.org/10.3390/antiox11010028

AMA Style

Cores Á, Carmona-Zafra N, Martín-Cámara O, Sánchez JD, Duarte P, Villacampa M, Bermejo-Bescós P, Martín-Aragón S, León R, Menéndez JC. Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation. Antioxidants. 2022; 11(1):28. https://doi.org/10.3390/antiox11010028

Chicago/Turabian Style

Cores, Ángel, Noelia Carmona-Zafra, Olmo Martín-Cámara, Juan D. Sánchez, Pablo Duarte, Mercedes Villacampa, Paloma Bermejo-Bescós, Sagrario Martín-Aragón, Rafael León, and J. C. Menéndez. 2022. "Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation" Antioxidants 11, no. 1: 28. https://doi.org/10.3390/antiox11010028

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