Publications by authors named "Paolo Tortorella"

86 Publications

Inhibition of bacterial and human zinc-metalloproteases by bisphosphonate- and catechol-containing compounds.

J Enzyme Inhib Med Chem 2021 Dec;36(1):819-830

Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway.

Compounds containg catechol or bisphosphonate were tested as inhibitors of the zinc metalloproteases, thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) which are bacterial virulence factors, and the human matrix metalloproteases MMP-9 and -14. Inhibition of virulence is a putative strategy in the development of antibacterial drugs, but the inhibitors should not interfere with human enzymes. Docking indicated that the inhibitors bound MMP-9 and MMP-14 with the phenyl, biphenyl, chlorophenyl, nitrophenyl or methoxyphenyl ringsystem in the S'-subpocket, while these ringsystems entered the S'- or S -subpockets or a region involving amino acids in the S'- and S'-subpockets of the bacterial enzymes. An arginine conserved among the bacterial enzymes seemed to hinder entrance deeply into the S'-subpocket. Only the bisphosphonate containing compound RC2 bound stronger to PLN and TLN than to MMP-9 and MMP-14. Docking indicated that the reason was that the conserved arginine (R203 in TLN and R198 in PLN) interacts with phosphate groups of RC2.
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http://dx.doi.org/10.1080/14756366.2021.1901088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993378PMC
December 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

Discovery of 7-aminophenanthridin-6-one as a new scaffold for matrix metalloproteinase inhibitors with multitarget neuroprotective activity.

Eur J Med Chem 2021 Jan 30;210:113061. Epub 2020 Nov 30.

Unidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, 28040, Madrid, Spain. Electronic address:

Matrix metalloproteinases (MMPs) are zinc-dependent hydrolytic enzymes of great biological relevance, and some of them are key to the neuroinflammatory events and the brain damage associated to stroke. Non-zinc binding ligands are an emerging trend in drug discovery programs in this area due to their lower tendency to show off-target effects. 7-Amino-phenanthridin-6-one is disclosed as a new framework able to inhibit matrix metalloproteinases by binding to the distal part of the enzyme S1' site, as shown by computational studies. A kinetic study revealed inhibition to be noncompetitive. Some of the compounds showed some degree of selectivity for the MMP-2 and MMP-9 enzymes, which are crucial for brain damage associated to ischemic stroke. Furthermore, some compounds also had a high neuroprotective activity against oxidative stress, which is also very relevant aspect of ischaemic stroke pathogenesis, both decreasing lipid peroxidation and protecting against the oxidative stress-induced reduction in cell viability. One of the compounds, bearing a 2-thienyl substituent at C-9 and a 4-methoxyphenylamino at C-7, had the best-balanced multitarget profile and was selected as a lead on which to base future structural manipulation.
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http://dx.doi.org/10.1016/j.ejmech.2020.113061DOI Listing
January 2021

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

Sulfonimide and Amide Derivatives as Novel PPARα Antagonists: Synthesis, Antiproliferative Activity, and Docking Studies.

ACS Med Chem Lett 2020 May 3;11(5):624-632. Epub 2020 Mar 3.

Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, Via Dei Vestini 31, 66100 Chieti, Italy.

An agonist-antagonist switching strategy was performed to discover novel PPARα antagonists. Phenyldiazenyl derivatives of fibrates were developed, bearing sulfonimide or amide functional groups. A second series of compounds was synthesized, replacing the phenyldiazenyl moiety with amide or urea portions. Final compounds were screened by transactivation assay, showing good PPARα antagonism and selectivity at submicromolar concentrations. When tested in cancer cell models expressing PPARα, selected derivatives induced marked effects on cell viability. Notably, , , and displayed remarkable antiproliferative effects in two paraganglioma cell lines, with CC lower than commercial PPARα antagonist GW6471 and a negligible toxicity on normal fibroblast cells. Docking studies were also performed to elucidate the binding mode of these compounds and to help interpretation of SAR data.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236056PMC
May 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

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

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

Synthesis of novel benzothiazole amides: Evaluation of PPAR activity and anti-proliferative effects in paraganglioma, pancreatic and colorectal cancer cell lines.

Bioorg Med Chem Lett 2019 08 18;29(16):2302-2306. Epub 2019 Jun 18.

Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università "G. d'Annunzio", Chieti, Italy.

The reduced activation of PPARs has a positive impact on cancer cell growth and viability in multiple preclinical tumor models, suggesting a new therapeutic potential for PPAR antagonists. In the present study, the benzothiazole amides 2a-g were synthesized and their activities on PPARs were investigated. Transactivation assay showed a moderate activity of the novel compounds as PPARα antagonists. Notably, in cellular assays they exhibited cytotoxicity in pancreatic, colorectal and paraganglioma cancer cells overexpressing PPARα. In particular, compound 2b showed the most remarkable inhibition of viability (greater than 90%) in two paraganglioma cell lines, with IC values in the low micromolar range. In addition, 2b markedly impaired colony formation capacity in the same cells. Taken together, these results show a relevant anti-proliferative potential of compound 2b, which appears particularly effective in paraganglioma, a rare tumor poorly responsive to chemotherapy.
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http://dx.doi.org/10.1016/j.bmcl.2019.06.020DOI Listing
August 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

Novel Phenyldiazenyl Fibrate Analogues as PPAR α/γ/δ Pan-Agonists for the Amelioration of Metabolic Syndrome.

ACS Med Chem Lett 2019 Apr 25;10(4):545-551. Epub 2019 Feb 25.

Department of Pharmacy, "Drug Discovery" Laboratory, University of Napoli "Federico II", Via D. Montesano, 49, 80131 Napoli, Italy.

The development of PPARα/γ dual or PPARα/γ/δ pan-agonists could represent an efficacious approach for a simultaneous pharmacological intervention on carbohydrate and lipid metabolism. Two series of new phenyldiazenyl fibrate derivatives of GL479, a previously reported PPARα/γ dual agonist, were synthesized and tested. Compound was identified as a PPAR pan-agonist with moderate and balanced activity on the three PPAR isoforms (α, γ, δ). Moreover, docking experiments showed that adopts a different binding mode in PPARγ compared to PPARα or PPARδ, providing a structural basis for further structure-guided design of PPAR pan-agonists. The beneficial effects of were evaluated both , on the expression of PPAR target key metabolic genes, and in two rat tissue inflammatory models. The obtained results allow considering this compound as an interesting lead for the development of a new class of PPAR pan-agonists endowed with an activation profile exploitable for therapy of metabolic syndrome.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466826PMC
April 2019

Novel bisphosphonates with antiresorptive effect in bone mineralization and osteoclastogenesis.

Eur J Med Chem 2018 Oct 18;158:184-200. Epub 2018 Aug 18.

Department of Pharmacy - Pharmaceutical Sciences, University of Bari "A. Moro", via E. Orabona 4, 70125, Bari, Italy. Electronic address:

Bisphosphonates such as zoledronic, alendronic and risedronic acids are a class of drugs clinically used to prevent bone density loss and osteoporosis. Novel P-C-P bisphosphonates were synthesized for targeting human farnesyl pyrophosphate synthase (hFPPS) and human geranylgeranyl pyrophosphate synthase (hGGPPS), key enzymes of the mevalonate pathway, and capable of anti-proliferative action on a number of cell lines (PC3, MG63, MC3T3, RAW 264.7, J774A.1, bone marrow cells and their co-colture with PC3) involved in bone homeostasis, bone formation and death. Among sixteen compounds, [1-hydroxy-2-(pyrimidin-2-ylamino)ethane-1,1-diyl]bis(phosphonic acid) (10) was effective in reducing PC3 and RAW 264.7 cell number in crystal-violet and cell-dehydrogenase activity assays at 100 μM concentration. 10 reduced differentiated osteoclasts number similarly with zoledronic acid in osteoclastogenesis assay. At nanomolar concentrations, 10 was more effective than zoledronic acid in inducing mineralization in MC3T3 and murine bone marrow cells. Further, 10 significantly inhibited the activity of hFPPS showing an IC of 0.31 μM and a remarkable hydroxyapatite binding of 90%. Docking calculations were performed identifying putative interactions between some representative novel bisphosphonates and both hFPPS and hGGPPS. Then, 10 was found to behave similarly or even better than zoledronic acid as a anti-resorptive agent.
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http://dx.doi.org/10.1016/j.ejmech.2018.08.044DOI Listing
October 2018

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

[The Adherence's indicators of cancer patients to oral chemotherapy. A sistematic literature review].

Prof Inferm 2018 Apr-Jun;71(2):67-78

Professore Associato. Dipartimento di Sanità pubblica, Sezione di Igiene, Università Cattolica del S. Cuore - Roma.

Introduction: Adherence has a key role in treating patients as influences the effectiveness of therapeutic treatment for improving overall survival, life expectancy, quality of life and reducing healthcare costs. There are gaps in identifying indicators to be used to evaluate adherence and ways in which these indicators should be adopted. The aim of this paper is to identify adherence's indicators in literature.

Methods: Systematic review was carried out in, Cinhal-EBSCO, Medline-PUBMED and Scopus including studies of measure patient's adherence in English and published from 2010 to 2016. Inclusion and exclusion criteria were used. The quality of the articles was assessed with the NewCastle Ottawa Scale for observational studies and the Cochrane Collaboration Risk of Bias for experimental studies.

Results: Of the 7,368 papers initially retrieved, 15 met the inclusion criteria (11 observational studies, 4 RCTs), for a total of 1,396 patients. The indicators found are: self-report tools, pill counts, drug recharge rate, continuous measures, metabolic dosage. A patient is considered adherent to the treatment if he or she assumes a percentage of drugs ≥ 80% of the prescribed medications.

Discussion: A better adherence rating is obtained by using multiple instruments at the same time. The objective indicators derive from the direct measurement methods of adherence, the subjective ones from the indirect.
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http://dx.doi.org/10.7429/pi.2018.712067DOI Listing
August 2019

Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study.

Int J Mol Med 2018 Jul 25;42(1):651-657. Epub 2018 Apr 25.

Department of Pharmacy, University 'G. d'Annunzio' Chieti‑Pescara, I‑66100 Chieti, Italy.

Periodontitis is an inflammatory disease caused by anaerobic bacteria, including Porphyromonas gingivalis. Lipopolysaccharide (LPS)‑stimulated persistent inflammation is responsible for an increase in matrix metalloproteinase (MMP) expression, resulting in periodontal tissue destruction. The aim of the present study was to investigate synthesized bisphosphonic MMP inhibitors, in an in vitro model consisting of human gingival fibroblasts exposed to LPS, and to compare the biological responses to those induced by zoledronate (ZA), a commercial bisphosphonate. MTT and lactate dehydrogenase (LDH) assays were used to measure cell viability and cytotoxicity, respectively. ELISA was performed to evaluate prostaglandin E2 (PGE2), interleukin (IL)6 and collagen secretion, while western blotting was used to analyze MMP expression. No effect on viability and low cytotoxicity were observed following treatment with bisphosphonate compounds. In the present study, treatment with compound 1 did not increase the release of PGE2 and IL6. Increased levels of collagen I secretion were reported when compound 3 and ZA were administered. An increase of MMP8 was observed following ZA treatment, while a decrease of MMP9 and MMP14 following treatment with compounds 1, 2 and ZA were reported. The performance of compound 1 was optimal in terms of cell viability. Compound 1 also did not induce inflammation, and had the ability to counteract LPS‑induced increases in MMP expression. These data suggested that compound 1 was the most suitable treatment to progress to an in vivo animal study, with the aim to confirm its use for the treatment of periodontitis.
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http://dx.doi.org/10.3892/ijmm.2018.3641DOI Listing
July 2018

Dual targeting of cancer-related human matrix metalloproteinases and carbonic anhydrases by chiral N-(biarylsulfonyl)-phosphonic acids.

J Enzyme Inhib Med Chem 2017 Dec;32(1):1260-1264

b Department of Pharmacy and Pharmaceutical Sciences , "A. Moro" University of Bari , Bari , Italy.

A series of nanomolar phosphonate matrix metalloproteinase (MPP) inhibitors was tested for inhibitory activity against a panel of selected human carbonic anhydrase (CA, EC 4.2.1.1) isozymes, covering the cancer-associated CA IX and XII. None of the reported sulfonyl and sulfonylamino-derivatives sensitively affected the catalytic activity of the cytosolic isoforms CA I and II, which are considered off-target isoforms in view of their physiological role. The most active inhibitors were in the series of chiral N-(sulfonyl)phosphovaline derivatives, which showed good to excellent inhibitory activity over target CAs, with compound 15 presenting the best isoform-selectivity toward CA IX. We suggest here that the phosphonates have the potential as dual inhibitors of MMPs and CAs, both involved in tumor formation, invasion and metastasis.
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http://dx.doi.org/10.1080/14756366.2017.1378192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009896PMC
December 2017

Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis.

Sci Rep 2017 07 18;7(1):5777. Epub 2017 Jul 18.

Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria Km. 29, 300, 00015, Monterotondo Stazione, Roma, Italy.

PPAR antagonists are ligands that bind their receptor with high affinity without transactivation activity. Recently, they have been demonstrated to maintain insulin-sensitizing and antidiabetic properties, and they serve as an alternative treatment for metabolic diseases. In this work, an affinity-based bioassay was found to be effective for selecting PPAR ligands from the dried extract of an African plant (Diospyros bipindensis). Among the ligands, we identified betulinic acid (BA), a compound already known for its anti-inflammatory, anti-tumour and antidiabetic properties, as a PPARγ and PPARα antagonist. Cell differentiation assays showed that BA inhibits adipogenesis and promotes osteogenesis; either down-regulates or does not affect the expression of a series of adipogenic markers; and up-regulates the expression of osteogenic markers. Moreover, BA increases basal glucose uptake in 3T3-L1 adipocytes. The crystal structure of the complex of BA with PPARγ sheds light, at the molecular level, on the mechanism by which BA antagonizes PPARγ, and indicates a unique binding mode of this antagonist type. The results of this study show that the natural compound BA could be an interesting and safe candidate for the treatment of type 2 diabetes and bone diseases.
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http://dx.doi.org/10.1038/s41598-017-05666-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516003PMC
July 2017

Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment.

Oncotarget 2017 Jun;8(26):41827-41840

Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Multiple myeloma is a plasma cell malignancy that homes aberrantly to bone causing extensive skeletal destruction. Despite the development of novel therapeutic agents that have significantly improved overall survival, multiple myeloma remains an incurable disease. Matrix metalloproteinase-2 (MMP-2) is associated with cancer and is significantly overexpressed in the bone marrow of myeloma patients. These data provide rationale for selectively inhibiting MMP-2 activity as a multiple myeloma treatment strategy. Given that MMP-2 is systemically expressed, we used novel "bone-seeking" bisphosphonate based MMP-2 specific inhibitors (BMMPIs) to target the skeletal tissue thereby circumventing potential off-target effects of MMP-2 inhibition outside the bone marrow-tumor microenvironment. Using in vivo models of multiple myeloma (5TGM1, U266), we examined the impact of MMP-2 inhibition on disease progression using BMMPIs. Our data demonstrate that BMMPIs can decrease multiple myeloma burden and protect against cancer-induced osteolysis. Additionally, we have shown that MMP-2 can be specifically inhibited in the multiple myeloma-bone microenvironment, underscoring the feasibility of developing targeted and tissue selective MMP inhibitors. Given the well-tolerated nature of bisphosphonates in humans, we anticipate that BMMPIs could be rapidly translated to the clinical setting for the treatment of multiple myeloma.
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http://dx.doi.org/10.18632/oncotarget.18103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522031PMC
June 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

Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth.

Mol Cancer Ther 2017 03 9;16(3):494-505. Epub 2017 Jan 9.

Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Bone metastasis is common during breast cancer progression. Matrix metalloproteinase-2 (MMP-2) is significantly associated with aggressive breast cancer and poorer overall survival. In bone, tumor- or host-derived MMP-2 contributes to breast cancer growth and does so by processing substrates, including type I collagen and TGFβ latency proteins. These data provide strong rationale for the application of MMP-2 inhibitors to treat the disease. However, , MMP-2 is systemically expressed. Therefore, to overcome potential toxicities noted with previous broad-spectrum MMP inhibitors (MMPIs), we used highly selective bisphosphonic-based MMP-2 inhibitors (BMMPIs) that allowed for specific bone targeting. , BMMPIs affected the viability of breast cancer cell lines and osteoclast precursors, but not osteoblasts. , we demonstrated using two bone metastatic models (PyMT-R221A and 4T1) that BMMPI treatment significantly reduced tumor growth and tumor-associated bone destruction. In addition, BMMPIs are superior in promoting tumor apoptosis compared with the standard-of-care bisphosphonate, zoledronate. We demonstrated MMP-2-selective inhibition in the bone microenvironment using specific and broad-spectrum MMP probes. Furthermore, compared with zoledronate, BMMPI-treated mice had significantly lower levels of TGFβ signaling and MMP-generated type I collagen carboxy-terminal fragments. Taken together, our data show the feasibility of selective inhibition of MMPs in the bone metastatic breast cancer microenvironment. We posit that BMMPIs could be easily translated to the clinical setting for the treatment of bone metastases given the well-tolerated nature of bisphosphonates. .
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0315-TDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337166PMC
March 2017

Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies.

Int J Mol Sci 2016 Oct 22;17(10). Epub 2016 Oct 22.

Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti, Via dei Vestini 31, 66100 Chieti, Italy.

Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs) have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data.
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http://dx.doi.org/10.3390/ijms17101768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085792PMC
October 2016

In vitro comparison of new bisphosphonic acids and zoledronate effects on human gingival fibroblasts viability, inflammation and matrix turnover.

Clin Oral Investig 2016 Nov 22;20(8):2013-2021. Epub 2015 Dec 22.

Section of Human Anatomy, Department of Pharmacy, University "G. d'Annunzio", Chieti-Pescara, via dei Vestini 31, 66100, Chieti, Italy.

Objectives: Bisphosphonates (BPs) are drugs clinically used in resorptive diseases. It was already proved that some clinically relevant BPs can inhibit a class of enzymes called matrix metalloproteinases (MMPs), required during tissue remodelling. Combining the arylsulfonamide function with the bisphosphonic group, several compounds were synthesized to obtain selective inhibitors of MMPs. The aim of the present study was to compare the effect of zoledronic acid (ZA), the most potent bisphosphonate available as therapy, with new sulfonamide containing BPs in an in vitro model of human gingival fibroblasts (HGFs).

Materials And Methods: Western blot was used to measure procollagen I, β1 integrin MMP-8 and MMP-9, phase contrast and MTT for cell viability; L-lactate-dehydrogenase (LDH) measurement was performed for toxicity evaluation and ELISA for prostaglandin E (PGE) secretion assessment.

Results: When compared with ZA, the treatment with the newly synthesized compounds shows increasing viability, procollagen I expression and decreased expression of β1 integrin in HGFs. Higher levels of released LDH, PGE and MMP-9 expression are recorded in ZA-treated HGFs. Increased levels of MMP-8 are recorded in newly synthesized compounds-treated samples.

Conclusions: These findings allowed to conclude that new tested BPs did not affect HGFs viability and adhesion, did not induce cellular toxicity, were not responsible for inflammatory event induction and could preserve the physiological matrix turnover.

Clinical Relevance: It could be hypothesized that the new molecules were better tolerated by soft tissues, resulting in lesser side effects.
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http://dx.doi.org/10.1007/s00784-015-1690-2DOI Listing
November 2016

Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode.

Sci Rep 2016 10 6;6:34792. Epub 2016 Oct 6.

Dipartimento di Farmacia, Università degli Studi di Napoli, Via Montesano 49, 80131 Napoli, Italy.

The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARγ full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a structure-based virtual screening approach that let us identify a novel PPAR pan-agonist with a very attractive activity profile and its crystal structure in the complex with PPARα and PPARγ, respectively. In PPARα this ligand occupies a new pocket whose filling is allowed by the ligand-induced switching of the F273 side chain from a closed to an open conformation. The comparison between this pocket and the corresponding cavity in PPARγ provides a rationale for the different activation of the ligand towards PPARα and PPARγ, suggesting a novel basis for ligand design.
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http://dx.doi.org/10.1038/srep34792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052532PMC
October 2016

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

Fragment-Based Discovery of 5-Arylisatin-Based Inhibitors of Matrix Metalloproteinases 2 and 13.

ChemMedChem 2016 09 15;11(17):1892-8. Epub 2016 Jul 15.

Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia.

Matrix metalloproteinases (MMPs) are well-established targets for several pathologies. In particular, MMP-2 and MMP-13 play a prominent role in cancer progression. In this study, a structure-based screening campaign was applied to prioritize metalloproteinase-oriented fragments. This computational model was applied to a representative fragment set from the publically available EDASA Scientific compound library. These fragments were prioritized, and the top-ranking hits were tested in a biological assay to validate the model. Two scaffolds showed consistent activity in the assay, and the isatin-based compounds were the most interesting. These latter fragments have significant potential as tools for the design and realization of novel MMP inhibitors. In addition to their micromolar activity, the chemical synthesis affords flexible and creative access to their analogues.
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http://dx.doi.org/10.1002/cmdc.201600266DOI Listing
September 2016