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Caspase activation in NT2 cells induced by MPP + and Abeta 1-42 or Brefeldin A (BFA). (A) Effect of compounds A, B, C, DFP and dantrolene (DNT) on caspase 2-like activity (Ac-VDVAD-pNA cleavage) increase; (B) Effect of compounds A, B, C
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The neuroprotective action of a set of new hydroxypyridinone-based (3,4-HP) compounds (A, B and C), which are iron chelators extra-functionalized with a propargylamino group for potential MAO-B inhibition, was evaluated after cell treatment with MPP+ (an in vivo inducer of parkinsonism) and Abeta(1-40) and/or Abeta(1-42) peptides. Our results show...
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... it means that all these compounds are able to protect cells against MPP + and Brefeldin A induced caspase-2 activation. Similar results were observed relatively to caspase-4 activation ( Figure 2B). Cell exposure to MPP + , but not to Abeta 1-42 peptide, for 24 h, resulted in a significant increase in LEVD cleavage, which was remarkably reduced in combinatorial treatments with A or DFP, most effective compounds in prevention of caspase-4 activation. ...
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... since caspase-3 is an effector caspase in the apoptotic process, and to better characterize the neuroprotection mechanisms mediated by these compounds, we analysed the protective effect of these compounds against ER and mitochondria stressors (Brefeldin A, and MPP + , respectively) on caspase-3 activation. As shown in Figure 2C, when cells were co-treated with A and C compounds, the caspase-3 activation was decreased. ...
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... our findings demonstrating that compound A markedly decreased Abeta toxicity (Figure 1) and suppressed caspase-4 activation ( Figure 2B) can be explained taking into account its antioxidant ability and the presence of a piperazine moiety which exhibits some affinity for Cu (II), preventing further Abeta aggregation. Therefore, the probable copper chelating action could prevent Abeta induced toxicity, by reducing the possibility of generation of toxic-amyloid peptides, which can disrupt intraneuronal Ca 2+ levels, leading to ER perturbated Ca 2+ homeostasis and, subsequently, to ER associated caspases activation. ...
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... it is plausible that stress responses from ER involves transcriptional signalling, intracellular Ca 2+ mobilization, activation of apical caspases like, caspases-4 or -2, that may proceed with or without the contribution of mitochondrial- dependent apoptotic pathway (50). In this case, the results of the present study show that compounds A and C significantly reduced MPP + -induced caspases-2, -4 and -3 activation (Figure 2 A, B and C) in a similar way than dantrolene, an inhibitor of ryanodine receptors of ER. Dantrolene prevents Ca 2+ release from ER lumen to cytosol, and was used as a control for neuroprotection activity (Figure 2 A). ...
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... this case, the results of the present study show that compounds A and C significantly reduced MPP + -induced caspases-2, -4 and -3 activation (Figure 2 A, B and C) in a similar way than dantrolene, an inhibitor of ryanodine receptors of ER. Dantrolene prevents Ca 2+ release from ER lumen to cytosol, and was used as a control for neuroprotection activity (Figure 2 A). In addition, caspases-mediated apoptotic cell death inhibition was corroborated by the efficiency of these compounds on rescue cells from MPP + mediated cell death (Figure 3). ...
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Citations
... Arduino et al. prepared a series of DFP derivatives with propargylamino groups similar to the MAOI, rasagiline, to produce MAOI-MC-1 and MAOI-MC-2, which were tested in animal models of AD and PD ( Figure 34). 813 The authors employed 1-methyl-4-phenylpyridinium (MPP + ), a toxic molecule that interferes with mitochondrial oxidative phosphorylation, leading to ATP depletion and cell death. 814 MPP + causes death of dopaminergic neurons in PD models. ...
... 815 Although primarily a PD model, MPP + was combined with Aβ 40 or Aβ 42 to induce damage to human teratocarcinoma NT2 cells. 813 They found that MAOI-MC-1 and MAOI-MC-2 could protect NT2 cells from toxicity induced by MPP + and Aβ 42 . 813 Albeit slated as a MAOI, their MAO inhibitory properties was not experimentally tested nor was the metal binding abilities of MAOI-MC-1 and MAOI-MC-2 or their influence on metal-triggered Aβ aggregation. ...
... 813 They found that MAOI-MC-1 and MAOI-MC-2 could protect NT2 cells from toxicity induced by MPP + and Aβ 42 . 813 Albeit slated as a MAOI, their MAO inhibitory properties was not experimentally tested nor was the metal binding abilities of MAOI-MC-1 and MAOI-MC-2 or their influence on metal-triggered Aβ aggregation. MAOI-MC-3 ( Figure 34) was highlighted as a potent multifunctional agent with inhibitory activities against hMAO-A (IC 50 = 4.3 μM), hMAO-B (IC 50 = 2.6 μM), EeAChE (IC 50 = 3.7 μM), and eqBuChE (IC 50 = 2.8 μM). ...
Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a negative outlook. Although a large amount of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathological features shared across multiple neurodegenerative disorders. In addition, these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compounds capable of simultaneously interacting with several pathological components has been suggested as a solution to undertake the complex pathologies of neurodegenerative diseases. In this review, we outline and discuss possible therapeutic targets in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis and molecules, previously designed or discovered as potential drug candidates for these disorders with emphasis on multifunctionality. In addition, underrepresented areas of research are discussed to indicate new directions.
... Some derivatizations have been recently reported [5], namely with: tertbutylhydroxy toluene to increase the radical scavenging capacity [19,22]; N-propargylamine groups to inhibit MAO-B in the brain and its catalytic role in the oxidative deamination of important neurotransmitters (e.g. dopamine and serotonin) [23,24]. However, the most newly exploited mono-HP multi-functionalization for anti-neurodegenerative drugs has envisaged the inhibition of Aβ aggregation, as illustrated in Fig. (2). ...
Hydroxypyridinones (HPs) are a family of N-heterocyclic metal chelators, which have been an attractive target in the development of a variety of new pharmaceutical drugs, due to its high metal chelating efficacy/specificity and easy derivatization to tune the desired biological properties. In fact, along the last decades, hydroxypyridinone derivatives, but mostly 3-hydroxy-4-pyridinone (3,4-HP), have been intensively used in drug design, following either a multitarget approach, in which one chelating unity is extrafunctionalized (hybridized) to enable the interaction with other important specific biological sites, or a polydenticity approach, in which more than one chelating moiety is conveniently attached to one scaffold, to increase the metal chelating efficacy. This review represents an update of the most recent publications (2014-2016) in mono-HP hybrids, namely as potential anti-Alzheimer?s drugs, inhibitors of metalloenzymes and anti-microbials, and also polychelating compounds (poly-HP), in view of potential application, such as anti-microbial/biostatic agents, luminescent biosensors or diagnostic agents.
... The first orally active aminepropargylated Fe-chelator was based on a 8-hydroxyquinoline scaffold (M30, Figure 8) but several other analogues have been subsequently studied [149]. More recently, aminopropargylation of HPs (3,4-HPs) has been also reported ( Figure 9) [171]. These two pharmacophores were linked by spacers with different size and type to account for some differentiation in the lipophilicity and membrane crossing abilities, as well as for potential interaction with other biological targets (e.g., the piperazine segment). ...
Although iron is one of the most important metal ions for living organisms, it becomes toxic when in excess or misplaced. This review presents a glance at representative examples of hydroxypyridinone (HP) based chelators, which have been recently developed as potential clinically useful drugs for metal overload diseases, mostly associated to excess of iron but also other hard metal-ions. It also includes a detailed discussion on the factors assisting chelator design strategy towards fulfillment of the most relevant biochemical properties of HP chelators, highlighting structure–activity relationships and a variety of potential clinical applications, beyond chelatotherapy. This study appears as a response to the growing interest on metal chelation therapy and opens new perspectives of possible applications in future medicine.
... The first orally active aminepropargylated Fe-chelator was based on a 8-hydroxyquinoline scaffold (M30, Figure 8) but several other analogues have been subsequently studied [149]. More recently, aminopropargylation of HPs (3,4-HPs) has been also reported ( Figure 9) [171]. These two pharmacophores were linked by spacers with different size and type to account for some differentiation in the lipophilicity and membrane crossing abilities, as well as for potential interaction with other biological targets (e.g., the piperazine segment). ...
Although iron is one of the most important metal ions for living organisms, it becomes
toxic when in excess or misplaced. This review presents a glance at representative
examples of hydroxypyridinone-based chelators, which have been recently developed
as potential clinically useful drugs for metal overload diseases, mostly associated with
excess of iron but also other hard metal-ions. It also includes a detailed discussion on
the factors assisting chelator design strategy toward fulfillment of the most relevant
biochemical properties of hydroxypyridinone chelators, highlighting structure–activity
relationships and a variety of potential clinical applications, beyond chelatotherapy.
This study appears as a response to the growing interest on metal chelation therapy
and opens new perspectives of possible applications in future medicine.
... Fe, Al, actinídeos) do corpo humano ou fluidos corporais [5,7,24,25], ou ainda como agentes anti-microbianos (Fe) [26]. ção de formação da placa amiloide em pacientes com AD e o combate do stresse oxidativo (anti-oxidação) por sequestração de radicais livres [27][28][29]. Com esta estratégia espera-se obter fármacos multi-funcionais com reconhecidas vantagens sobre o uso de protocolos complexos com administração de vários fármacos mono-funcionais [31]. ...
Assim como a natureza usa metais em sistemas biológicos, também os químicos se aliaram à Medicina na descoberta de medicamentos cujo mecanismo de ação está associado a uma interação (coordenação) com iões metálicos, de que resultou a Química Inorgânica Medicinal. As suas aplicações dividem-se em duas classes principais: a dos fármacos como compostos orgânicos (ligandos) cuja ação resulta da sua coordenação com iões metálicos existentes no organismo, não ligados ou ligados a proteínas; a dos fármacos como complexos de metais (metalofármacos), cuja resposta clínica depende intrinsecamente do metal, e que são usados na terapia ou no diagnóstico de doenças. Serão aqui apresentados exemplos representativos destas duas classes de fármacos em uso clínico, seguido de uma referência genérica às suas propriedades mais relevantes. Por fim apresenta-se uma seleção de exemplos de resultados recentes em desenvolvimento.
... [9][10][11] However, the complexity of combined therapy protocols leads to the recent search for alternative therapeutic strategies based on multifunctional compounds. [12][13][14][15][16] Thus, following the same strategy, we have decided to develop new bifunctional compounds as drug candidates for anti-AD therapy, by conjugating, in the same compound, molecular fragments for both neurorestorative and neuroprotective roles, such as the inhibition of acetylcholinesterase (AChE) and the antioxidation. ...
... These include their AChE inhibitory and antioxidant activities, and the neuroprotective efficacy in 1-methyl-4-phenylpyridinium ion (MPP + ) and 42 residues-long β-amyloid peptides (Abeta 1-42 ) induced cell death, as mimics of Parkinson's disease (PD) and AD, respectively. 16 ...
Cited By (since 1996):3, Export Date: 18 October 2014
Hydroxypyridinones (HOPOs) are excellent class of chelators that have been gaining attention in the field of pharmaceutical drugs by their high chelating efficacy and specificity with different metal ions. Among all the metal ions, they exhibit a high binding affinity towards iron (III) and are clinically used as iron chelators nowadays. The HOPO family has different isomers, out of which 3,4-HOPO possesses applicability for designing drugs. The effect of methyl substitution on different positions of pyridinone ring also plays an essential role in deciding the pM values, thus describing the metal affinity. Several metal ions like Fe, Al, Cu, Zn, and some actinides are found to exhibit good chelation efficacy with HOPOs. In terms of denticity, there are various forms of HOPO. Among these, discussion on bidentate, tetradentate, hexadentate, octadentate, and dendrimers will be done here. This review systematically summarizes the various literature reports on the design and pharmacological activities of the newly developed HOPOs and their derivatives, including antibiotics, anticancer, and antineurodegeneratives.
AD is a progressive brain disorder. Because of the lack of remarkable single-target drugs against neurodegenerative disorders, the multitarget-directed ligand strategy has received attention as a promising therapeutic approach. Herein, we rationally designed twenty-nine hybrids of N-propargylamine-hydroxypyridinone. The designed hybrids possessed excellent iron-chelating activity (pFe³⁺ = 17.09-22.02) and potent monoamine oxidase B inhibitory effects. Various biological evaluations of the optimal compound 6b were performed step by step, including inhibition screening of monoamine oxidase (hMAO-B IC50 = 0.083 ± 0.001 µM, hMAO-A IC50 = 6.11 ± 0.08 µM; SI = 73.5), prediction of blood-brain barrier permeability and mouse behavioral research. All of these favorable results proved that the N-propargylamine-hydroxypyridinone scaffold is a promising structure for the discovery of multitargeted ligands for AD therapy.
Iron plays an essential role in all living cells because of its unique chemical properties. It is also the most abundant trace element in mammals. However, when iron is present in excess or inappropriately located, it becomes toxic. Excess iron can become involved in free radical formation, resulting in oxidative stress and cellular damage. Iron chelators are used to treat serious pathological disorders associated with systemic iron overload. Hydroxypyridinones stand out for their outstanding chelation properties, including high selectivity for Fe3+ in the biological environment, ease of derivatization, and good biocompatibility. Herein, we overview the potential for multifunctional hydroxypyridinone-based chelators to be used as therapeutic agents against a wide range of diseases associated either with systemic or local elevated iron levels.
According to the literature, iron chelators have been used to inhibit tumor cell proliferation. Hydroxypyridinones, due to easy derivatization and high affinity for iron, have been suggested as an attractive target for the development of iron scavenging ligands. N-arylhydroxypyridinone derivatives as iron chelators have been previously designed and synthesized, and the present study is performed in order to evaluate the antitumor efficacy of these compounds,. Four derivatives of hydroxypyridinone were tested against HCT116 and SW480 colon cancer cell lines for 48 h using MTT assay. One compound (3-hydroxy-2-methyl-1-phenylpyridin-4(1H)-one, PMPO) showed the maximum cytotoxic activity on both HCT116 and SW480 cancer cells with IC50 = 243 and 180 μmol, respectively, for 48 h treatment. The obtained results demonstrated that various concentrations of test compounds exhibited significant reduction of the cell viability (P < 0.05) in a concentration dependent manner. Our findings indicate that the proposed hydroxypyridinone derivatives can be considered as a new option for the treatment of colon cancer.
