Publications by authors named "Luca Piemontese"

37 Publications

Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease.

Molecules 2021 Mar 16;26(6). Epub 2021 Mar 16.

Centro de Química Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid- (A) aggregation. Some of these hybrids also prevented A-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound emerged as a promising multi-target lead compound (AChE inhibition (IC 1.6 μM); A aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.
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http://dx.doi.org/10.3390/molecules26061658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002323PMC
March 2021

(2-Aminobenzothiazole)-Methyl-1,1-Bisphosphonic Acids: Targeting Matrix Metalloproteinase 13 Inhibition to the Bone.

Pharmaceuticals (Basel) 2021 Jan 24;14(2). Epub 2021 Jan 24.

Department of Pharmacy and Pharmaceutical Sciences, University of Bari "A. Moro", via E. Orabona 4, 70125 Bari, Italy.

Matrix Metalloproteinases (MMPs) are a family of secreted and membrane-bound enzymes, of which 24 isoforms are known in humans. These enzymes degrade the proteins of the extracellular matrix and play a role of utmost importance in the physiological remodeling of all tissues. However, certain MMPs, such as MMP-2, -9, and -13, can be overexpressed in pathological states, including cancer and metastasis. Consequently, the development of MMP inhibitors (MMPIs) has been explored for a long time as a strategy to prevent and hinder metastatic growth, but the important side effects linked to promiscuous inhibition of MMPs prevented the clinical use of MMPIs. Therefore, several strategies were proposed to improve the therapeutic profile of this pharmaceutical class, including improved selectivity toward specific MMP isoforms and targeting of specific organs and tissues. Combining both approaches, we conducted the synthesis and preliminary biological evaluation of a series of (2-aminobenzothiazole)-methyl-1,1-bisphosphonic acids active as selective inhibitors of MMP-13 via in vitro and in silico studies, which could prove useful for the treatment of bone metastases thanks to the bone-targeting capabilities granted by the bisphosphonic acid group.
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http://dx.doi.org/10.3390/ph14020085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912614PMC
January 2021

Derivatives of Tenuazonic Acid as Potential New Multi-Target Anti-Alzheimer's Disease Agents.

Biomolecules 2021 01 15;11(1). Epub 2021 Jan 15.

Department of Pharmacy and Pharmaceutical Sciences, University of Bari "A. Moro", via E. Orabona 4, 70125 Bari, Italy.

Alzheimer's disease (AD) is generally recognized as a multifactorial neurodegenerative pathology with an increasing impact on society. Tenuazonic acid (TA) is a natural compound that was recently identified as a potential multitarget ligand with anti-cholinesterase, anti-amyloidogenic and antioxidant activities. Using its structure as a chemical scaffold, we synthesized and evaluated new derivatives (1-5), including tenuazonic-donepezil (TA-DNP) hybrids (4 and 5) due to the clinical importance of the anti-AD drug donepezil. These novel compounds all achieved activity in the micromolar range towards all selected targets and demonstrated to be potentially orally absorbed. Moreover, a selected compound (1) was further investigated as a chelating agent towards copper (II), zinc (II) and iron (III) and showed good chelating ability (pFe = 16.6, pCu = 11.6, pZn = 6.0 at pH 7.4). Therefore, the TA motif can be considered an interesting building block in the search for innovative multi-functional anti-neurodegenerative drugs, as exemplified by hybrid 5, a promising non-cytotoxic lead compound adequate for the early stages of AD, and capable of ameliorating the oxidative status of SH-SY5Y human neuroblastoma cells.
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http://dx.doi.org/10.3390/biom11010111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830597PMC
January 2021

Natural Compounds for the Prevention and Treatment of Cardiovascular and Neurodegenerative Diseases.

Foods 2020 Dec 24;10(1). Epub 2020 Dec 24.

Dipartimento di Farmacia-Scienze del Farmaco-University of Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.

Secondary metabolites from plants and fungi are stimulating growing interest in consumers and, consequently, in the food and supplement industries. The beneficial effects of these natural compounds are being thoroughly studied and there are frequent updates about the biological activities of old and new molecules isolated from plants and fungi. In this article, we present a review of the most recent literature regarding the recent discovery of secondary metabolites through isolation and structural elucidation, as well as the in vitro and/or in vivo evaluation of their biological effects. In particular, the possibility of using these bioactive molecules in the prevention and/or treatment of widely spread pathologies such as cardiovascular and neurodegenerative diseases is discussed.
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http://dx.doi.org/10.3390/foods10010029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824130PMC
December 2020

Beyond the Canonical Endocannabinoid System. A Screening of PPAR Ligands as FAAH Inhibitors.

Int J Mol Sci 2020 Sep 24;21(19). Epub 2020 Sep 24.

Department of Pharmacy and Pharmaceutical Sciences, University of Bari "A. Moro", via E. Orabona 4, 70125 Bari, Italy.

In recent years, Peroxisome Proliferator-Activated Receptors (PPARs) have been connected to the endocannabinoid system. These nuclear receptors indeed mediate the effects of anandamide and similar substances such as oleoyl-ethanolamide and palmitoyl-ethanolamide. An increasing body of literature describing the interactions between the endocannabinoid system and PPARs has slowly but surely been accumulating over the past decade, and a multitarget approach involving these receptors and endocannabinoid degrading enzyme FAAH has been proposed for the treatment of inflammatory states, cancer, and Alzheimer's disease. The lack of knowledge about compounds endowed with such an activity profile therefore led us to investigate a library of readily available, well-characterized PPAR agonists that we had synthesized over the years in order to find a plausible lead compound for further development. Moreover, we propose a rationalization of our results via a docking study, which sheds some light on the binding mode of these PPAR agonists to FAAH and opens the way for further research in this field.
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http://dx.doi.org/10.3390/ijms21197026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582602PMC
September 2020

Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy.

Pharmaceuticals (Basel) 2020 Jun 1;13(6). Epub 2020 Jun 1.

Department of Pharmacy and Pharmaceutical Sciences, University of Bari "A. Moro", via E. Orabona 4, 70125 Bari, Italy.

Matrix metalloproteinases (MMPs) are a family of enzymes involved at different stages of cancer progression and metastasis. We previously identified a novel class of bisphosphonic inhibitors, selective for MMPs crucial for bone remodeling, such as MMP-2. Due to the increasing relevance of specific MMPs at various stages of tumor malignancy, we focused on improving potency towards certain isoforms. Here, we tackled MMP-9 because of its confirmed role in tumor invasion, metastasis, angiogenesis, and immuno-response, making it an ideal target for cancer therapy. Using a computational analysis, we designed and characterized potent MMP-2/MMP-9 inhibitors. This is a promising approach to develop and clinically translate inhibitors that could be used in combination with standard care therapy for the treatment of skeletal malignancies.
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http://dx.doi.org/10.3390/ph13060113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344628PMC
June 2020

A Review of Recent Patents (2016-2019) on Plant Food Supplements with Potential Application in the Treatment of Neurodegenerative and Metabolic Disorders.

Recent Pat Food Nutr Agric 2020 ;11(2):145-153

Dipartimento di Farmacia-Scienze del Farmaco, Universita degli Studi di Bari "Aldo Moro", Via E. Orabona 4, I-70125 Bari, Italy.

In the near future, it is expected that the prevalence of illnesses related to the increasing life expectancies and quality of life, such as neurodegenerative diseases and cardiovascular diseases related to metabolic disorders, will soar to unprecedented levels, leading to high socioeconomic costs. To address this rising threat, natural products are emerging as a novel strategy for the prevention and therapy of these ages- and lifestyle-related diseases, thanks to their high marketability and few side effects. In this patent review, we summarize selected patents for food supplements, functional and fortified foods, filed from 2016 to 2019, categorizing them based on the biological activity of their components.
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http://dx.doi.org/10.2174/2212798411666200313145824DOI Listing
January 2020

Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease.

Molecules 2020 Feb 22;25(4). Epub 2020 Feb 22.

Centro de Química Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.

A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer's disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound , containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds and displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.
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http://dx.doi.org/10.3390/molecules25040985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070709PMC
February 2020

Deep Eutectic Solvents as Effective Reaction Media for the Synthesis of 2-Hydroxyphenylbenzimidazole-based Scaffolds en Route to Donepezil-Like Compounds.

Molecules 2020 Jan 28;25(3). Epub 2020 Jan 28.

Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari «Aldo Moro», Via E. Orabona 4, I-70125 Bari, Italy.

An unsubstituted 2-hydroxyphenylbenzimidazole has recently been included as a scaffold in a series of hybrids (including the hit compound PZ1) based on the framework of the acetylcholinesterase (AChE) inhibitor Donepezil, which is a new promising multi-target ligand in Alzheimer's disease (AD) treatment. Building upon these findings, we have now designed and completed the whole synthesis of PZ1 in the so-called deep eutectic solvents (DESs), which have emerged as an unconventional class of bio-renewable reaction media in green synthesis. Under optimized reaction conditions, the preparation of a series of 2-hydroxyphenylbenzimidazole-based nuclei has also been perfected in DESs, and comparison with other routes which employ toxic and volatile organic solvents (VOCs) provided. The functionalization of the aromatic ring can have implications on some important biological properties of the described derivatives and will be the subject of future studies of structure-activity relationships (SARs).
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http://dx.doi.org/10.3390/molecules25030574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037276PMC
January 2020

Virtual screening identification and chemical optimization of substituted 2-arylbenzimidazoles as new non-zinc-binding MMP-2 inhibitors.

Bioorg Med Chem 2020 02 9;28(3):115257. Epub 2019 Dec 9.

Department of Pharmacy and Pharmaceutical Sciences, "A. Moro" University of Bari, Bari, Italy. Electronic address:

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases known to exert multiple regulatory roles in tumor progression and invasiveness. This encouraged over the years the approach of MMP, and particularly MMP-2, targeting for anticancer treatment. Early generations of MMP inhibitors, based on aspecific zinc binding groups (ZBGs) assembled on (pseudo)peptide scaffolds, have been discontinued due to the clinical emergence of toxicity and further drawbacks, giving the way to inhibitors with alternative zinc-chelator moieties or not binding the catalytic zinc ion. In the present paper, we continue the search for new non-zinc binding MMP-2 inhibitors: exploiting previously identified compounds, a virtual screening (VS) campaign was carried out and led to the identification of a new class of ligands. The structure-activity relationship (SAR) of the benzimidazole scaffold was explored by synthesis of several analogues whose inhibition activity was tested with enzyme inhibition assays. By performing the molecular simplification approach, we disclosed different sets of single-digit micromolar inhibitors of MMP-2, with up to a ten-fold increase in inhibitory activity and ameliorated selectivity towards off-target MMP-8, compared to selected lead compound. Molecular dynamics calculations conducted on complexes of MMP-2 with docked privileged structures confirmed that analyzed inhibitors avoid targeting the zinc ion and dip inside the S1' pocket. Present results provide a further enrichment of our insights for the design of novel MMP-2 selective inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2019.115257DOI Listing
February 2020

Novel tacrine-benzofuran hybrids as potential multi-target drug candidates for the treatment of Alzheimer's Disease.

J Enzyme Inhib Med Chem 2020 Dec;35(1):211-226

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.

Pursuing the widespread interest on multi-target drugs to combat Alzheimer´s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aβ aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aβ induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.
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http://dx.doi.org/10.1080/14756366.2019.1689237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567501PMC
December 2020

Effects of temperature and water activity change on ecophysiology of ochratoxigenic Aspergillus carbonarius in field-simulating conditions.

Int J Food Microbiol 2020 Feb 5;315:108420. Epub 2019 Nov 5.

Institute of Sciences of Food Production (ISPA), National Research Council (CNR), Bari, Italy.

Ochratoxin A (OTA) is the primary mycotoxin threat in wine and dried vine fruits. Its presence in grape and wine is strongly related to climatic conditions and the expected climate change could represent a risk of increasing fungal colonization and OTA contamination in grapes. In this regard, the interacting effect of i) different conditions of water availability (0.93 and 0.99a) and ii) different 10 h/14 h dark/light alternating temperature conditions simulating a nowadays (18/31 °C) and climate change scenario (20/37 °C) in high OTA risk areas of Apulia region, were studied. Lag phases prior to growth, mycelial growth rate, the expression of biosynthesis, transcription factors and regulatory genes of OTA cluster and OTA production were analysed in Aspergillus carbonarius ITEM 5010 under the combined effect of different climatic factors. At 18/31 °C and under water stress conditions (0.93 a) the growth rate was slower than at 0.99 a; on the contrary, at 20/37 °C a higher growth rate was observed at 0.93 a. An over-expression of OTA genes and genes belonging to the global regulator Velvet complex was observed at 18/31 °C and 0.99 a, with the specific OTA pathway transcription factor bZIP showing the highest expression level. The up-regulated transcription profile of the genes positively correlated with OTA production higher at 18/31 °C than at 20/37 °C and 0.99 a; while no OTA production was detected at 0.93 a at each of the temperature conditions tested. These findings provide preliminary evidence that the possible increase of the temperature, likely to happen in some areas of the Apulia region, may results in a reduction of both A. carbonarius spoilage and OTA production in grapes.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2019.108420DOI Listing
February 2020

New Approaches to Cancer Therapy: Combining Fatty Acid Amide Hydrolase (FAAH) Inhibition with Peroxisome Proliferator-Activated Receptors (PPARs) Activation.

J Med Chem 2019 12 22;62(24):10995-11003. Epub 2019 Aug 22.

Dipartimento di Farmacia-Scienze del Farmaco , Università degli Studi di Bari "Aldo Moro" , via Orabona 4 , 70125 Bari , Italy.

Over the course of the past decade, peroxisome proliferator-activated receptors (PPARs) have been identified as part of the cannabinoid signaling system: both phytocannabinoids and endocannabinoids are capable of binding and activating these nuclear receptors. Fatty acid amide hydrolase (FAAH) hydrolyzes the endocannabinoid anandamide and other -acylethanolamines. These substances have been shown to have numerous anticancer effects, and indeed the inhibition of FAAH has multiple beneficial effects that are mediated by PPARα subtype and by PPARγ subtype, especially antiproliferation and activation of apoptosis. The substrates of FAAH are also PPAR agonists, which explains the PPAR-mediated effects of FAAH inhibitors. Much like cannabinoid ligands and FAAH inhibitors, PPARγ agonists show antiproliferative effects on cancer cells, suggesting that additive or synergistic effects may be achieved through the positive modulation of both signaling systems. In this Miniperspective, we discuss the development of novel FAAH inhibitors able to directly act as PPAR agonists and their promising utilization as leads for the discovery of highly effective anticancer compounds.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00885DOI Listing
December 2019

An update about the crucial role of stereochemistry on the effects of Peroxisome Proliferator-Activated Receptor ligands.

Eur J Med Chem 2019 Aug 11;176:326-342. Epub 2019 May 11.

Dipartimento Farmacia-Scienze Del Farmaco, Università Degli Studi di Bari "Aldo Moro", Via Orabona 4, 70125, Bari, Italy. Electronic address:

Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular disease, obesity, and diabetes. These receptors show a high degree of stereoselectivity towards several classes of drugs. This review covers the most relevant findings that have been made in the last decade and takes into consideration only those compounds in which stereochemistry led to unexpected results or peculiar interactions with the receptors. These cases are reviewed and discussed with the aim to show how enantiomeric recognition originates at the molecular level. The structural characterization by crystallographic methods and docking experiments of complexes formed by PPARs with their ligands turns out to be an essential tool to explain receptor stereoselectivity.
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http://dx.doi.org/10.1016/j.ejmech.2019.05.012DOI Listing
August 2019

Chiral phenoxyacetic acid analogues inhibit colon cancer cell proliferation acting as PPARγ partial agonists.

Sci Rep 2019 04 1;9(1):5434. Epub 2019 Apr 1.

Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli Federico II, via D. Montesano 49, 80131, Napoli, Italy.

Peroxisome Proliferator-Activated Receptor γ (PPARγ) is an important sensor at the crossroad of diabetes, obesity, immunity and cancer as it regulates adipogenesis, metabolism, inflammation and proliferation. PPARγ exerts its pleiotropic functions upon binding of natural or synthetic ligands. The molecular mechanisms through which PPARγ controls cancer initiation/progression depend on the different mode of binding of distinctive ligands. Here, we analyzed a series of chiral phenoxyacetic acid analogues for their ability to inhibit colorectal cancer (CRC) cells growth by binding PPARγ as partial agonists as assessed in transactivation assays of a PPARG-reporter gene. We further investigated compounds (R,S)-3, (S)-3 and (R,S)-7 because they combine the best antiproliferative activity and a limited transactivation potential and found that they induce cell cycle arrest mainly via upregulation of p21. Interestingly, they also counteract the β-catenin/TCF pathway by repressing c-Myc and cyclin D1, supporting their antiproliferative effect. Docking experiments provided insight into the binding mode of the most active compound (S)-3, suggesting that its partial agonism could be related to a better stabilization of H3 rather than H11 and H12. In conclusion, we identified a series of PPARγ partial agonists affecting distinct pathways all leading to strong antiproliferative effects. These findings may pave the way for novel therapeutic strategies in CRC.
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http://dx.doi.org/10.1038/s41598-019-41765-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443668PMC
April 2019

An innovative approach for the treatment of Alzheimer's disease: the role of peroxisome proliferator-activated receptors and their ligands in development of alternative therapeutic interventions.

Authors:
Luca Piemontese

Neural Regen Res 2019 Jan;14(1):43-45

Dipartimento Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Bari, Italy.

Alzheimer's disease is a multifactorial pathology, for which no cure is currently available. Nowadays, researchers are moving towards a new hypothesis of the onset of the illness, linking it to a metabolic impairment. This innovative approach will lead to the identification of new targets for the preparation of new effective drugs. Peroxisome proliferator-activated receptors and their ligands are the ideal candidates to reach the necessary breakthrough to defeat this complicate disease.
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http://dx.doi.org/10.4103/1673-5374.241043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262998PMC
January 2019

Identification of the First PPARα/γ Dual Agonist Able To Bind to Canonical and Alternative Sites of PPARγ and To Inhibit Its Cdk5-Mediated Phosphorylation.

J Med Chem 2018 09 18;61(18):8282-8298. Epub 2018 Sep 18.

Dipartimento Farmacia-Scienze del Farmaco , Università degli Studi di Bari "Aldo Moro" , Via Orabona 4 , 70125 Bari , Italy.

A new series of derivatives of the PPARα/γ dual agonist 1 allowed us to identify the ligand ( S)-6 as a potent partial agonist of both PPARα and γ subtypes. X-ray studies in PPARγ revealed two different binding modes of ( S)-6 to the canonical site. However, ( S)-6 was also able to bind an alternative site as demonstrated by transactivation assay in the presence of a canonical PPARγ antagonist and supported from docking experiments. This compound did not activate the PPARγ-dependent program of adipocyte differentiation inducing a very less severe lipid accumulation compared to rosiglitazone but increased the insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Finally, ( S)-6 inhibited the Cdk5-mediated phosphorylation of PPARγ at serine 273 that is currently considered the mechanism by which some PPARγ partial agonists exert antidiabetic effects similar to thiazolidinediones, without showing their typical side effects. This is the first PPARα/γ dual agonist reported to show this inhibitory effect representing the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00835DOI Listing
September 2018

Donepezil structure-based hybrids as potential multifunctional anti-Alzheimer's drug candidates.

J Enzyme Inhib Med Chem 2018 Dec;33(1):1212-1224

a Centro de Química Estrutural, Instituto Superior Técnico , Universidade de Lisboa , Lisbon , Portugal.

A new series of multifunctional hybrids, based on the structure of the donepezil (DNP) drug, have been developed and evaluated as potential anti Alzheimer's disease (AD) agents. The rationale of this study was the conjugation of a benzylpiperidine/benzylpiperazine moiety with derivatives of bioactive heterocyclics (benzimidazole or benzofuran), to mimic the main structure of DNP and to endow the hybrids with additional relevant properties such as inhibition of amyloid beta (Aβ) peptide aggregation, antioxidant activity and metal chelation. Overall, they showed good activity for AChE inhibition (IC=4.0-30.0 μΜ) and moderate ability for inhibition of Aβ self-mediated aggregation. The hybrids containing chelating groups showed improvement in the inhibition of Cu-induced Aβ aggregation and the antioxidant capacity. Moreover, neuroprotective effects of these compounds were evidenced in neuroblastoma cells after Aβ induced toxicity. Structure-activity relationship allowed the identification of some promising compounds and the main determinant structural features for the targeted properties.
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http://dx.doi.org/10.1080/14756366.2018.1491564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127844PMC
December 2018

Natural Scaffolds with Multi-Target Activity for the Potential Treatment of Alzheimer's Disease.

Molecules 2018 Aug 29;23(9). Epub 2018 Aug 29.

Consiglio Nazionale delle Ricerche-Istituto di Scienze delle Produzioni Alimentari (CNR-ISPA), via Amendola, 122/O, 70125 Bari, Italy.

A few symptomatic drugs are currently available for Alzheimer's Disease (AD) therapy, but these molecules are only able to temporary improve the cognitive capacity of the patients if administered in the first stages of the pathology. Recently, important advances have been achieved about the knowledge of this complex condition, which is now considered a multi-factorial disease. Researchers are, thus, more oriented toward the preparation of molecules being able to contemporaneously act on different pathological features. To date, the inhibition of acetylcholinesterase (AChE) and of β-amyloid (Aβ) aggregation as well as the antioxidant activity and the removal and/or redistribution of metal ions at the level of the nervous system are the most common investigated targets for the treatment of AD. Since many natural compounds show multiple biological properties, a series of secondary metabolites of plants or fungi with suitable structural characteristics have been selected and assayed in order to evaluate their potential role in the preparation of multi-target agents. Out of six compounds evaluated, showed the best activity as an antioxidant (EC = 2.6 ± 0.2 μmol/µmol of DPPH) while compound proved to be effective in the inhibition of AChE (IC = 6.86 ± 0.67 μM) and Aβ aggregation (IC = 74 ± 1 μM). Furthermore, compound inhibited BChE (IC = 1.75 ± 0.59 μM) with a good selectivity toward AChE (IC = 86.0 ± 15.0 μM). Moreover, preliminary tests on metal chelation suggested a possible interaction between compounds and and copper (II). Molecules with the best multi-target profiles will be used as starting hit compounds to appropriately address future studies of Structure-Activity Relationships (SARs).
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http://dx.doi.org/10.3390/molecules23092182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225478PMC
August 2018

Effect of gaseous ozone treatments on DON, microbial contaminants and technological parameters of wheat and semolina.

Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2018 Apr 19;35(4):760-771. Epub 2018 Jan 19.

a National Research Council (CNR), Institute of Sciences of Food Production (ISPA) , Bari , Italy.

Deoxynivalenol (DON) is an important mycotoxin produced by several species of Fusarium. It occurs often in wheat grain and is frequently associated with significant levels of its modified form DON-3-glucoside (DON-3-Glc). Ozone (O) is a powerful disinfectant and oxidant, classified as GRAS (Generally Recognised As Safe), that reacts easily with specific compounds including the mycotoxins aflatoxins, ochratoxin A, trichothecenes and zearalenone. It degrades DON in aqueous solution and can be effective for decontamination of grain. This study reports the efficacy of gaseous ozone treatments in reducing DON, DON-3-Glc, bacteria, fungi and yeasts in naturally contaminated durum wheat. A prototype was used to dispense ozone continuously and homogeneously at different concentrations and exposure time, in 2 kg aliquots of durum wheat. The optimal conditions, which do not affect chemical and rheological parameters of durum wheat, semolina and pasta, were identified (55 g O h for 6 h). The measured mean reductions of DON and DON-3-Glc in ozonated wheat were 29% and 44%, respectively. Ozonation also produced a significant (p < 0.05) reduction of total count (CFU/g) of bacteria, fungi and yeasts in wheat grains.
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http://dx.doi.org/10.1080/19440049.2017.1419285DOI Listing
April 2018

Heterocyclic compounds as key structures for the interaction with old and new targets in Alzheimer's disease therapy.

Neural Regen Res 2017 Aug;12(8):1256-1261

Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Bari, Italy.

Nowadays, Alzheimer's disease (AD) is widely recognized as a real social problem. In fact, only five drugs are FDA approved for the therapy of this widespread neurodegenerative disease, but with low results so far. Three of them (rivastigmine, donepezil and galantamine) are acetylcholinesterase inhibitors, memantine is a N-methyl-D-aspartate receptor antagonist, whereas the fifth formulation is a combination of donepezil with memantine. The prevention and treatment of AD is the new challenge for pharmaceutical industry, as well as for public institutions, physicians, patients, and their families. The discovery of a new and safe way to cure this neurodegenerative disease is urgent and should not be delayed further. Because of the multiple origin of this pathology, a multi-target strategy is currently strongly pursued by researchers. In this review, we have discussed new structures designed to better the activity on the classical AD targets. We have also examined old and new potential drugs that could prove useful future for the therapy of the pathology by acting on innovative, not usual, and not yet fully explored targets like peroxisome proliferator-activated receptor (PPARs).
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http://dx.doi.org/10.4103/1673-5374.213541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607816PMC
August 2017

New approaches for prevention and treatment of Alzheimer's disease: a fascinating challenge.

Authors:
Luca Piemontese

Neural Regen Res 2017 Mar;12(3):405-406

Dipartimento Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Bari, Italy; Centro de Química Estrutural, Instituto Superior Técnico-Universidade Técnica de Lisboa, Lisboa, Portugal.

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http://dx.doi.org/10.4103/1673-5374.202942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399716PMC
March 2017

Hydroxypyridinone Derivatives: A Fascinating Class of Chelators with Therapeutic Applications - An Update.

Curr Med Chem 2018 ;25(1):97-112

Centro de Quimica Estrutural, Instituto Superior Tecnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa. Portugal.

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 their 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.
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http://dx.doi.org/10.2174/0929867324666170330092304DOI Listing
February 2018

Deep Eutectic Solvents as Novel and Effective Extraction Media for Quantitative Determination of Ochratoxin A in Wheat and Derived Products.

Molecules 2017 Jan 12;22(1). Epub 2017 Jan 12.

Consiglio Nazionale delle Ricerche, Istituto di Scienze delle Produzioni Alimentari, Via G. Amendola 122/O, I-70126 Bari, Italy.

An unprecedented, environmentally friendly, and faster method for the determination of Ochratoxin A (OTA) (a mycotoxin produced by several species of and and largely widespread in nature, in wheat and derived products) has, for the first time, been set up and validated using choline chloride (ChCl)-based deep eutectic solvents (DESs) (e.g., ChCl/glycerol (1:2) and ChCl/ urea (1:2) up to 40% (/) water) as privileged, green, and biodegradable extraction solvents. This also reduces worker exposure to toxic chemicals. Results are comparable to those obtained using conventional, hazardous and volatile organic solvents (VOCs) typical of the standard and official methods. OTA recovery from spiked durum wheat samples, in particular, was to up to 89% versus 93% using the traditional acetonitrile-water mixture with a repeatability of the results (RSD) of 7%. Compatibility of the DES mixture with the antibodies of the immunoaffinity column was excellent as it was able to retain up to 96% of the OTA. Recovery and repeatability for durum wheat, bread crumbs, and biscuits proved to be within the specifications required by the current European Commission (EC) regulation. Good results in terms of accuracy and precision were achieved with mean recoveries between 70% (durum wheat) and 88% (bread crumbs) and an RSD between 2% (biscuits) and 7% (bread).
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http://dx.doi.org/10.3390/molecules22010121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155845PMC
January 2017

New diphenylmethane derivatives as peroxisome proliferator-activated receptor alpha/gamma dual agonists endowed with anti-proliferative effects and mitochondrial activity.

Eur J Med Chem 2017 Feb 24;127:379-397. Epub 2016 Dec 24.

Dipartimento Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via Orabona 4, 70125 Bari, Italy. Electronic address:

We screened a short series of new chiral diphenylmethane derivatives and identified potent dual PPARα/γ partial agonists. As both enantiomers of the most active compound 1 displayed an unexpected similar transactivation activity, we performed docking experiments to provide a molecular understanding of their similar partial agonism. We also evaluated the ability of both enantiomers of 1 and racemic 2 to inhibit colorectal cancer cells proliferation: (S)-1 displayed a more robust activity due, at least in part, to a partial inhibition of the Wnt/β-catenin signalling pathway that is upregulated in the majority of colorectal cancers. Finally, we investigated the effects of (R)-1, (S)-1 and (R,S)-2 on mitochondrial function and demonstrated that they activate the carnitine shuttle system through upregulation of carnitine/acylcarnitine carrier (CAC) and carnitine-palmitoyl-transferase 1 (CPT1) genes. Consistent with the notion that these are PPARα target genes, we tested and found that PPARα itself is regulated by a positive loop. Moreover, these compounds induced a significant mitochondrial biogenesis. In conclusion, we identified a new series of dual PPARα/γ agonists endowed with novel anti-proliferative properties associated with a strong activation of mitochondrial functions and biogenesis, a potential therapeutic target of the treatment of insulin resistance.
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http://dx.doi.org/10.1016/j.ejmech.2016.12.047DOI Listing
February 2017

Plant Food Supplements with Antioxidant Properties for the Treatment of Chronic and Neurodegenerative Diseases: Benefits or Risks?

Authors:
Luca Piemontese

J Diet Suppl 2017 Jul 28;14(4):478-484. Epub 2016 Nov 28.

a Dipartimento Farmacia-Scienze del Farmaco , Università degli Studi di Bari "Aldo Moro" , Bari , Italy.

Wine by-products, in particular grape pomace, can be an important source of polyphenols and dietary fibers and are increasingly being used as a starting material in the industrial production of plant food supplements, such as other matrices containing biomolecules, with antioxidant properties. The risk associated with the consumption of these products was recently analyzed through a study of potential genotoxic and carcinogenic compounds that can be found in the marketed products. In particular, occurrence data about contamination with the mycotoxin ochratoxin A were also reported. This short review aims at giving an overview about the quality and benefits of these kinds of food supplements, and also about risks of incorrect use, focusing on the emerging need for stricter European regulations.
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http://dx.doi.org/10.1080/19390211.2016.1247936DOI Listing
July 2017

Catechol-based matrix metalloproteinase inhibitors with additional antioxidative activity.

J Enzyme Inhib Med Chem 2016 24;31(sup4):25-37. Epub 2016 Aug 24.

b Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi "A. Moro" di Bari , Bari , Italy.

New catechol-containing chemical entities have been investigated as matrix metalloproteinase inhibitors as well as antioxidant molecules. The combination of the two properties could represent a useful feature due to the potential application in all the pathological processes characterized by increased proteolytic activity and radical oxygen species (ROS) production, such as inflammation and photoaging. A series of catechol-based molecules were synthesized and tested for both proteolytic and oxidative inhibitory activity, and the detailed binding mode was assessed by crystal structure determination of the complex between a catechol derivative and the matrix metalloproteinase-8. Surprisingly, X-ray structure reveals that the catechol oxygens do not coordinates the zinc atom.
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http://dx.doi.org/10.1080/14756366.2016.1217853DOI Listing
February 2017

Reduction of Aflatoxins in Apricot Kernels by Electronic and Manual Color Sorting.

Toxins (Basel) 2016 Jan 19;8(1). Epub 2016 Jan 19.

Institute of Sciences of Food Production (ISPA), National Research Council of Italy (CNR), Via Amendola 122/O, Bari 70126, Italy.

The efficacy of color sorting on reducing aflatoxin levels in shelled apricot kernels was assessed. Naturally-contaminated kernels were submitted to an electronic optical sorter or blanched, peeled, and manually sorted to visually identify and sort discolored kernels (dark and spotted) from healthy ones. The samples obtained from the two sorting approaches were ground, homogenized, and analysed by HPLC-FLD for their aflatoxin content. A mass balance approach was used to measure the distribution of aflatoxins in the collected fractions. Aflatoxin B₁ and B₂ were identified and quantitated in all collected fractions at levels ranging from 1.7 to 22,451.5 µg/kg of AFB₁ + AFB₂, whereas AFG₁ and AFG₂ were not detected. Excellent results were obtained by manual sorting of peeled kernels since the removal of discolored kernels (2.6%-19.9% of total peeled kernels) removed 97.3%-99.5% of total aflatoxins. The combination of peeling and visual/manual separation of discolored kernels is a feasible strategy to remove 97%-99% of aflatoxins accumulated in naturally-contaminated samples. Electronic optical sorter gave highly variable results since the amount of AFB₁ + AFB₂ measured in rejected fractions (15%-18% of total kernels) ranged from 13% to 59% of total aflatoxins. An improved immunoaffinity-based HPLC-FLD method having low limits of detection for the four aflatoxins (0.01-0.05 µg/kg) was developed and used to monitor the occurrence of aflatoxins in 47 commercial products containing apricot kernels and/or almonds commercialized in Italy. Low aflatoxin levels were found in 38% of the tested samples and ranged from 0.06 to 1.50 μg/kg for AFB₁ and from 0.06 to 1.79 μg/kg for total aflatoxins.
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http://dx.doi.org/10.3390/toxins8010026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728548PMC
January 2016

Food coloring agents and plant food supplements derived from Vitis vinifera: a new source of human exposure to ochratoxin A.

J Agric Food Chem 2015 Apr 26;63(13):3609-14. Epub 2015 Mar 26.

‡Department of Chemistry, University of Bari "Aldo Moro", Via Orabona 4, 70126 Bari, Italy.

Grape pomaces are increasingly being used as starting material in the industrial production of plant food supplements (PFS), food coloring, and tartrates, but they are at risk of ochratoxin A (OTA) contamination, a mycotoxin with nephrotoxic and carcinogenic effects. We analyzed 24 commercial PFS and 13 food coloring samples derived from Vitis vinifera, mainly pomaces, using a HPLC-FLD method for OTA determination. OTA was found in 75% of PFS samples and 69% of food coloring samples at levels of <1.16-20.23 μg/kg and <1.16-32.00 μg/kg, respectively. The four commercial leavening agents containing tartrates were found to be negative for OTA. All eight samples collected in two distilleries that use grape pomaces and wine lees to produce tartrates and other byproducts contained OTA at levels of <1.16-240.93 μg/kg. The high incidence of OTA contamination in PFS and food coloring agents derived from V. vinifera suggests that maximum permitted level(s) should be established for this mycotoxin in these products.
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http://dx.doi.org/10.1021/acs.jafc.5b00326DOI Listing
April 2015