Publications by authors named "Tiziano Tuccinardi"

174 Publications

From Anti-infective Agents to Cancer Therapy: a Drug Repositioning Study Revealed a New Use for Nitrofuran Derivatives.

Med Chem 2021 May 10. Epub 2021 May 10.

Pathology Unit, Centro di Riferimento Oncologico (CRO) IRCCS, Aviano, Italy.

Background: The progression of ovarian cancer seems to be related to HDAC1, HDAC3 and HDAC6 activity. A possible strategy for improving therapies for treating ovarian carcinoma, minimizing the preclinical screenings, is the repurposing of already approved pharmaceutical products as inhibitors of these enzymes.

Objective: This work was aimed to implement a computational strategy for identifying new HDAC inhibitors for ovarian carcinoma treatment among approved drugs.

Method: The CHEMBL database was used to construct training, test and decoys sets for performing and validating HDAC1, HDAC3 and HDAC6 3D-QSAR models obtained by using FLAP program. Docking and MD simulations were used in combination with the generated models to identify novel potential HDAC inhibitors. Cell viability assays and Western blot analyses were performed on normal and cancer cells for a direct evaluation of the anti-proliferative activity and an in vitro estimation of HDAC inhibition of the compounds selected through in silico screening.

Result: The best quantitative prediction was obtained for the HDAC6 3D-QSAR model. The screening of approved drugs highlighted a new potential use as HDAC inhibitors for some compounds, in particular nitrofuran derivatives, usually known for their antibacterial activity, and frequently used as antimicrobial adjuvant therapy in cancer treatment. Experimental evaluation of these derivatives highlighted a significant antiproliferative activity against cancer cell lines overexpressing HDAC6, and an increase in acetylated alpha-tubulin levels.

Conclusion: Experimental results support the hypothesis of a potential direct interaction of nitrofuran derivatives with HDACs. In addition to the possible repurposing of already approved drugs, this work suggests the nitro group as a new zinc binding group, able to interact with the catalytic zinc ion of HDACs.
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http://dx.doi.org/10.2174/1573406417666210511001241DOI Listing
May 2021

CAG RNAs induce DNA damage and apoptosis by silencing expression in polyglutamine degeneration.

Proc Natl Acad Sci U S A 2021 May;118(19)

Laboratory of Drosophila Research, The Chinese University of Hong Kong, Hong Kong, China;

DNA damage plays a central role in the cellular pathogenesis of polyglutamine (polyQ) diseases, including Huntington's disease (HD). In this study, we showed that the expression of untranslatable expanded CAG RNA per se induced the cellular DNA damage response pathway. By means of RNA sequencing (RNA-seq), we found that expression of the () gene was down-regulated in mutant CAG RNA-expressing cells. The loss of NUDT16 function results in a misincorporation of damaging nucleotides into DNAs and leads to DNA damage. We showed that small CAG (sCAG) RNAs, species generated from expanded CAG transcripts, hybridize with CUG-containing mRNA and form a CAG-CUG RNA heteroduplex, resulting in gene silencing of and leading to the DNA damage and cellular apoptosis. These results were further validated using expanded CAG RNA-expressing mouse primary neurons and in vivo R6/2 HD transgenic mice. Moreover, we identified a bisamidinium compound, DB213, that interacts specifically with the major groove of the CAG RNA homoduplex and disfavors the CAG-CUG heteroduplex formation. This action subsequently mitigated RNA-induced silencing complex (RISC)-dependent silencing in both in vitro cell and in vivo mouse disease models. After DB213 treatment, DNA damage, apoptosis, and locomotor defects were rescued in HD mice. This work establishes NUDT16 deficiency by CAG repeat RNAs as a pathogenic mechanism of polyQ diseases and as a potential therapeutic direction for HD and other polyQ diseases.
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http://dx.doi.org/10.1073/pnas.2022940118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126783PMC
May 2021

Predicting Isoform-Selective Carbonic Anhydrase Inhibitors via Machine Learning and Rationalizing Structural Features Important for Selectivity.

ACS Omega 2021 Feb 26;6(5):4080-4089. Epub 2021 Jan 26.

Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Friedrich-Hirzebruch-Allee 6, D-53115 Bonn, Germany.

Carbonic anhydrases (CAs) catalyze the physiological hydration of carbon dioxide and are among the most intensely studied pharmaceutical target enzymes. A hallmark of CA inhibition is the complexation of the catalytic zinc cation in the active site. Human () CA isoforms belonging to different families are implicated in a wide range of diseases and of very high interest for therapeutic intervention. Given the conserved catalytic mechanisms and high similarity of many CA isoforms, a major challenge for CA-based therapy is achieving inhibitor selectivity for CA isoforms that are associated with specific pathologies over other widely distributed isoforms such as CA I or CA II that are of critical relevance for the integrity of many physiological processes. To address this challenge, we have attempted to predict compounds that are selective for isoform CA IX, which is a tumor-associated protein and implicated in metastasis, over CA II on the basis of a carefully curated data set of selective and nonselective inhibitors. Machine learning achieved surprisingly high accuracy in predicting CA IX-selective inhibitors. The results were further investigated, and compound features determining successful predictions were identified. These features were then studied on the basis of X-ray structures of CA isoform-inhibitor complexes and found to include substructures that explain compound selectivity. Our findings lend credence to selectivity predictions and indicate that the machine learning models derived herein have considerable potential to aid in the identification of new CA IX-selective compounds.
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http://dx.doi.org/10.1021/acsomega.0c06153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876851PMC
February 2021

Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide.

Sci Rep 2021 Jan 13;11(1):949. Epub 2021 Jan 13.

Department of Immunology and Inflammation, Imperial College London, Du Cane Road, London, W12 0NN, UK.

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl-D-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors.
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http://dx.doi.org/10.1038/s41598-020-80294-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806935PMC
January 2021

Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study.

Molecules 2020 Dec 26;26(1). Epub 2020 Dec 26.

Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.

Monoacylglycerol lipase (MAGL) is an important enzyme of the endocannabinoid system that catalyzes the degradation of the major endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL is associated with pathological conditions such as pain, inflammation and neurodegenerative diseases like Parkinson's and Alzheimer's disease. Furthermore, elevated levels of MAGL have been found in aggressive breast, ovarian and melanoma cancer cells. Due to its different potential therapeutic implications, MAGL is considered as a promising target for drug design and the discovery of novel small-molecule MAGL inhibitors is of great interest in the medicinal chemistry field. In this context, we developed a pharmacophore-based virtual screening protocol combined with molecular docking and molecular dynamics simulations, which showed a final hit rate of 50% validating the reliability of the in silico workflow and led to the identification of two promising and structurally different reversible MAGL inhibitors, VS1 and VS2. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent MAGL inhibitors.
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http://dx.doi.org/10.3390/molecules26010078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794939PMC
December 2020

Cancer Extracellular Vesicles: Next-Generation Diagnostic and Drug Delivery Nanotools.

Cancers (Basel) 2020 Oct 28;12(11). Epub 2020 Oct 28.

Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy.

Nanosized extracellular vesicles (EVs) with dimensions ranging from 100 to 1000 nm are continuously secreted from different cells in their extracellular environment. They are able to encapsulate and transfer various biomolecules, such as nucleic acids, proteins, and lipids, that play an essential role in cell‒cell communication, reflecting a novel method of extracellular cross-talk. Since EVs are present in large amounts in most bodily fluids, challengeable hypotheses are analyzed to unlock their potential roles. Here, we review EVs by discussing their specific characteristics (structure, formation, composition, and isolation methods), focusing on their key role in cell biology. Furthermore, this review will summarize the biomedical applications of EVs, in particular those between 30 and 150 nm (like exosomes), as next-generation diagnostic tools in liquid biopsy for cancer and as novel drug delivery vehicles.
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http://dx.doi.org/10.3390/cancers12113165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692229PMC
October 2020

An updated patent review of monoacylglycerol lipase (MAGL) inhibitors (2018-present).

Expert Opin Ther Pat 2021 Feb 1;31(2):153-168. Epub 2020 Nov 1.

Department of Pharmacy, University of Pisa , Pisa, Italy.

Introduction: Monoacylglycerol lipase (MAGL) belongs to the endocannabinoid system and is responsible for the inactivation of endocannabinoid 2-arachidonoylglycerol. Importantly, it was found that MAGL degradation of lipids in cancer cells enhances the availability of free fatty acids for new cellular membrane formation and pro-oncogenic lipid modulators. The multifaceted role of MAGL has greatly stimulated the search for MAGL inhibitors, which could be effective to treat diseases, such as inflammation, neurodegeneration and cancer.

Areas Covered: This review covers patents published since 2018 up to now, concerning new MAGL inhibitors and their potential therapeutic applications.

Expert Opinion: In the years 2018-2020, several well-known chemical scaffolds of MAGL inhibitors have been further optimized and developed and some new chemical classes have also been identified as MAGL inhibitors. Moreover, an increasing number of scientific publications covering MAGL inhibitors is focused on MAGL-specific positron emission tomography (PET) ligands. The numerous efforts of pharmaceutical companies and academic research groups finalized to find new potent MAGL inhibitors confirm that this research area is rapidly growing. Nevertheless, most of the patented compounds still belong to the large group of irreversible MAGL inhibitors, highlighting that the development of reversible MAGL inhibitors is still an unmet pharmaceutical need.
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http://dx.doi.org/10.1080/13543776.2021.1841166DOI Listing
February 2021

Design, synthesis and biological evaluation of second-generation benzoylpiperidine derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors.

Eur J Med Chem 2021 Jan 7;209:112857. Epub 2020 Oct 7.

Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012, Bern, Switzerland.

An interesting enzyme of the endocannabinoid system is monoacylglycerol lipase (MAGL). This enzyme, which metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG), has attracted great interest due to its involvement in several physiological and pathological processes, such as cancer progression. Experimental evidences highlighted some drawbacks associated with the use of irreversible MAGL inhibitors in vivo, therefore the research field concerning reversible inhibitors is rapidly growing. In the present manuscript, the class of benzoylpiperidine-based MAGL inhibitors was further expanded and optimized. Enzymatic assays identified some compounds in the low nanomolar range and steered molecular dynamics simulations predicted the dissociation itinerary of one of the best compounds from the enzyme, confirming the observed structure-activity relationship. Biological evaluation, including assays in intact U937 cells and competitive activity-based protein profiling experiments in mouse brain membranes, confirmed the selectivity of the selected compounds for MAGL versus other components of the endocannabinoid system. An antiproliferative ability in a panel of cancer cell lines highlighted their potential as potential anticancer agents. Future studies on the potential use of these compounds in the clinical setting are also supported by the inhibition of cell growth observed both in cancer organoids derived from high grade serous ovarian cancer patients and in pancreatic ductal adenocarcinoma primary cells, which showed genetic and histological features very similar to the primary tumors.
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http://dx.doi.org/10.1016/j.ejmech.2020.112857DOI Listing
January 2021

The endocannabinoid system dual-target ligand N-cycloheptyl-1,2-dihydro-5-bromo-1-(4-fluorobenzyl)-6-methyl-2-oxo-pyridine-3-carboxamide improves disease severity in a mouse model of multiple sclerosis.

Eur J Med Chem 2020 Dec 29;208:112858. Epub 2020 Sep 29.

Department of Pharmacy, University of Pisa, 56126, Pisa, Italy. Electronic address:

Multiple sclerosis is a chronic inflammatory demyelinating disorder of the central nervous system that eventually leads to progressive neurodegeneration and disability. Recent findings highlighted the emerging role of each target of the endocannabinoid system in controlling the symptoms and disease progression of multiple sclerosis. Therefore, multi-target modulators of the endocannabinoid system could provide a more effective pharmacological strategy as compared to the single target modulation. In this work, N-cycloheptyl-1,2-dihydro-5-bromo-1-(4-fluorobenzyl)-6-methyl-2-oxo-pyridine-3-carboxamide (B2) was identified as the most promising compound with dual agonism at cannabinoid receptors type-1 and cannabinoid receptors type-2 and good drug-like properties. In in vitro assays, B2 reduced glutamate release from rat synaptosomes through interaction with cannabinoid receptors type-1 and modulated the production of the pro- and anti-inflammatory cytokines (interleukins IL-1β and IL-6 and interleukin IL-10 respectively) via cannabinoid receptors type-2 activation. Furthermore, B2 demonstrated antinociceptive effects in an animal model of neuropathic pain and efficacy in an experimental autoimmune encephalomyelitis model of multiple sclerosis.
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http://dx.doi.org/10.1016/j.ejmech.2020.112858DOI Listing
December 2020

Three-Dimensional Interactions Analysis of the Anticancer Target c-Src Kinase with Its Inhibitors.

Cancers (Basel) 2020 Aug 18;12(8). Epub 2020 Aug 18.

Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.

Src family kinases (SFKs) constitute the biggest family of non-receptor tyrosine kinases considered as therapeutic targets for cancer therapy. An aberrant expression and/or activation of the proto-oncogene c-Src kinase, which is the oldest and most studied member of the family, has long been demonstrated to play a major role in the development, growth, progression and metastasis of numerous human cancers, including colon, breast, gastric, pancreatic, lung and brain carcinomas. For these reasons, the pharmacological inhibition of c-Src activity represents an effective anticancer strategy and a few compounds targeting c-Src, together with other kinases, have been approved as drugs for cancer therapy, while others are currently undergoing preclinical studies. Nevertheless, the development of potent and selective inhibitors of c-Src aimed at properly exploiting this biological target for the treatment of cancer still represents a growing field of study. In this review, the co-crystal structures of c-Src kinase in complex with inhibitors discovered in the past two decades have been described, highlighting the key ligand-protein interactions necessary to obtain high potency and the features to be exploited for addressing selectivity and drug resistance issues, thus providing useful information for the design of new and potent c-Src kinase inhibitors.
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http://dx.doi.org/10.3390/cancers12082327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466017PMC
August 2020

Aldose Reductase Differential Inhibitors in Green Tea.

Biomolecules 2020 07 6;10(7). Epub 2020 Jul 6.

Biochemistry Unit, Department of Biology, University of Pisa, via S. Zeno, 51, 56123 Pisa, Italy.

Aldose reductase (AKR1B1), the first enzyme in the polyol pathway, is likely involved in the onset of diabetic complications. Differential inhibition of AKR1B1 has been proposed to counteract the damaging effects linked to the activity of the enzyme while preserving its detoxifying ability. Here, we show that epigallocatechin gallate (EGCG), one of the most representative catechins present in green tea, acts as a differential inhibitor of human recombinant AKR1B1. A kinetic analysis of EGCG, and of its components, gallic acid (GA) and epigallocatechin (EGC) as inhibitors of the reduction of L-idose, 4-hydroxy2,3-nonenal (HNE), and 3-glutathionyl l-4-dihydroxynonanal (GSHNE) revealed for the compounds a different model of inhibition toward the different substrates. While EGCG preferentially inhibited L-idose and GSHNE reduction with respect to HNE, gallic acid, which was still active in inhibiting the reduction of the sugar, was less active in inhibiting HNE and GSHNE reduction. EGC was found to be less efficient as an inhibitor of AKR1B1 and devoid of any differential inhibitory action. A computational study defined different interactive modes for the three substrates on the AKR1B1 active site and suggested a rationale for the observed differential inhibition. A chromatographic fractionation of an alcoholic green tea extract revealed that, besides EGCG and GA, other components may exhibit the differential inhibition of AKR1B1.
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http://dx.doi.org/10.3390/biom10071003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407822PMC
July 2020

Shedding X-ray Light on the Role of Magnesium in the Activity of Salicylate Synthase (MbtI) for Drug Design.

J Med Chem 2020 07 25;63(13):7066-7080. Epub 2020 Jun 25.

Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via L. Mangiagalli 25, 20133 Milano,Italy.

The Mg-dependent salicylate synthase (MbtI) is a key enzyme involved in the biosynthesis of siderophores. Because iron is essential for the survival and pathogenicity of the microorganism, this protein constitutes an attractive target for antitubercular therapy, also considering the absence of homologous enzymes in mammals. An extension of the structure-activity relationships of our furan-based candidates allowed us to disclose the most potent competitive inhibitor known to date (, = 4 μM), which also proved effective on mycobacterial cultures. By structural studies, we characterized its unexpected Mg-independent binding mode. We also investigated the role of the Mg cofactor in catalysis, analyzing the first crystal structure of the MbtI-Mg-salicylate ternary complex. Overall, these results pave the way for the development of novel antituberculars through the rational design of improved MbtI inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008425PMC
July 2020

Discovery of a new ATP-citrate lyase (ACLY) inhibitor identified by a pharmacophore-based virtual screening study.

J Biomol Struct Dyn 2020 Jun 2:1-9. Epub 2020 Jun 2.

Department of Pharmacy, University of Pisa, Pisa, Italy.

ATP citrate lyase (ACLY) is an important enzyme that catalyzes the conversion of citrate to acetyl-CoA in normal cells, facilitating the fatty acid synthesis. Lipids and fatty acids were found to be accumulated in different types of tumors, such as brain, breast, rectal and ovarian cancer, representing a great source of energy for cancer cell growth and metabolism. Since ACLY-mediated conversion of citrate to acetyl-CoA constitutes the basis for fatty acid synthesis, ACLY seems to be quite an unexplored and promising therapeutic target for anticancer drug design. A pharmacophore-based virtual screening (VS) protocol with the aid of hierarchical docking, consensus docking (CD), molecular dynamics (MD) simulations and ligand-protein binding free energy calculations led to the identification of compound VS1, which showed a moderate but promising inhibitory activity, demonstrating to be 2.5 times more potent than reference inhibitor 2-hydroxycitrate. These results validate the reliability of our VS workflow and pave the way for the design of novel and more potent ACLY inhibitors.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1773314DOI Listing
June 2020

N-aryl-N'-ureido-O-sulfamates as potent and selective inhibitors of hCA VB over hCA VA: Deciphering the binding mode of new potential agents in mitochondrial dysfunctions.

Bioorg Chem 2020 07 4;100:103896. Epub 2020 May 4.

University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address:

N-aryl-N'-ureido-O-sulfamates (AUSs) were recently reported as new class of Carbonic Anhydrase Inhibitors (CAIs), endowed of high potency and selectivity against hCA VII and XII. In this work, we extended the investigational study on this new class of CAIs profiling them against the mitochondrial CA isoforms hCA VA and VB. The results revealed a very interesting selectivity profile, with dramatic selectivity against hCA VB over the VA isoform observed for all the analyzed compounds 2-22. On derivative 15, selected as one of the most promising among the series, molecular modeling studies were conducted, highlighting the importance of small residue substitution between the two isoforms in substantially changing the tail orientation and interaction with the enzymes.
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http://dx.doi.org/10.1016/j.bioorg.2020.103896DOI Listing
July 2020

Application of MM-PBSA Methods in Virtual Screening.

Molecules 2020 Apr 23;25(8). Epub 2020 Apr 23.

Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.

Computer-aided drug design techniques are today largely applied in medicinal chemistry. In particular, receptor-based virtual screening (VS) studies, in which molecular docking represents the gold standard in silico approach, constitute a powerful strategy for identifying novel hit compounds active against the desired target receptor. Nevertheless, the need for improving the ability of docking in discriminating true active ligands from inactive compounds, thus boosting VS hit rates, is still pressing. In this context, the use of binding free energy evaluation approaches can represent a profitable tool for rescoring ligand-protein complexes predicted by docking based on more reliable estimations of ligand-protein binding affinities than those obtained with simple scoring functions. In the present review, we focused our attention on the Molecular Mechanics-Poisson Boltzman Surface Area (MM-PBSA) method for the calculation of binding free energies and its application in VS studies. We provided examples of successful applications of this method in VS campaigns and evaluation studies in which the reliability of this approach has been assessed, thus providing useful guidelines for employing this approach in VS.
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http://dx.doi.org/10.3390/molecules25081971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221544PMC
April 2020

Antibacterial and ATP Synthesis Modulating Compounds from .

J Nat Prod 2020 04 17;83(4):1027-1042. Epub 2020 Mar 17.

Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Salerno, Italy.

A surface extract of the aerial parts of afforded a nor-sesterterpenoid () and eight new sesterterpenoids (-̵), along with five known sesterterpenoids, five labdane and one abietane diterpenoid, one sesquiterpenoid, and four flavonoids. The structures of the new compounds were established by 1D and 2D NMR spectroscopy, HRESIMS, and VCD data and Mosher's esters analysis. The antimicrobial activity of compounds was evaluated against 30 human pathogens including 27 clinical strains and three isolates of marine origin for their possible implications on human health. The methyl ester of salvileucolide (), salvileucolide-6,23-lactone (), sclareol (), and manool () were the most active against Gram-positive bacteria. The compounds were also tested for the inhibition of ATP production in purified mammalian rod outer segments. Terpenoids , , , and inhibited ATP production, while only inhibited also ATP hydrolysis. Molecular modeling studies confirmed the capacity of to interact with mammalian ATP synthase. A significant reduction of ATP production in the presence of was observed in and isolates.
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http://dx.doi.org/10.1021/acs.jnatprod.9b01024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997632PMC
April 2020

1,3-Dipolar Cycloaddition, HPLC Enantioseparation, and Docking Studies of Saccharin/Isoxazole and Saccharin/Isoxazoline Derivatives as Selective Carbonic Anhydrase IX and XII Inhibitors.

J Med Chem 2020 03 4;63(5):2470-2488. Epub 2020 Feb 4.

Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.

Two series of saccharin/isoxazole and saccharin/isoxazoline hybrids were synthesized by 1,3-dipolar cycloaddition. The new compounds showed to be endowed with potent and selective inhibitory activity against the cancer-related human carbonic anhydrase (hCA) IX and XII isoforms in the nanomolar range, while no affinity was encountered for off-targets, such as hCA I and II. Successive enantioseparation on a milligram scale of the most representative compounds led to the discovery that (S)-isomers were more potent than their corresponding (R)-enantiomers. Lastly, molecular modeling studies were conducted to define those structural requirements that were responsible for the discrimination among selected human isoforms of carbonic anhydrases. Two nanomolar hCA IX and XII inhibitors were also screened for their selective toxicity against non tumoral primary cells (fibroblasts) and against a breast adenocarcinoma cell line (MCF7) in hypoxic environment. The efficacious combination of these compounds with doxorubicin on MCF7 cells was demonstrated after 72 h of treatment.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01434DOI Listing
March 2020

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-6.

Molecules 2019 Dec 28;25(1). Epub 2019 Dec 28.

Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências, Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal [...].
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http://dx.doi.org/10.3390/molecules25010119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983133PMC
December 2019

The History of Nanoscience and Nanotechnology: From Chemical-Physical Applications to Nanomedicine.

Molecules 2019 Dec 27;25(1). Epub 2019 Dec 27.

Pathology Unit, IRCCS CRO Aviano-National Cancer Institute, 33081 Aviano, Italy.

Nanoscience breakthroughs in almost every field of science and nanotechnologies make life easier in this era. Nanoscience and nanotechnology represent an expanding research area, which involves structures, devices, and systems with novel properties and functions due to the arrangement of their atoms on the 1-100 nm scale. The field was subject to a growing public awareness and controversy in the early 2000s, and in turn, the beginnings of commercial applications of nanotechnology. Nanotechnologies contribute to almost every field of science, including physics, materials science, chemistry, biology, computer science, and engineering. Notably, in recent years nanotechnologies have been applied to human health with promising results, especially in the field of cancer treatment. To understand the nature of nanotechnology, it is helpful to review the timeline of discoveries that brought us to the current understanding of this science. This review illustrates the progress and main principles of nanoscience and nanotechnology and represents the pre-modern as well as modern timeline era of discoveries and milestones in these fields.
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http://dx.doi.org/10.3390/molecules25010112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982820PMC
December 2019

Development of a cheminformatics platform for selectivity analyses of carbonic anhydrase inhibitors.

J Enzyme Inhib Med Chem 2020 Dec;35(1):365-371

Department of Pharmacy, University of Pisa, Pisa, Italy.

The selectivity for a specific human Carbonic Anhydrase (hCA) isoform is an important property a hCA inhibitor (CAI) should be endowed with, in order to constitute a valuable therapeutic tool for the treatment of a desired pathology. In this context, we developed a chemoinformatic platform that allows the analysis of the structure and selectivity profile of known CAIs reported in literature, with the aim of identifying structural motifs connected to ligand selectivity, thus providing useful guidelines for the design of novel ligands selective for the desired hCA isoform. The platform is able to perform ultrafast structure and selectivity analyses through ligand fingerprint similarity, with no need of structural information about the target receptor and ligands' binding mode. It is easily accessible to the non-expert user through the implementation of a KNIME Analytic Platform workflow and could be extended to analyze the selectivity profile of known ligands of different target proteins.
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http://dx.doi.org/10.1080/14756366.2019.1705291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968703PMC
December 2020

The Extra-Virgin Olive Oil Polyphenols Oleocanthal and Oleacein Counteract Inflammation-Related Gene and miRNA Expression in Adipocytes by Attenuating NF-κB Activation.

Nutrients 2019 Nov 21;11(12). Epub 2019 Nov 21.

Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.

Inflammation of the adipose tissue plays an important role in the development of several chronic diseases associated with obesity. Polyphenols of extra virgin olive oil (EVOO), such as the secoiridoids oleocanthal (OC) and oleacein (OA), have many nutraceutical proprieties. However, their roles in obesity-associated adipocyte inflammation, the NF-κB pathway and related sub-networks have not been fully elucidated. Here, we investigated impact of OC and OA on the activation of NF-κB and the expression of molecules associated with inflammatory and dysmetabolic responses. To this aim, fully differentiated Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were pre-treated with OC or OA before stimulation with TNF-α. EVOO polyphenols significantly reduced the expression of genes implicated in adipocyte inflammation (IL-1β, COX-2), angiogenesis (VEGF/KDR, MMP-2), oxidative stress (NADPH oxidase), antioxidant enzymes (SOD and GPX), leukocytes chemotaxis and infiltration (MCP-1, CXCL-10, MCS-F), and improved the expression of the anti-inflammatory/metabolic effector PPARγ. Accordingly, miR-155-5p, miR-34a-5p and let-7c-5p, tightly connected with the NF-κB pathway, were deregulated by TNF-α in both cells and exosomes. The miRNA modulation and NF-κB activation by TNF-α was significantly counteracted by EVOO polyphenols. Computational studies suggested a potential direct interaction between OC and NF-κB at the basis of its activity. This study demonstrates that OC and OA counteract adipocyte inflammation attenuating NF-κB activation. Therefore, these compounds could be novel dietary tools for the prevention of inflammatory diseases associated with obesity.
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http://dx.doi.org/10.3390/nu11122855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950227PMC
November 2019

Modification on the 1,2-dihydro-2-oxo-pyridine-3-carboxamide core to obtain multi-target modulators of endocannabinoid system.

Bioorg Chem 2020 01 17;94:103353. Epub 2019 Oct 17.

Department of Pharmacy, University of Pisa, 56126 Pisa, Italy. Electronic address:

Several preclinical evidence indicate that the modulation of the endocannabinoid system (ECS) represents a promising therapeutic approach for different diseases. However, only few modulators of this system have reached so far an advanced stage of clinical development, mainly due to limited efficacy and CB1 receptor-dependent side effects. Those limitations might be overcome by multi-target compounds that exert pro-cannabinoid activities through the modulation of two or more targets in the ECS. This approach can offer a safer and more effective pharmacological strategy as compared to the modulation of a single target. In this work, we report the synthesis and biological characterization of new 6-aryl-1,2-dihydro-2-oxo-pyridine-3-carboxamide derivatives. Our results identified several compounds exhibiting interesting multi-target profiles within the ECS. In particular, compound B1 showed moderate-to-high affinity for cannabinoid receptors (Ki CB1R = 304 nM, partial agonist, Ki CB2R = 3.1 nM, inverse agonist) and a potent inhibition of AEA uptake (IC = 62 nM) with moderate inhibition of FAAH (IC = 2.9 μM). The corresponding 2-alkoxypyridine analogue B14 exhibited significant inhibitor activity on both FAAH (IC = 69 nM) and AEA uptake (IC = 76 nM) without significantly binding to both cannabinoid receptor subtypes. Molecular docking analysis was carried out on the three-dimensional structures of CB1R and CB2R and of FAAH to rationalize the structure-activity relationships of this series of compounds.
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http://dx.doi.org/10.1016/j.bioorg.2019.103353DOI Listing
January 2020

Stereoselectivity of Aldose Reductase in the Reduction of Glutathionyl-Hydroxynonanal Adduct.

Antioxidants (Basel) 2019 Oct 22;8(10). Epub 2019 Oct 22.

Biochemistry Unit, Department of Biology, University of Pisa, via S. Zeno 51, 56127 Pisa, Italy.

The formation of the adduct between the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) and glutathione, which leads to the generation of 3-glutathionyl-4-hydroxynonane (GSHNE), is one of the main routes of HNE detoxification. The aldo-keto reductase AKR1B1 is involved in the reduction of the aldehydic group of both HNE and GSHNE. In the present study, the effect of chirality on the recognition by aldose reductase of HNE and GSHNE was evaluated. AKR1B1 discriminates very modestly between the two possible enantiomers of HNE as substrates. Conversely, a combined kinetic analysis of the glutathionyl adducts obtained starting from either 4R- or 4S-HNE and mass spectrometry analysis of GSHNE products obtained from racemic HNE revealed that AKR1B1 possesses a marked preference toward the 3S,4R-GSHNE diastereoisomer. Density functional theory and molecular modeling studies revealed that this diastereoisomer, besides having a higher tendency to be in an open aldehydic form (the one recognized by AKR1B1) in solution than other GSHNE diastereoisomers, is further stabilized in its open form by a specific interaction with the enzyme active site. The relevance of this stereospecificity to the final metabolic fate of GSHNE is discussed.
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http://dx.doi.org/10.3390/antiox8100502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827081PMC
October 2019

Synthesis and Biological Evaluation of New Glycoconjugated LDH Inhibitors as Anticancer Agents.

Molecules 2019 Sep 28;24(19). Epub 2019 Sep 28.

Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via G. Moruzzi 3, 56124 Pisa, Italy.

Conjugation of known biologically active molecules to carbohydrate frameworks represents a valuable option for the preparation of hybrid, structurally-related families of compounds with the aim of modulating their biological response. Therefore, we present here a study on the preparation of d-, d-, d-, and d- glycoconjugates of an established -hydroxyindole-based (NHI) inhibitor of lactated dehydrogenase (LDH). Structural variations involved the sugar stereochemistry and size as well as the anchoring point of the NHI on the carbohydrate frame (either C-1 or C-6). In the case of the galactose anomeric glycoconjugate (C-1), intriguing solvent-dependent effects were observed in the glycosylation stereochemical outcome. The biological activity of the deprotected glycoconjugates in contrasting lactate formation and cancer cell proliferation are described.
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http://dx.doi.org/10.3390/molecules24193520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804087PMC
September 2019

The dichotomous role of the glycolytic metabolism pathway in cancer metastasis: Interplay with the complex tumor microenvironment and novel therapeutic strategies.

Semin Cancer Biol 2020 02 21;60:238-248. Epub 2019 Aug 21.

Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6 and 33, 56126, Pisa, Italy.

Cancer metastasis to distant organs is initiated by tumor cells that disseminate from primary heterogeneous tumors. The subsequent growth and survival of tumor metastases depend on different metabolic changes, which constitute one of the enigmatic properties of tumor cells. Aerobic glycolysis, 'the Warburg effect', contributes to tumor energy supply, by oxidizing glucose in a faster manner compared to oxidative phosphorylation, leading to an increased lactate production by lactate dehydrogenase A (LDH-A), which in turn affects the immune response. Surrounding stromal cells contribute to feedback mechanisms further prompting the acquisition of pro-invasive metabolic features. Hence, therapeutic strategies targeting the glycolytic pathway are intensively investigated, with a special interest on their anti-metastatic properties. Various small molecules, such as LDH-A inhibitors, have shown pre-clinical activity against different cancer types, and blocking LDH-A could also help in designing future complimentary therapies. Modulation of specific targets in cells with an altered glycolytic metabolism should indeed result in a milder and distinct toxicity profile, compared to conventional cytotoxic therapy, while a combination treatment with vitamin C leading to increasing reactive oxygen species levels, should further inhibit cancer cell survival and invasion. In this review we describe the impact of metabolic reprogramming in cancer metastasis, the contribution of lactate in this aberrant process and its effect on oncogenic processes. Furthermore, we discuss experimental compounds that target glycolytic metabolism, such as LDH-A inhibitors, and their potential to improve current and experimental therapeutics against metastatic tumors.
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http://dx.doi.org/10.1016/j.semcancer.2019.08.025DOI Listing
February 2020

Editorial: Peptidyl-Prolyl Isomerases in Human Pathologies.

Front Pharmacol 2019 11;10:794. Epub 2019 Jul 11.

Department of Translational Research, Pathology Unit, National Cancer Institute-CRO-IRCSS, Aviano, Italy.

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http://dx.doi.org/10.3389/fphar.2019.00794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637298PMC
July 2019

The influence of Echinacea purpurea leaf microbiota on chicoric acid level.

Sci Rep 2019 07 26;9(1):10897. Epub 2019 Jul 26.

Department of Biology, University of Florence, Via Madonna del Piano 6, 50019, Sesto Fiorentino, Italy.

The controversial anti-proliferative effects of Echinacea purpurea (L.) Moench (Asteraceae) might be related to different plant metabolites contained in plant samples, extracts and products. The influence of bacterial endophytes on the synthesis of bioactive compounds in the medicinal plants has been previously demonstrated but there are only few studies addressing anticancer effects and mechanisms of E. purpurea extracts following endophytic colonization. The present study aimed to test and compare the lactate dehydrogenase (LDH) inhibition potential of n-hexane and methanol extracts from in vitro endophyte non-inoculated and inoculated E. purpurea plants. An in vitro model was previously set up to perform the infection of axenic E. purpurea plants with bacterial endophytic strains isolated from E. purpurea aerial part. Only methanol extracts showed LDH5 inhibition, in particular the richest in chicoric acid and most strongly inhibiting extract was obtained from inoculated stem and leaves of E. purpurea (IC = 0.9 mg/ml). Chicoric acid showed an IC value (66.7 µM) in enzymatic assays better than that of the reference compound galloflavin. Modeling studies were carried out to suggest the putative interaction mode of chicoric acid in the enzyme active site. This in vitro model on plant-bacterial interaction may lead to obtain extracts from plants enriched in bioactive compounds and it is a new approach for the discovery of novel anticancer compounds.
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http://dx.doi.org/10.1038/s41598-019-47329-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659708PMC
July 2019

Former Foodstuff Products in Rearing: Effects on Growth, Chemical Composition, Microbiological Load, and Antioxidant Status.

Animals (Basel) 2019 Jul 25;9(8). Epub 2019 Jul 25.

Department of Veterinary Sciences, University of Pisa, Viale delle Piagge 2, 56124 Pisa, Italy.

(mealworm) larvae represent one of the most interesting edible insects and could be reared on alternative feeds, such as former foodstuff products (FFPs). In the present work, five different FFPs (brewery spent grains, bread and cookie leftovers, and mixes of brewer's spent grain or bread with cookies) were employed as feeding substrates. Larvae's growth performances, chemical composition, microbial loads, and antioxidant status were determined. Chemical compositions of the substrates affected all the tested parameters. Brewery spent grains-fed larvae showed a faster growth period and higher crude protein and carbohydrate contents. The use of cookies as a single substrate or their addition to spent grains or bread increased the lipids contents, while growth was delayed. Microbial loads were partially affected by the fed diet. The antioxidant status of larvae showed different concentrations of tocopherols isoforms (δ, γ, α) in relation to the diet; however, no differences were detected in relation to the global antioxidant capacity (2,2-azinobis-(3 ethylbenzothiazoline-6-sulfonic acid), ABTS reducing activity; 1,1-diphenyl-2-pircydrazyl, DPPH radical scavenging activity; ferric reducing ability, FRAP). Results point out a high plasticity of mealworm larvae and the potential to tailor the final outcomes in relation to the substrate employed. Mealworms could be practically reared on FFPs to produce food-feed with high nutrient values.
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http://dx.doi.org/10.3390/ani9080484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720556PMC
July 2019