Person:
León Martínez, Rafael

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First Name
Rafael
Last Name
León Martínez
URI
https://hdl.handle.net/20.500.14352/77525
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Química en Ciencias Farmacéuticas
Area
Química Orgánica
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2015 - 201912020 - 20212
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Now showing 1 - 3 of 3
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    New melatonin–cinnamate hybrids as multi-target drugs for neurodegenerative diseases: Nrf2-induction, antioxidant effect and neuroprotection
    (Future Medicinal Chemistry, 2015) Buendia, Izaskun; Navarro González De Mesa, Elisa; Michalska Dziama, Patrycja; Gameiro, Isabel; Egea, Javier; Abril, Sheila; López, Alicia; González-Lafuente, Laura; G. López, Manuela; León Martínez, Rafael
    Neurodegenerative diseases share many pathological pathways, such as abnormal protein aggregation, mitochondrial dysfunction, extensive oxidative stress and neuroinflammation. Cells have an intrinsic mechanism of protection, the Nrf2 transcriptional factor, known as the master regulator of redox homeostasis. Results: Based on the common features of these diseases we have designed a multi-target hybrid structure derived from melatonin and ethyl cinnamate. The obtained derivatives were Nrf2 inducers and potent-free radical scavengers. These new compounds showed a very interesting neuroprotective profile in several in vitro models of oxidative stress, Alzheimer's disease and brain ischemia. Conclusion: We have designed a new hybrid structure with complementary activities. We have identified compound 5h as an interesting Nrf2 inducer, very potent antioxidant and neuroprotectant.
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    When It Comes to an End: Oxidative Stress Crosstalk with Protein Aggregation and Neuroinflammation Induce Neurodegeneration
    (Antioxidants, 2020) Michalska Dziama, Patrycja; León Martínez, Rafael
    Neurodegenerative diseases are characterized by a progressive loss of neurons in the brain or spinal cord that leads to a loss of function of the affected areas. The lack of effective treatments and the ever-increasing life expectancy is raising the number of individuals affected, having a tremendous social and economic impact. The brain is particularly vulnerable to oxidative damage given the high energy demand, low levels of antioxidant defenses, and high levels of metal ions. Driven by age-related changes, neurodegeneration is characterized by increased oxidative stress leading to irreversible neuronal damage, followed by cell death. Nevertheless, neurodegenerative diseases are known as complex pathologies where several mechanisms drive neuronal death. Herein we discuss the interplay among oxidative stress, proteinopathy, and neuroinflammation at the early stages of neurodegenerative diseases. Finally, we discuss the use of the Nrf2-ARE pathway as a potential therapeutic strategy based on these molecular mechanisms to develop transformative medicines.
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    Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation
    (Antioxidants, 2021) Cores Esperón, Ángel; Carmona Zafra, Noelia; Martín Cámara, Olmo; Sánchez Cebrián, Juan Domingo; Duarte, Pablo; Villacampa Sanz, Mercedes; Bermejo Bescos, María De La Paloma; Martín-Aragón Álvarez, Sagrario; León Martínez, Rafael; Menéndez Ramos, José Carlos
    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.