Publications by authors named "Pier Giovanni Baraldi"

159 Publications

Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2- d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors.

J Med Chem 2019 02 18;62(3):1274-1290. Epub 2019 Jan 18.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia , Università di Padova , 35131 Padova , Italy.

The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3',4',5'-trimethoxyanilino)thieno[3,2- d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3',4',5'-trimethoxyanilino)-6-( p-tolyl)thieno[3,2- d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC value of 0.71 μM, and 6g inhibited EGFR activity with an IC value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01391DOI Listing
February 2019

3-Aryl/Heteroaryl-5-amino-1-(3',4',5'-trimethoxybenzoyl)-1,2,4-triazoles as antimicrotubule agents. Design, synthesis, antiproliferative activity and inhibition of tubulin polymerization.

Bioorg Chem 2018 10 30;80:361-374. Epub 2018 Jun 30.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy. Electronic address:

Many natural and synthetic substances are known to interfere with the dynamic assembly of tubulin, preventing the formation of microtubules. In our search for potent and selective antitumor agents, a novel series of 1-(3',4',5'-trimethoxybenzoyl)-5-amino-1,2,4-triazoles were synthesized. The compounds had different heterocycles, including thiophene, furan or the three isomeric pyridines, and they possessed a phenyl ring bearing electron-releasing or electron-withdrawing substituents at the 3-position of the 5-amino-1,2,4-triazole system. Most of the twenty-two tested compounds showed moderate to potent antiproliferative activities against a panel of solid tumor and leukemic cell lines, with four (5j, 5k, 5o and 5p) showing strong antiproliferative activity (IC < 1 μM) against selected cancer cells. Among them, several molecules preferentially inhibited the proliferation of leukemic cell lines, showing IC values 2-100-fold lower for Jurkat and RS4;11 cells than those for the three lines derived from solid tumors (HeLa, HT-29 and MCF-7 cells). Compound 5k strongly inhibited tubulin assembly, with an IC value of 0.66 μM, half that obtained in simultaneous experiments with CA-4 (IC = 1.3 μM).
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http://dx.doi.org/10.1016/j.bioorg.2018.06.037DOI Listing
October 2018

Synthesis and biological evaluation of alpha-bromoacryloylamido indolyl pyridinyl propenones as potent apoptotic inducers in human leukaemia cells.

J Enzyme Inhib Med Chem 2018 Dec;33(1):727-742

c Departamento de Bioquímica y Biología Molecular , Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de las Palmas de Gran Canaria , Spain.

The combination of two pharmacophores into a single molecule represents one of the methods that can be adopted for the synthesis of new anticancer molecules. To investigate the influence of the position of the pyridine nitrogen on biological activity, two different series of α-bromoacryloylamido indolyl pyridinyl propenones 3a-h and 4a-d were designed and synthesized by a pharmacophore hybridization approach and evaluated for their antiproliferative activity against a panel of six human cancer cell lines. These hybrid molecules were prepared to combine the α-bromoacryloyl moiety with two series of indole-inspired chalcone analogues, possessing an indole derivative and a 3- or 4-pyridine ring, respectively, linked on either side of 2-propen-1-one system. The structure-activity relationship was also investigated by the insertion of alkyl or benzyl moieties at the N-1 position of the indole nucleus. We found that most of the newly synthesized displayed high antiproliferative activity against U-937, MOLT-3, K-562, and NALM-6 leukaemia cell lines, with one-digit to double-digit nanomolar IC values. The antiproliferative activities of 3-pyridinyl derivatives 3f-h revealed that N-benzyl indole analogues generally exhibited lower activity compared to N-H or N-alkyl derivatives 3a-b and 3c-e, respectively. Moreover, cellular mechanism studies elucidated that compound 4a induced apoptosis along with a decrease of mitochondrial membrane potential and activated caspase-3 in a concentration-dependent manner.
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http://dx.doi.org/10.1080/14756366.2018.1450749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009983PMC
December 2018

Discovery of 1,5-Diphenylpyrazole-3-Carboxamide Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors.

J Med Chem 2018 02 22;61(3):1340-1354. Epub 2018 Jan 22.

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

Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays an important role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol, which is implicated in many physiological processes. Beyond the possible utilization of MAGL inhibitors as anti-inflammatory, antinociceptive, and anticancer agents, their application has encountered obstacles due to the unwanted effects caused by the irreversible inhibition of this enzyme. The possible application of reversible MAGL inhibitors has only recently been explored, mainly due to the deficiency of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of reversible MAGL inhibitors. Among them, compound 26 showed to be a potent MAGL inhibitor (IC = 0.51 μM, K = 412 nM) with a good selectivity versus fatty acid amide hydrolase (FAAH), α/β-hydrolase domain-containing 6 (ABHD6), and 12 (ABHD12). Interestingly, this compound also possesses antiproliferative activities against two different cancer cell lines and relieves the neuropathic hypersensitivity induced in vivo by oxaliplatin.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01845DOI Listing
February 2018

2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition.

Eur J Med Chem 2018 Jan;143:683-698

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia Pediatrica, Università di Padova, 35131 Padova, Italy. Electronic address:

Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity. Of the tested compounds, derivatives 4a, 4c, 4i and 4k possessed the highest overall potency and displayed high antiproliferative activities at submicromolar concentrations, with IC values ranging from 0.13 to 0.84 μM against four different cancer cell lines. Three agents (4a, 4c and 4i) in the present series had similar effects, and these were comparable to those of the reference compound combretastatin A-4 (CA-4) as inhibitors of tubulin assembly. The antitubulin effects correlated with the cytostatic activities and indicate that these compounds inhibit cell growth through inhibition of tubulin polymerization by binding at the colchicine site. Compound 4c, containing the 2'-thienyl ring at the 5-position of the 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold, exhibited substantial antiproliferative activity with a mean IC value of 140 nM, inhibited tubulin polymerization with an IC value of 1.2 μM, similar to that of CA-4 (IC: 1.1 μM), and induced apoptosis in HeLa cells.
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http://dx.doi.org/10.1016/j.ejmech.2017.11.096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791907PMC
January 2018

A Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy.

Med Res Rev 2018 07 6;38(4):1031-1072. Epub 2017 Jul 6.

Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121, Ferrara, Italy.

The A adenosine receptor (A AR) subtype is a novel, promising therapeutic target for inflammatory diseases, such as rheumatoid arthritis (RA) and psoriasis, as well as liver cancer. A AR is coupled to inhibition of adenylyl cyclase and regulation of mitogen-activated protein kinase (MAPK) pathways, leading to modulation of transcription. Furthermore, A AR affects functions of almost all immune cells and the proliferation of cancer cells. Numerous A AR agonists, partial agonists, antagonists, and allosteric modulators have been reported, and their structure-activity relationships (SARs) have been studied culminating in the development of potent and selective molecules with drug-like characteristics. The efficacy of nucleoside agonists may be suppressed to produce antagonists, by structural modification of the ribose moiety. Diverse classes of heterocycles have been discovered as selective A AR blockers, although with large species differences. Thus, as a result of intense basic research efforts, the outlook for development of A AR modulators for human therapeutics is encouraging. Two prototypical selective agonists, N6-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA; CF101) and 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA; CF102), have progressed to advanced clinical trials. They were found safe and well tolerated in all preclinical and human clinical studies and showed promising results, particularly in psoriasis and RA, where the A AR is both a promising therapeutic target and a biologically predictive marker, suggesting a personalized medicine approach. Targeting the A AR may pave the way for safe and efficacious treatments for patient populations affected by inflammatory diseases, cancer, and other conditions.
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http://dx.doi.org/10.1002/med.21456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756520PMC
July 2018

Design, synthesis and biological evaluation of 3-substituted-2-oxindole hybrid derivatives as novel anticancer agents.

Eur J Med Chem 2017 Jul 13;134:258-270. Epub 2017 Apr 13.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy. Electronic address:

The 2-oxindole nucleus is the central core to develop new anticancer agents and its substitution at the 3-position can effect antitumor activity. Utilizing a pharmacophore hybridization approach, a novel series of antiproliferative agents was obtained by the modification of the structure of 3-substituted-2-oxindole pharmacophore by the attachment of the α-bromoacryloyl moiety, acting as a Michael acceptor, at the 5-position of 2-oxindole framework. The impact of the substituent at the 3-position of 2-oxindole core on the potency and selectivity against a panel of seven different cancer cell lines was examined. We found that these hybrid molecules displayed potent antiproliferative activity against a panel of four cancer cell lines, with one-to double digit nanomolar 50% inhibitory concentrations (IC). A distinctive selective antiproliferative activity was obtained towards CCRF-CEM and RS4; 11 leukemic cell lines. In order to study the possible mechanism of action, we observed that the two most active compounds namely 3(E) and 6(Z) strongly induce apoptosis that follow the mitochondrial pathway. Interestingly a decrease of intracellular reduced glutathione content (GSH) and reactive oxygen species (ROS) production was detected in treated cells compared with controls suggesting that these effects may be involved in their mechanism of action.
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http://dx.doi.org/10.1016/j.ejmech.2017.03.089DOI Listing
July 2017

Synthesis and Biological Evaluation of 2-Methyl-4,5-Disubstituted Oxazoles as a Novel Class of Highly Potent Antitubulin Agents.

Sci Rep 2017 04 13;7:46356. Epub 2017 Apr 13.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.

Antimitotic agents that interfere with microtubule formation are one of the major classes of cytotoxic drugs for cancer treatment. Multiple 2-methyl-4-(3',4',5'-trimethoxyphenyl)-5-substituted oxazoles and their related 4-substituted-5-(3',4',5'-trimethoxyphenyl) regioisomeric derivatives designed as cis-constrained combretastatin A-4 (CA-4) analogues were synthesized and evaluated for their antiproliferative activity in vitro against a panel of cancer cell lines and, for selected highly active compounds, interaction with tubulin, cell cycle effects and in vivo potency. Both these series of compounds were characterized by the presence of a common 3',4',5'-trimethoxyphenyl ring at either the C-4 or C-5 position of the 2-methyloxazole ring. Compounds 4g and 4i, bearing a m-fluoro-p-methoxyphenyl or p-ethoxyphenyl moiety at the 5-position of 2-methyloxazole nucleus, respectively, exhibited the greatest antiproliferative activity, with IC values of 0.35-4.6 nM (4g) and 0.5-20.2 nM (4i), which are similar to those obtained with CA-4. These compounds bound to the colchicine site of tubulin and inhibited tubulin polymerization at submicromolar concentrations. Furthermore, 4i strongly induced apoptosis that follows the mitochondrial pathway. In vivo, 4i in a mouse syngeneic model demonstrated high antitumor activity which significantly reduced the tumor mass at doses ten times lower than that required for CA-4P, suggesting that 4i warrants further evaluation as a potential anticancer drug.
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http://dx.doi.org/10.1038/srep46356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390315PMC
April 2017

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists.

Med Res Rev 2017 07 15;37(4):936-983. Epub 2016 Dec 15.

Section of Pharmacology, Department of Medical Sciences, University of Ferrara, 44121, Ferrara, Italy.

Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium-dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure-activity relationships (SARs) focusing on new strategies to target this channel.
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http://dx.doi.org/10.1002/med.21427DOI Listing
July 2017

Positive allosteric modulation of A adenosine receptors as a novel and promising therapeutic strategy for anxiety.

Neuropharmacology 2016 12 14;111:283-292. Epub 2016 Sep 14.

Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy. Electronic address:

Activation of A adenosine receptors (ARs) has been associated with anxiolytic-like effects in different behavioral tests, but development of AAR agonists for therapeutic use has been hampered, most likely due to the presence of side effects. With the aim to identify a safer approach for the treatment of anxiety, we investigated, in mice, the anxiolytic-like properties of a novel AAR positive allosteric modulator, TRR469. Acute administration of TRR469 (0.3-3 mg/kg) resulted in robust anxiolytic-like effects in the elevated plus maze, the dark/light box, the open field and the marble burying tests. The magnitude of the anxiolytic action of TRR469 was comparable to that obtained with benzodiazepine diazepam (1 mg/kg). The use of the AAR antagonist DPCPX (3 mg/kg) suggested that the effects of TRR469 were mediated by this receptor subtype. In contrast to diazepam, the novel positive allosteric modulator did not potentiate the sedative effect of ethanol (3.5 g/kg) evaluated by the loss of righting reflex. While diazepam produced motor coordination impairment in the rotarod test, this effect being enhanced by the presence of ethanol (1.5 g/kg), TRR469 did not elicit locomotor disturbances either when administered alone or in the presence of ethanol. In vitro, TRR469 was able to increase the number of AAR recognizable by the agonist radioligand [H]-CCPA in mouse brain regions involved in emotional processes. TRR469 markedly increased the affinity of the agonist CCPA, suggesting the capability, in vivo, to increase the affinity of endogenous adenosine. Taken together, these findings indicate that the positive allosteric modulation of AAR may represent a promising approach for the treatment of anxiety-related disorders.
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http://dx.doi.org/10.1016/j.neuropharm.2016.09.015DOI Listing
December 2016

Design and Synthesis of Potent in Vitro and in Vivo Anticancer Agents Based on 1-(3',4',5'-Trimethoxyphenyl)-2-Aryl-1H-Imidazole.

Sci Rep 2016 05 24;6:26602. Epub 2016 May 24.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.

A novel series of tubulin polymerization inhibitors, based on the 1-(3',4',5'-trimethoxyphenyl)-2-aryl-1H-imidazole scaffold and designed as cis-restricted combretastatin A-4 analogues, was synthesized with the goal of evaluating the effects of various patterns of substitution on the phenyl at the 2-position of the imidazole ring on biological activity. A chloro and ethoxy group at the meta- and para-positions, respectively, produced the most active compound in the series (4o), with IC50 values of 0.4-3.8 nM against a panel of seven cancer cell lines. Except in HL-60 cells, 4o had greater antiproliferative than CA-4, indicating that the 3'-chloro-4'-ethoxyphenyl moiety was a good surrogate for the CA-4 B-ring. Experiments carried out in a mouse syngenic model demonstrated high antitumor activity of 4o, which significantly reduced the tumor mass at a dose thirty times lower than that required for CA-4P, which was used as a reference compound. Altogether, our findings suggest that 4o is a promising anticancer drug candidate that warrants further preclinical evaluation.
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http://dx.doi.org/10.1038/srep26602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877593PMC
May 2016

Synthesis and structure activity relationship investigation of triazolo[1,5-a]pyrimidines as CB2 cannabinoid receptor inverse agonists.

Eur J Med Chem 2016 May 16;113:11-27. Epub 2016 Feb 16.

Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.

CB2 cannabinoid receptor ligands are known to be therapeutically important for the treatment of numerous diseases. Recently, we have identified the heteroaryl-4-oxopyridine/7-oxopyrimidine derivatives as highly potent and selective CB2 receptor ligands, showing that the pharmakodynamics of the new compounds was controlled by the nature of the heterocycle core. In this paper we describe the synthesis and biological evaluation of 7-oxo-4-pentyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide derivatives that led to the identification of novel CB2 receptor inverse agonists. Cyclic AMP experiments on CB2 receptors expressed in CHO cells revealed that introduction of structural modifications at position 2 of triazolopyrimidine template changes the functional activity from partial to inverse agonism. The molecular docking analysis of the novel structures is reported.
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http://dx.doi.org/10.1016/j.ejmech.2016.02.032DOI Listing
May 2016

Medicinal Chemistry, Pharmacology, and Potential Therapeutic Benefits of Cannabinoid CB2 Receptor Agonists.

Chem Rev 2016 Jan 7;116(2):519-60. Epub 2016 Jan 7.

Department of Chemical and Pharmaceutical Sciences and ‡Department of Medical Science, Pharmacology Section, University of Ferrara , Ferrara 44121, Italy.

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http://dx.doi.org/10.1021/acs.chemrev.5b00411DOI Listing
January 2016

Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation.

Eur J Med Chem 2016 Jan 27;108:39-52. Epub 2015 Nov 27.

Centro Interdipartimentale di Ricerca in Oncologia Clinica e Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Malattie Infettive, Università di Palermo, 90125 Palermo, Italy.

Signal Transducer and Activator of Transcription 5 (STAT5) protein, a component of the STAT family of signaling proteins, is considered to be an attractive therapeutic target because of its involvement in the progression of acute myeloid leukemia. In an effort to discover potent molecules able to inhibit the phosphorylation-activation of STAT5, twenty-two compounds were synthesized and evaluated on the basis of our knowledge of the activity of 2-(3',4',5'-trimethoxybenzoyl)-3-iodoacetamido-6-methoxy benzo[b]furan derivative 1 as a potent STAT5 inhibitor. Most of these molecules, structurally related to compound 1, were characterized by the presence of a common 3',4',5'-trimethoxybenzoyl moiety at the 2-position of different benzoheterocycles such as benzo[b]furan, benzo[b]thiophene, indole and N-methylindole. Effects on biological activity of the iodoacetamido group and of different moieties (methyl and methoxy) at the C-3 to C-7 positions were examined. In the series of benzo[b]furan derivatives, moving the iodoacetylamino group from the C-4 to the C-5 or C-6 positions did not significantly affect antiproliferative activity. Compounds 4, 15, 20 and 23 blocked STAT5 signals and induced apoptosis of K562 BCR-ABL positive cells. For compound 23, the trimethoxybenzoyl moiety at the 2-position of the benzo[b]furan core was not essential for potent inhibition of STAT5 activation.
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http://dx.doi.org/10.1016/j.ejmech.2015.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724257PMC
January 2016

Current status of A1 adenosine receptor allosteric enhancers.

Future Med Chem 2015 ;7(10):1247-59

Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy.

Adenosine is an ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1, A2A, A2B and A3 adenosine receptors (ARs). Allosteric enhancers to A1ARs may represent novel therapeutic agents because they increase the activity of these receptors by mediating a shift to their active form in the A1AR-G protein ternary complex. In this manner, they are able to amplify the action of endogenous adenosine, which is produced in high concentrations under conditions of metabolic stress. A1AR allosteric enhancers could be used as a justifiable alternative to the exogenous agonists that are characterized by receptor desensitization and downregulation. In this review, an analysis of some of the most interesting allosteric modulators of A1ARs has been reported.
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http://dx.doi.org/10.4155/fmc.15.65DOI Listing
January 2016

Design, synthesis and antiproliferative activity of novel heterobivalent hybrids based on imidazo[2,1-b][1,3,4]thiadiazole and imidazo[2,1-b][1,3]thiazole scaffolds.

Eur J Med Chem 2015 Aug 25;101:205-17. Epub 2015 Jun 25.

Department of Biochemistry, University of Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria, Spain.

Heterobivalent ligands constituted by two different pharmacophores that bind to different molecular targets or to two distinct sites on the same molecular target could be one of the methods used for the treatment of cancer. In view of the importance of imidazo[1,2-b][1,3]thiazole and imidazo[1,2-b][1,3,4]thiadiazole as privileged structures for the preparation of novel anticancer agents, we decided to explore the synthesis and biological evaluation of molecular conjugates comprising these fused bicyclic systems tethered at their C-6 position by a meta-(α-bromoacryloylamido)phenyl moiety. We found that most of the hybrid compounds displayed high antiproliferative activity toward a wide panel of cancer cell lines, with one-digit micromolar to submicromolar 50% inhibitory concentrations (IC50). We have observed that selected compounds 7d, 7e, 7n and 8c induced apoptosis, which was associated with the release of cytochrome c and cleavage of multiple caspases. Overexpression of the protective mitochondrial protein Bcl-2 did not confer protection to cell death induced by these compounds.
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http://dx.doi.org/10.1016/j.ejmech.2015.06.042DOI Listing
August 2015

Synthesis and biological evaluation of a new series of 2-amino-3-aroyl thiophene derivatives as agonist allosteric modulators of the A1 adenosine receptor. A position-dependent effect study.

Eur J Med Chem 2015 Aug 24;101:185-204. Epub 2015 Jun 24.

Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy.

The 2-amino-3-(p-chlorobenzoyl)thiophene scaffold has been widely employed as a pharmacophore for the identification of small molecules acting as allosteric modulators at the adenosine A1 receptor. A new series of 2-amino-3-(p-chlorobenzoyl)-4-benzyl-5-arylthiophene derivatives, characterized by the absence as well as the presence of electron-releasing or electron-withdrawing groups on the phenyl ring at the 4- and 5-positions of the thiophene ring, were identified as positive allosteric enhancers at the adenosine A1 receptor in binding (saturation, competition and dissociation kinetics) and functional assays. To better understand the positional requirements of substituents on the 2-amino-3-(p-chlorobenzoyl)thiophene core, the corresponding regioisomeric 4-aryl-5-benzylthiophene analogues were synthesized and found to possess reduced allosteric enhancer activity.
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http://dx.doi.org/10.1016/j.ejmech.2015.06.041DOI Listing
August 2015

One-pot reaction to obtain N,N'-disubstituted guanidines of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold as human A3 adenosine receptor antagonists.

J Med Chem 2015 Jul 17;58(13):5355-60. Epub 2015 Jun 17.

‡Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy.

In this paper we describe an extension SAR study of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus as A3AR antagonist. Our initial aim was to replace the phenylcarbamoyl moiety at the 5 position of PTP nucleus with a thiourea functionality to evaluate the contribution of new structural modification against the A3AR. The synthesized 12-25 were not characterized by the predicted side chain but by a 1,3-disubstituted guanidine and are shown to be interesting A3AR antagonists.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00551DOI Listing
July 2015

Pyrazole phenylcyclohexylcarbamates as inhibitors of human fatty acid amide hydrolases (FAAH).

Eur J Med Chem 2015 Jun 5;97:289-305. Epub 2015 May 5.

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

Fatty acid amide hydrolase (FAAH) inhibitors have gained attention as potential therapeutic targets in the management of neuropathic pain. Here, we report a series of pyrazole phenylcyclohexylcarbamate derivatives standing on the known carbamoyl FAAH inhibitor URB597. Structural modifications led to the recognition of compound 22 that inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM). The most active compounds of this series showed significant selectivity toward monoacylglycerol lipase (MAGL) enzyme. In addition, molecular modeling and reversibility behavior of the new class of FAAH inhibitors are presented in this article.
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http://dx.doi.org/10.1016/j.ejmech.2015.04.064DOI Listing
June 2015

History and perspectives of A2A adenosine receptor antagonists as potential therapeutic agents.

Med Res Rev 2015 Jul 27;35(4):790-848. Epub 2015 Mar 27.

Section of Pharmacology, Department of Medical Science, University of Ferrara, 44121, Ferrara, Italy.

Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD.
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http://dx.doi.org/10.1002/med.21344DOI Listing
July 2015

Design, synthesis, in vitro, and in vivo anticancer and antiangiogenic activity of novel 3-arylaminobenzofuran derivatives targeting the colchicine site on tubulin.

J Med Chem 2015 Apr 26;58(7):3209-22. Epub 2015 Mar 26.

∞Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.

A new series of compounds characterized by the presence of a 2-methoxy/ethoxycarbonyl group, combined with either no substituent or a methoxy group at each of the four possible positions of the benzene portion of the 3-(3',4',5'-trimethoxyanilino)benzo[b]furan skeleton, were evaluated for antiproliferative activity against cancer cells in culture and, for selected, highly active compounds, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. The greatest antiproliferative activity occurred with a methoxy group introduced at the C-6 position, the least with this substituent at C-4. Thus far, the most promising compound in this series was 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-6-methoxybenzo[b]furan (3g), which inhibited cancer cell growth at nanomolar concentrations (IC50 values of 0.3-27 nM), bound to the colchicine site of tubulin, induced apoptosis, and showed, both in vitro and in vivo, potent vascular disrupting properties derived from the effect of this compound on vascular endothelial cells. Compound 3g had in vivo antitumor activity in a murine model comparable to the activity obtained with combretastatin A-4 phosphate.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407803PMC
April 2015

Design, synthesis, and biological evaluation of novel 2-((2-(4-(substituted)phenylpiperazin-1-yl)ethyl)amino)-5'-N-ethylcarboxamidoadenosines as potent and selective agonists of the A2A adenosine receptor.

J Med Chem 2015 Apr 25;58(7):3253-67. Epub 2015 Mar 25.

‡Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy.

Stimulation of A2A adenosine receptors (AR) promotes anti-inflammatory responses in animal models of allergic rhinitis, asthma, chronic obstructive pulmonary disease, and rheumatic diseases. Herein we describe the results of a research program aimed at identifying potent and selective agonists of the A2AAR as potential anti-inflammatory agents. The recent crystallographic analysis of A2AAR agonists and antagonists in complex with the receptor provided key information on the structural determinants leading to receptor activation or blocking. In light of this, we designed a new series of 2-((4-aryl(alkyl)piperazin-1-yl)alkylamino)-5'-N-ethylcarboxamidoadenosines with high A2AAR affinity, activation potency and selectivity obtained by merging distinctive structural elements of known agonists and antagonists of the investigated target. Docking-based SAR optimization allowed us to identify compound 42 as one of the most potent and selective A2A agonist discovered so far (Ki hA2AAR = 4.8 nM, EC50 hA2AAR = 4.9 nM, Ki hA1AR > 10 000 nM, Ki hA3AR = 1487 nM, EC50 hA2BAR > 10 000 nM).
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http://dx.doi.org/10.1021/acs.jmedchem.5b00215DOI Listing
April 2015

Synthesis and Biological Evaluation of Pyrazolo[3,4-b]pyridin-4-ones as a New Class of Topoisomerase II Inhibitors.

Med Chem 2015 ;11(4):342-53

Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17- 19, 44121, Ferrara, Italy.

A series of 1,3,6-triphenylpyrazolo[3,4-b]pyridin-4-one derivatives was designed, synthesized and evaluated for cytotoxic activity in A375 human melanoma and human erythroleukemia (HEL) cells. The new pyrazolopyridones displayed comparable activities to the antitumor compound etoposide. The inhibitory effect of compounds 17, 18, 27 and 32 against topoisomerase II-mediated cleavage activities was measured finding good correlation with the results obtained from MTS assay. Docking studies into bacterial topoisomerase II (DNA Gyrase), topoisomerase IIα and topoisomerase IIβ binding sites in the DNA binding interface were performed.
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http://dx.doi.org/10.2174/1573406411666141210141317DOI Listing
February 2016

The A3 adenosine receptor: history and perspectives.

Pharmacol Rev 2015 ;67(1):74-102

Department of Medical Sciences, Pharmacology Section (P.A.B., K.V., F.V., S.M., S.G.), and Department of Pharmaceutical Sciences, University of Ferrara, Italy (P.G.B., M.A.T.).

By general consensus, the omnipresent purine nucleoside adenosine is considered a major regulator of local tissue function, especially when energy supply fails to meet cellular energy demand. Adenosine mediation involves activation of a family of four G protein-coupled adenosine receptors (ARs): A(1), A(2)A, A(2)B, and A(3). The A(3) adenosine receptor (A(3)AR) is the only adenosine subtype to be overexpressed in inflammatory and cancer cells, thus making it a potential target for therapy. Originally isolated as an orphan receptor, A(3)AR presented a twofold nature under different pathophysiologic conditions: it appeared to be protective/harmful under ischemic conditions, pro/anti-inflammatory, and pro/antitumoral depending on the systems investigated. Until recently, the greatest and most intriguing challenge has been to understand whether, and in which cases, selective A(3) agonists or antagonists would be the best choice. Today, the choice has been made and A(3)AR agonists are now under clinical development for some disorders including rheumatoid arthritis, psoriasis, glaucoma, and hepatocellular carcinoma. More specifically, the interest and relevance of these new agents derives from clinical data demonstrating that A(3)AR agonists are both effective and safe. Thus, it will become apparent in the present review that purine scientists do seem to be getting closer to their goal: the incorporation of adenosine ligands into drugs with the ability to save lives and improve human health.
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http://dx.doi.org/10.1124/pr.113.008540DOI Listing
June 2015

Synthesis and biological evaluation of novel allosteric enhancers of the A1 adenosine receptor based on 2-amino-3-(4'-chlorobenzoyl)-4-substituted-5-arylethynyl thiophene.

J Med Chem 2014 Sep 12;57(18):7673-86. Epub 2014 Sep 12.

Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara , Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.

A Sonogashira coupling strategy was employed to synthesize a new series of allosteric modulators for the A1 adenosine receptor based on the 2-amino-3-(p-chlorobenzoyl)-4-substituted thiophene skeleton, with a two-carbon (rigid or flexible) linker between the 5-position of the thiophene ring and a (hetero)aryl or alkyl moiety. Among the compounds characterized by the presence of a common phenylacetylene moiety at the 5-position of the thiophene ring, the neopentyl substitution at the 4-position supported a strong activity. In the series of 4-neopentyl derivatives, the presence of an acetylene spacer at the 5-position of the thiophene is optimal for activity, whereas reduction of the acetylene to an ethyl moiety decreased activity, both in functional and binding assays. Derivatives 4e, 4g-h, 4j, 4l, and 4m were the most promising compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor, with 4e as the best compound of the series. The latter compound also retarded the dissociation of another radiolabeled agonist, [(3)H]NECA, from the receptor.
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http://dx.doi.org/10.1021/jm5008853DOI Listing
September 2014

Synthesis, antimitotic and antivascular activity of 1-(3',4',5'-trimethoxybenzoyl)-3-arylamino-5-amino-1,2,4-triazoles.

J Med Chem 2014 Aug 28;57(15):6795-808. Epub 2014 Jul 28.

Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara , Ferrara, Italy.

A new class of compounds that incorporated the structural motif of the 1-(3',4',5'-trimethoxtbenzoyl)-3-arylamino-5-amino-1,2,4-triazole molecular skeleton was synthesized and evaluated for their antiproliferative activity in vitro, interactions with tubulin, and cell cycle effects. The most active agent, 3c, was evaluated for antitumor activity in vivo. Structure-activity relationships were elucidated with various substituents on the phenyl ring of the anilino moiety at the C-3 position of the 1,2,4-triazole ring. The best results for inhibition of cancer cell growth were obtained with the p-Me, m,p-diMe, and p-Et phenyl derivatives 3c, 3e, and 3f, respectively, and overall, these compounds were more or less as active as CA-4. Their vascular disrupting activity was evaluated in HUVEC cells, with compound 3c showing activity comparable with that of CA-4. Compound 3c almost eliminated the growth of syngeneic hepatocellular carcinoma in Balb/c mice, suggesting that 3c could be a new antimitotic agent with clinical potential.
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http://dx.doi.org/10.1021/jm5008193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159078PMC
August 2014

Design, synthesis and biological evaluation of arylcinnamide hybrid derivatives as novel anticancer agents.

Eur J Med Chem 2014 Jun 10;81:394-407. Epub 2014 May 10.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy. Electronic address:

The combination of two pharmacophores into a single molecule represents one of the methods that can be adopted for the synthesis of new anticancer molecules. A series of novel antiproliferative agents designed by a pharmacophore hybridization approach, combining the arylcinnamide skeleton and an α-bromoacryloyl moiety, was synthesized and evaluated for its antiproliferative activity against a panel of seven human cancer cell lines. In addition, the new derivatives were also active on multidrug-resistant cell lines over-expressing P-glycoprotein. The biological effects of various substituents on the N-phenyl ring of the benzamide portion were also described. In order to study the possible mechanism of action, we observed that 4p slightly increased the Reactive Oxygen Species (ROS) production in HeLa cells, but, more importantly, a remarkable decrease of intracellular reduced glutathione content was detected in treated cells compared with controls. These results were confirmed by the observation that only thiol-containing antioxidants were able to significantly protect the cells from induced cell death. Altogether our results indicate that the new derivatives are endowed with good anticancer activity in vitro, and their properties may result in the development of new cancer therapeutic strategies.
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http://dx.doi.org/10.1016/j.ejmech.2014.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094378PMC
June 2014

TRR469, a potent A(1) adenosine receptor allosteric modulator, exhibits anti-nociceptive properties in acute and neuropathic pain models in mice.

Neuropharmacology 2014 Jun 31;81:6-14. Epub 2014 Jan 31.

Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy. Electronic address:

A(1) adenosine receptors (ARs) have been identified as a potential target for the development of anti-nociceptive compounds. The present study explores the analgesic effects of a novel A(1)AR positive allosteric modulator, TRR469, in different models of acute and chronic pain in mice. To evaluate the allosteric enhancement, in vitro binding experiments were performed. The anti-nociceptive properties were investigated in formalin and writhing tests, and in the streptozotocin-induced diabetic neuropathic pain model. Rotarod and catalepsy tests were used to identify potential side effects, while the functional effect of TRR469 was studied using [(3)H]-d-aspartate release from synaptosomes. TRR469 effectively inhibited nociceptive responses in the formalin and writhing tests, with effects comparable to those of the reference analgesic morphine. Isobolographic analysis of the combination of TRR469 and morphine revealed an additive interaction. TRR469 was anti-allodynic in the neuropathic pain model and did not display locomotor or cataleptic side effects. TRR469 enhanced the binding of the agonist radioligand [(3)H]-CCPA and induced a 33-fold increase of adenosine affinity in spinal cord membranes. In mouse spinal cord synaptosomes, TRR469 enhanced the inhibitory effect of A(1)AR activation on [(3)H]-d-aspartate release, a non-metabolizable analogue of glutamate. In conclusion, this research demonstrates the anti-nociceptive effect of the novel compound TRR469, one of the most potent and effective A(1)AR positive allosteric modulators so far synthesized. The use of TRR469 allows for the possibility of exploiting analgesic properties of endogenous adenosine, with a minor potential to develop the various side effects often associated with the use of direct receptor agonists.
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http://dx.doi.org/10.1016/j.neuropharm.2014.01.028DOI Listing
June 2014

Design, synthesis and biological evaluation of 3,5-disubstituted 2-amino thiophene derivatives as a novel class of antitumor agents.

Bioorg Med Chem 2014 Sep 24;22(18):5097-109. Epub 2013 Dec 24.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy. Electronic address:

In search of new compounds with strong antiproliferative activity and simple molecular structure, we designed a novel series of agents based on the 2-amino-3-alkoxycarbonyl/cyano-5-arylethylthiophene scaffold. The presence of the ethyl spacer between the 2',5'-dimethoxyphenyl and the 5-position of the thiophene ring, as well as the number and location of methoxy substitutents on the phenyl ring, played a profound role in affecting the antiproliferative activity. Among the synthesized compounds, we identified the 2-amino-3-cyano-[2-(2,5-dimethoxyphenyl)ethyl] thiophene 2c as the most promising derivative against a wide panel of cancer cell lines (IC50=17-130 nM). The antiproliferative activity of this compound appears to correlate well with its ability to inhibit tubulin assembly and the binding of colchicine to tubulin. Moreover 2c, as determined by flow cytometry, strongly induced arrest in the G2/M phase of the cell cycle, and annexin-V and propidium iodide staining indicate that cell death proceeds through an apoptotic mechanism that follows the intrinsic mitochondrial pathway.
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http://dx.doi.org/10.1016/j.bmc.2013.12.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170804PMC
September 2014

Synthesis and biological evaluation of novel 2-amino-3-aroyl-4-neopentyl-5-substituted thiophene derivatives as allosteric enhancers of the A₁ adenosine receptor.

Bioorg Med Chem 2014 Jan 1;22(1):148-66. Epub 2013 Dec 1.

Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy.

2-Amino-3-benzoyl thiophenes have been widely reported to act as allosteric enhancers at the A1 adenosine receptor. Their activity can be increased considerably by appropriate substitutions at the 4- and 5-positions of the thiophene ring. Substituent size at the thiophene C-4 position seemed to be a factor closely related to activity, with the 4-neopentyl (2,2-dimethylpropyl) substitution showing the greatest enhanced activity. A wide series of 2-amino-3-aroyl-4-neopentylthiophene derivatives with general structure 3, characterized by the presence of different substituents (bromine, aryl and heteroaryl) at the 5-position of the thiophene ring, have been identified as potent AEs at the A1AR. With only one exception, all of the synthesized compounds proved to be superior to the reference compound PD 81,723 in a functional assay. Derivatives 3p, 3u, 3am, 3ap and 3ar were the most active compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor.
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http://dx.doi.org/10.1016/j.bmc.2013.11.043DOI Listing
January 2014