Publications by authors named "Delia Preti"

87 Publications

Novel Mixed NOP/Opioid Receptor Peptide Agonists.

J Med Chem 2021 05 17;64(10):6656-6669. Epub 2021 May 17.

Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, Ferrara 44121, Italy.

The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt,Xaa]N/OFQ(1-13)-NH were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr and Thr at the N-terminal portion of N/OFQ(1-13)-NH with the noncanonical amino acid Dmt. [Dmt]N/OFQ(1-13)-NH has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an model of cough.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c02062DOI Listing
May 2021

Concise synthesis and biological evaluation of 2-Aryl-3-Anilinobenzo[b]thiophene derivatives as potent apoptosis-inducing agents.

Bioorg Chem 2021 Jul 20;112:104919. Epub 2021 Apr 20.

Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy.

Many clinically used agents active in cancer chemotherapy exert their activity through the induction of cell death (apoptosis) by targeting microtubules, altering protein function or inhibiting DNA synthesis. The benzo[b]thiophene scaffold holds a pivotal place as a pharmacophore for the development of anticancer agents, and, in addition, this scaffold has many pharmacological activities. We have developed a flexible method for the construction of a new series of 2-aryl-3-(3,4,5-trimethoxyanilino)-6-methoxybenzo[b]thiophenes as potent antiproliferative agents, giving access to a wide range of substitution patterns at the 2-position of the 6-methoxybenzo[b]thiophene common intermediate. In the present study, all the synthesized compounds retained the 3-(3,4,5-trimethoxyanilino)-6-methoxybenzo[b]thiophene moiety, and the structure-activity relationship was examined by modification of the aryl group at its 2-position with electron-withdrawing (F) or electron-releasing (alkyl and alkoxy) groups. We found that small substituents, such as fluorine or methyl, could be placed in the para-position of the 2-phenyl ring, and these modifications only slightly reduced antiproliferative activity relative to the unsubstituted 2-phenyl analogue. Compounds 3a and 3b, bearing the phenyl and para-fluorophenyl at the 2-position of the 6-methoxybenzo[b]thiophene nucleus, respectively, exhibited the greatest antiproliferative activity among the tested compounds. The treatment of both Caco2 (not metastatic) and HCT-116 (metastatic) colon carcinoma cells with 3a or 3b triggered a significant induction of apoptosis as demonstrated by the increased expression of cleaved-poly(ADP-ribose) polymerase (PARP), receptor-interacting protein (RIP) and caspase-3 proteins. The same effect was not observed with non-transformed colon 841 CoN cells. A potential additional effect during mitosis for 3a in metastatic cells and for 3b in non-metastatic cells was also observed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2021.104919DOI Listing
July 2021

Structure-Activity Relationship Studies on Oxazolo[3,4-]pyrazine Derivatives Leading to the Discovery of a Novel Neuropeptide S Receptor Antagonist with Potent Activity.

J Med Chem 2021 04 18;64(7):4089-4108. Epub 2021 Mar 18.

Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy.

Neuropeptide S modulates important neurobiological functions including locomotion, anxiety, and drug abuse through interaction with its G protein-coupled receptor known as neuropeptide S receptor (NPSR). NPSR antagonists are potentially useful for the treatment of substance abuse disorders against which there is an urgent need for new effective therapeutic approaches. Potent NPSR antagonists have been discovered which, however, require further optimization of their pharmacological profile. This work describes a new series of NPSR antagonists of the oxazolo[3,4-]pyrazine class. The guanidine derivative exhibited nanomolar activity and 5-fold improved potency compared to , a reference pharmacological tool in this field. Compound can be considered a new tool for research studies on the translational potential of the NPSergic system. An in-depth molecular modeling investigation was also performed to gain new insights into the observed structure-activity relationships and provide an updated model of ligand/NPSR interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c02223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041306PMC
April 2021

Discovery of Novel Fetal Hemoglobin Inducers through Small Chemical Library Screening.

Int J Mol Sci 2020 Oct 8;21(19). Epub 2020 Oct 8.

Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy.

The screening of chemical libraries based on cellular biosensors is a useful approach to identify new hits for novel therapeutic targets involved in rare genetic pathologies, such as -thalassemia and sickle cell disease. In particular, pharmacologically mediated stimulation of human -globin gene expression, and increase of fetal hemoglobin (HbF) production, have been suggested as potential therapeutic strategies for these hemoglobinopathies. In this article, we screened a small chemical library, constituted of 150 compounds, using the cellular biosensor K562.GR, carrying enhanced green fluorescence protein (EGFP) and red fluorescence protein (RFP) genes under the control of the human -globin and -globin gene promoters, respectively. Then the identified compounds were analyzed as HbF inducers on primary cell cultures, obtained from -thalassemia patients, confirming their activity as HbF inducers, and suggesting these molecules as lead compounds for further chemical and biological investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21197426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582302PMC
October 2020

Biased Agonism at Nociceptin/Orphanin FQ Receptors: A Structure Activity Study on N/OFQ(1-13)-NH.

J Med Chem 2020 10 24;63(19):10782-10795. Epub 2020 Sep 24.

Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy.

Nociceptin/orphanin FQ (N/OFQ) controls different biological functions selective stimulation of the N/OFQ peptide (NOP) receptor. The pleiotropic actions of N/OFQ may limit the development of NOP ligands as innovative drugs in different therapeutic areas. The pharmacological concept of functional selectivity (aka biased agonism) might be useful for amplifying beneficial actions and/or counteracting side effects. Thus, molecules with large bias factors toward G protein or β arrestin are required for investigating the translational value of NOP biased modulation. Herein, the biased behavior of a heterogeneous library of NOP-targeting peptide derivatives was evaluated with the aim to provide possible insights into the structural determinants that govern the selective activation of G protein β-arrestin. Our results demonstrate that lipidation of N/OFQ(1-13)-NH is a useful strategy for obtaining G protein biased agonists for the NOP receptor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b02057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011926PMC
October 2020

Tetrabranched Hetero-Conjugated Peptides as Bifunctional Agonists of the NOP and Mu Opioid Receptors.

Bioconjug Chem 2019 09 4;30(9):2444-2451. Epub 2019 Sep 4.

Department of Chemical and Pharmaceutical Sciences , University of Ferrara , Via Luigi Borsari 46 , Ferrara 44121 , Italy.

The general aim of the work was the validation of a new synthetic methodology designed for obtaining bifunctional heterotetrabranched peptide ligands. Applying an easily accessible synthetic route, we provided a small series of heteromultimeric peptide conjugates targeting the nociceptin/orphanin FQ (N/OFQ) peptide receptors (NOP) and mu opioid receptors. Among these, H-PWT1-N/OFQ-[Dmt]dermorphin demonstrated a similar and high agonist potency at the NOP and mu receptors. The achieved results confirmed the robustness of the approach that is extremely versatile and virtually applicable to different peptide sequences whose pharmacological activity can be combined for generating dual acting multimeric compounds. These innovative pharmacological tools will be extremely helpful for investigating the consequences of the simultaneous activation and/or blockage of different peptidergic receptors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.bioconjchem.9b00519DOI Listing
September 2019

Synthesis and Biological Activity of Peptide α-Ketoamide Derivatives as Proteasome Inhibitors.

ACS Med Chem Lett 2019 Jul 6;10(7):1086-1092. Epub 2019 Jun 6.

Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy.

Proteasome activity affects cell cycle progression as well as the immune response, and it is largely recognized as an attractive pharmacological target for potential therapies against several diseases. Herein we present the synthesis of a series of pseudodi/tripeptides bearing at the C-terminal position different α-ketoamide moieties as pharmacophoric units for the interaction with the catalytic threonine residue that sustains the proteolytic action of the proteasome. Among these, we identified the 1-naphthyl derivative as a potent and selective inhibitor of the β5 subunit of the 20S proteasome, exhibiting nanomolar potency in vitro (β5 IC = 7 nM, β1 IC = 60 μM, β2 IC > 100 μM). Furthermore, it significantly inhibited proliferation and induced apoptosis of the human colorectal carcinoma cell line HCT116.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.9b00233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627721PMC
July 2019

Role of TRPA1 receptors in skin inflammation induced by volatile chemical irritants in mice.

Eur J Pharmacol 2019 Sep 20;858:172460. Epub 2019 Jun 20.

Department of Pharmacology, Federal University of Paraná, Centro Politécnico - Jardim das Américas, Curitiba, PR, Brazil. Electronic address:

Contact dermatitis is a very common inflammatory reaction in the skin, causing not only aesthetic problems but also loss functionality at work. The molecular mechanisms of contact dermatitis induced by chemical irritants are still unclear. Considering that transient receptor potential channels (TRP) may induce neurogenic inflammation and the exacerbation of inflammatory responses, here we investigated the role of transient receptor potential channel ankyrin type-1 (TRPA1) in skin inflammation evoked by chemical irritants. Ear oedema and nociceptive responses elicited by the topical application of xylene and toluene were measured in Swiss mice, wild type and TRPA1 knockout (Trpa1) C57BL/6 mice. Histological analyses were performed in mice subjected to the ear oedema assay. Topical application of xylene and toluene in the mouse ear induced an edematogenic response (0.113 ± 0.008 mm and 0.067 ± 0.011 mm), compared to vehicle (0.008 ± 0.008 mm), assessed by ear thickness measurements and histological analyses. These responses were prevented by topical pretreatment with a selective TRPA1 antagonist, HC-030031 (% inhibition: xylene 36.8 ± 9.4% and toluene 50.7 ± 11.0%), and by the genetic deletion of TRPA1 ((% inhibition: xylene 66.6 ± 16.7% and toluene 75 ± 0%). In addition, the topical application of xylene and toluene to the mouse paw elicited nociceptive responses, which were significantly reduced by oral treatment with HC-030031 ((% of inhibition: 84.9 ± 1.3% and 27.1 ± 8.0%, respectively); nociceptive responses were almost completely abolished in Trpa1mice. Our data suggest that the activation of TRPA1 could be involved in some of the symptoms of irritant-mediated contact dermatitis, such as oedema, pain and neurogenic inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2019.172460DOI Listing
September 2019

The acyl-glucuronide metabolite of ibuprofen has analgesic and anti-inflammatory effects via the TRPA1 channel.

Pharmacol Res 2019 04 19;142:127-139. Epub 2019 Feb 19.

Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy. Electronic address:

Ibuprofen is a widely used non-steroidal anti-inflammatory drug (NSAID) that exerts analgesic and anti-inflammatory actions. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed primarily in nociceptors, mediates the action of proalgesic and inflammatory agents. Ibuprofen metabolism yields the reactive compound, ibuprofen-acyl glucuronide, which, like other TRPA1 ligands, covalently interacts with macromolecules. To explore whether ibuprofen-acyl glucuronide contributes to the ibuprofen analgesic and anti-inflammatory actions by targeting TRPA1, we used in vitro tools (TRPA1-expressing human and rodent cells) and in vivo mouse models of inflammatory pain. Ibuprofen-acyl glucuronide, but not ibuprofen, inhibited calcium responses evoked by reactive TRPA1 agonists, including allyl isothiocyanate (AITC), in cells expressing the recombinant and native human channel and in cultured rat primary sensory neurons. Responses by the non-reactive agonist, menthol, in a mutant human TRPA1 lacking key cysteine-lysine residues, were not affected. In addition, molecular modeling studies evaluating the covalent interaction of ibuprofen-acyl glucuronide with TRPA1 suggested the key cysteine residue C621 as a probable alkylation site for the ligand. Local administration of ibuprofen-acyl glucuronide, but not ibuprofen, in the mouse hind paw attenuated nociception by AITC and other TRPA1 agonists and the early nociceptive response (phase I) to formalin. Systemic ibuprofen-acyl glucuronide and ibuprofen, but not indomethacin, reduced phase I of the formalin response. Carrageenan-evoked allodynia in mice was reduced by local ibuprofen-acyl glucuronide, but not by ibuprofen, whereas both drugs attenuated PGE levels. Ibuprofen-acyl glucuronide, but not ibuprofen, inhibited the release of IL-8 evoked by AITC from cultured bronchial epithelial cells. The reactive ibuprofen metabolite selectively antagonizes TRPA1, suggesting that this novel action of ibuprofen-acyl glucuronide might contribute to the analgesic and anti-inflammatory activities of the parent drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2019.02.019DOI Listing
April 2019

NOP-Targeted Peptide Ligands.

Handb Exp Pharmacol 2019 ;254:17-36

Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.

The nociceptin/orphanin FQ (N/OFQ)-N/OFQ peptide (NOP) receptor system is widely distributed at both the peripheral and central level where it modulates important biological functions with increasing therapeutic implications. This chapter wants to provide a comprehensive and updated overview focused on the available structure-activity relationship studies on NOP receptor peptide ligands developed through different rational approaches. Punctual modifications and cyclizations of the N/OFQ sequence have been properly combined furnishing potent NOP selective ligands with different pharmacological activities (full and partial agonists, pure antagonists) and enhanced metabolic stability in vivo. The screening of peptide libraries provided a second family of NOP ligands that have been successfully optimized. Moreover, recent findings suggest the possibility to apply different multimerization strategies for the realization of multi-target NOP/opioid receptor ligands or tetrabranched N/OFQ derivatives with extraordinarily prolonged duration of action in vivo. The diverse approaches led to the identification of important pharmacological tools along with drug candidates currently in clinical development such as Rec 0438 (aka UFP-112) for the treatment of overactive bladder and SER 100 (aka ZP120) for the clinical management of systolic hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/164_2018_198DOI Listing
July 2019

Pharmacological profile of the neuropeptide S receptor: Dynamic mass redistribution studies.

Pharmacol Res Perspect 2018 12 3;6(6):e00445. Epub 2018 Dec 3.

Department of Medical Sciences Section of Pharmacology National Institute of Neuroscience University of Ferrara Ferrara Italy.

Neuropeptide S (NPS) is the endogenous ligand of the neuropeptide S receptor (NPSR). NPS modulates several biological functions including anxiety, wakefulness, pain, and drug abuse. The aim of this study was the investigation of the pharmacological profile of NPSR using the dynamic mass redistribution (DMR) assay. DMR is a label-free assay that offers a holistic view of cellular responses after receptor activation. HEK293 cells stably transfected with the murine NPSR (HEK293) have been used. To investigate the nature of the NPS-evoked DMR signaling, FR900359 (Gq inhibitor), pertussis toxin (Gi inhibitor), and rolipram (phosphodiesterase inhibitor) were used. To determine the pharmacology of NPSR, several selective ligands (agonists, partial agonists, antagonists) have been tested. NPS, through selective NPSR activation, evoked a robust DMR signal with potency in the nanomolar range. This signal was predominantly, but not completely, blocked by FR900359, suggesting the involvement of the Gq-dependent signaling cascade. NPSR ligands (agonists and antagonists) displayed potency values in DMR experiments similar, but not identical, to those reported in the literature. Furthermore, partial agonists produced a higher efficacy in DMR than in calcium experiments. DMR can be successfully used to study the pharmacology and signaling properties of novel NPSR ligands. This innovative approach will likely increase the translational value of in vitro pharmacological studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/prp2.445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277375PMC
December 2018

Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3',4',5'-trimethoxyphenyl)-3-(2'-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach.

J Enzyme Inhib Med Chem 2018 Dec;33(1):1225-1238

d Department of Biochemistry and Molecular Biology, Research Institute in Biomedical and Health Sciences (IUIBS) , University of Las Palmas de Gran Canaria (ULPGC) , Spain.

Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3',4',5'-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3',4',5'-trimethoxyphenyl)-2-propen-1-one framework. The structure-activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC values of 0.37, 0.16 and 0.17 μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC: 18 μM). This derivative also displayed cytotoxic properties (IC values ∼1 μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3',4',5'-trimethoxyphenyl scaffold.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14756366.2018.1493473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116705PMC
December 2018

Discovery of Novel 1,3,8-Triazaspiro[4.5]decane Derivatives That Target the c Subunit of F/F-Adenosine Triphosphate (ATP) Synthase for the Treatment of Reperfusion Damage in Myocardial Infarction.

J Med Chem 2018 08 9;61(16):7131-7143. Epub 2018 Aug 9.

Maria Cecilia Hospital , GVM Care & Research , 48033 , Cotignola , Ravenna , Italy.

Recent cardiology research studies have reported the role, function, and structure of the mitochondrial permeability transition pore (mPTP) and have shown that its opening plays a key role in the progression of myocardial cell death secondary to reperfusion. In this manuscript, we validated a new pharmacological approach as an adjunct to reperfusion in myocardial infarction (MI) treatment and describe the discovery, optimization, and structure-activity relationship (SAR) studies of the first small-molecule mPTP opening inhibitors based on a 1,3,8-triazaspiro[4.5]decane scaffold that targets the c subunit of the F/F-ATP synthase complex. We identified three potential compounds with good mPTP inhibitory activity and beneficial effects in a model of MI, including a decreased apoptotic rate in the whole heart and overall improvement of cardiac function upon administration during reperfusion. The selected compounds did not show off-target effects at the cellular and mitochondrial levels. Moreover, the compounds preserved the mitochondrial ATP content despite interacting with the ATP synthase complex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b00278DOI Listing
August 2018

Naphthoquinone amino acid derivatives, synthesis and biological activity as proteasome inhibitors.

J Enzyme Inhib Med Chem 2017 Dec;32(1):865-877

a Department of Chemical and Pharmaceutical Sciences , University of Ferrara , Ferrara , Italy.

The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division. Because of their antitumour activity, different classes of proteasome inhibitors have been identified to date. Some of these compounds are currently employed in the clinical treatment of several types of cancer among which multiple myeloma. Here, we describe the design, chemistry, biological activity and modelling studies of a large series of amino acid derivatives linked to a naphthoquinone pharmacophoric group through variable spacers. Some analogues showed interesting inhibitory potency for the β1 and β5 subunits of the proteasome with IC values in the sub-µm range.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14756366.2017.1334649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445160PMC
December 2017

Structure- and conformation-activity studies of nociceptin/orphanin FQ receptor dimeric ligands.

Sci Rep 2017 04 6;7:45817. Epub 2017 Apr 6.

Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, 44121 Ferrara, Italy.

The peptide nociceptin/orphanin FQ (N/OFQ) and the N/OFQ receptor (NOP) constitute a neuropeptidergic system that modulates various biological functions and is currently targeted for the generation of innovative drugs. In the present study dimeric NOP receptor ligands with spacers of different lengths were generated using both peptide and non-peptide pharmacophores. The novel compounds (12 peptide and 7 nonpeptide ligands) were pharmacologically investigated in a calcium mobilization assay and in the mouse vas deferens bioassay. Both structure- and conformation-activity studies were performed. Results demonstrated that dimerization did not modify the pharmacological activity of both peptide and non-peptide pharmacophores. Moreover, when dimeric compounds were obtained with low potency peptide pharmacophores, dimerization recovered ligand potency. This effect depends on the doubling of the C-terminal address sequence rather than the presence of an additional N-terminal message sequence or modifications of peptide conformation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep45817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382891PMC
April 2017

Neuropeptide S receptor ligands: a patent review (2005-2016).

Expert Opin Ther Pat 2017 Mar 9;27(3):347-362. Epub 2016 Nov 9.

c Department of Chemical and Pharmaceutical Sciences , University of Ferrara , Ferrara , Italy.

Introduction: Neuropeptide S (NPS) is a 20-residue peptide and endogenous ligand of the NPS receptor (NPSR). This receptor was a formerly orphan GPCR whose activation increases calcium and cyclic adenosine monophosphate levels. The NPS/NPSR system is expressed in several brain regions where it controls important biological functions including locomotor activity, arousal and sleep, anxiety, food intake, memory, pain, and drug addiction. Areas covered: This review furnishes an updated overview of the patent literature covering NPSR ligands since 2005, when the first example of an NPSR antagonist was disclosed. Expert opinion: Several potent NPSR antagonists are available as valuable pharmacological tools despite showing suboptimal pharmacokinetic properties in vivo. The optimization of these ligands is needed to speed up their potential clinical advancement as pharmaceuticals to treat drug addiction. In order to support the design of novel NPSR antagonists, we performed a ligand-based conformational analysis recognizing some structural requirements for NPSR antagonism. The identification of small-molecule NPSR agonists now represents an unmet challenge to be addressed. These molecules will allow investigation of the beneficial effects of selective NPSR activation in a large panel of psychiatric disorders and to foresee their therapeutic potential as anxiolytics, nootropics, and analgesics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13543776.2017.1254195DOI Listing
March 2017

Ozone-Induced Hypertussive Responses in Rabbits and Guinea Pigs.

J Pharmacol Exp Ther 2016 Apr 2;357(1):73-83. Epub 2016 Feb 2.

Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (E.C., D.S., C.P.); Department of Corporate Drug Development (R.P.), and Department of Pharmacology (M.T.), Chiesi Farmaceutici SpA, Parma, Italy; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy (D.P.); and Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy (M.P.B.)

Cough remains a major unmet clinical need, and preclinical animal models are not predictive for new antitussive agents. We have investigated the mechanisms and pharmacological sensitivity of ozone-induced hypertussive responses in rabbits and guinea pigs. Ozone induced a significant increase in cough frequency and a decrease in time to first cough to inhaled citric acid in both conscious guinea pigs and rabbits. This response was inhibited by the established antitussive drugs codeine and levodropropizine. In contrast to the guinea pig, hypertussive responses in the rabbit were not inhibited by bronchodilator drugs (β2 agonists or muscarinic receptor antagonists), suggesting that the observed hypertussive state was not secondary to bronchoconstriction in this species. The ozone-induced hypertussive response in the rabbit was inhibited by chronic pretreatment with capsaicin, suggestive of a sensitization of airway sensory nerve fibers. However, we could find no evidence for a role of TRPA1 in this response, suggesting that ozone was not sensitizing airway sensory nerves via activation of this receptor. Whereas the ozone-induced hypertussive response was accompanied by a significant influx of neutrophils into the airway, the hypertussive response was not inhibited by the anti-inflammatory phosphodiesterase 4 inhibitor roflumilast at a dose that clearly exhibited anti-inflammatory activity. In summary, our results suggest that ozone-induced hypertussive responses to citric acid may provide a useful model for the investigation of novel drugs for the treatment of cough, but some important differences were noted between the two species with respect to sensitivity to bronchodilator drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.115.230227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977573PMC
April 2016

Transient receptor potential ankyrin 1 (TRPA1) antagonists.

Pharm Pat Anal 2015 ;4(2):75-94

Department of Chemical & Pharmaceutical Sciences, University of Ferrara, Italy.

The transient receptor potential ankyrin 1 (TRPA1) channel is an irritant sensor highly expressed on nociceptive neurons. The clinical use of TRPA1 antagonists is based on the concept that TRPA1 is active during disease states like neuropathic pain. Indeed, in Phase 2a proof-of-concept studies the TRPA1 antagonist GRC17536 has shown efficacy in patients with painful diabetic neuropathy. Moreover, animal studies suggest that the therapeutic value of TRPA1 antagonists extends beyond pain to pruritus, asthma and cough with limited safety concerns. This review provides a comprehensive overview of the patent literature (since 2007) on small-molecule inhibitors of the TRPA1 channel. Despite the clear progress, many unanswered questions remain. Future advancement to Phase 3 studies will assess the real translational potential of this research field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4155/ppa.14.60DOI Listing
March 2016

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/med.21344DOI Listing
July 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).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.5b00215DOI Listing
April 2015

The TRPA1 channel mediates the analgesic action of dipyrone and pyrazolone derivatives.

Br J Pharmacol 2015 Jul 24;172(13):3397-411. Epub 2015 Apr 24.

Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.

Background And Purpose: Although still used by hundreds of millions of people worldwide, the mechanism of the analgesic action of the pyrazolone derivatives (PDs), dipyrone, propyphenazone and antipyrine remains unknown. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed by nociceptors, is emerging as a major pain transduction pathway. We hypothesized that PDs target the TRPA1 channel and by this mechanism produce their analgesic effect.

Experimental Approach: Calcium responses and currents were studied in cultured TRPA1-expressing rodent dorsal root ganglion neurons and human cells. Acute nociception and mechanical hypersensitivity were investigated in naïve and genetically manipulated mice.

Key Results: Pyrazolone and PDs selectively inhibited calcium responses and currents in TRPA1-expressing cells and acute nocifensor responses in mice evoked by reactive channel agonists (allyl isothiocyanate, acrolein and H2 O2 ). In line with recent results obtained with TRPA1 antagonists and TRPA1 gene deletion, the two most largely used PDs, dipyrone and propyphenazone, attenuated TRPA1-mediated nociception and mechanical allodynia in models of inflammatory and neuropathic pain (formalin, carrageenan, partial sciatic nerve ligation and the chemotherapeutic drug, bortezomib). Notably, dipyrone and propyphenazone attenuated carrageenan-evoked mechanical allodynia, without affecting PGE2 levels. The main metabolites of PDs did not target TRPA1 and did not affect TRPA1-dependent nociception and allodynia.

Conclusions And Implications: Evidence that in rodents the nociceptive/hyperalgesic effect produced by TRPA1 activation is blocked by PDs suggests that a similar pathway is attenuated by PDs in humans and that TRPA1 antagonists could be novel analgesics, devoid of the adverse haematological effects of PDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.13129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500374PMC
July 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1573406411666141210141317DOI Listing
February 2016

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm5008853DOI Listing
September 2014

The blockade of transient receptor potential ankirin 1 (TRPA1) signalling mediates antidepressant- and anxiolytic-like actions in mice.

Br J Pharmacol 2014 Sep;171(18):4289-99

Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, RN, Brazil.

Background And Purpose: Transient receptor potential vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) are involved in many biological processes, including nociception and hyperalgesia. Whereas the involvement of TRPV1 in psychiatric disorders such as anxiety and depression has been reported, little is known regarding the role of TRPA1 in these conditions.

Experimental Approach: We investigated the role of TRPA1 in mice models of depression [forced swimming test (FST)] and anxiety [elevated plus maze (EPM) test].

Key Results: Administration of the TRPA1 antagonist (HC030031, 30 nmol in 2 μL, i.c.v.) reduced immobility time in the FST. Similar results were obtained after oral administration of HC030031 (30-300 mg·kg(-1) ). The reduction in immobility time in FST induced by HC030031 (100 mg·kg(-1) ) was completely prevented by pretreatment with TRPA1 agonist, cinnamaldehyde (50 mg·kg(-1) , p.o.), which per se was inactive. In the EPM test, pretreatment with cinnamaldehyde (50 mg·kg(-1) , p.o.), which per se did not affect behaviour response, prevented the anxiolytic-like effect (increased open arm exploration) evoked by TRPA1 blockade (HC030031, 100 mg·kg(-1) , p.o.). Treatment with either cinnamaldehyde or HC030031 did not affect spontaneous ambulation. Furthermore, TRPA1-deficient mice showed anxiolytic- and antidepressant-like phenotypes in the FST and EPM test respectively.

Conclusion And Implications: The present findings indicate that genetic deletion or pharmacological blockade of TRPA1 produces inhibitory activity in mouse models of anxiety and depression. These results imply that TRPA1 exerts tonic control, promoting anxiety and depression, and that TRPA1 antagonism has potential as an innovative strategy for the treatment of anxiety and mood disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.12786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241094PMC
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2013.11.043DOI Listing
January 2014

Concise synthesis and biological evaluation of 2-Aroyl-5-amino benzo[b]thiophene derivatives as a novel class of potent antimitotic agents.

J Med Chem 2013 Nov 11;56(22):9296-309. Epub 2013 Nov 11.

Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara , 44121 Ferrara, Italy.

The biological importance of microtubules make them an interesting target for the synthesis of antitumor agents. The 2-(3',4',5'-trimethoxybenzoyl)-5-aminobenzo[b]thiophene moiety was identified as a novel scaffold for the preparation of potent inhibitors of microtubule polymerization acting through the colchicine site of tubulin. The position of the methoxy group on the benzo[b]thiophene was important for maximal antiproliferative activity. Structure-activity relationship analysis established that the best activities were obtained with amino and methoxy groups placed at the C-5 and C-7 positions, respectively. Compounds 3c-e showed more potent inhibition of tubulin polymerization than combretastatin A-4 and strong binding to the colchicine site. These compounds also demonstrated substantial antiproliferative activity, with IC50 values ranging from 2.6 to 18 nM in a variety of cancer cell lines. Importantly, compound 3c (50 mg/kg), significantly inhibited the growth of the human osteosarcoma MNNG/HOS xenograft in nude mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm4013938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899843PMC
November 2013

Synthesis and biological effects of novel 2-amino-3-(4-chlorobenzoyl)-4-substituted thiophenes as allosteric enhancers of the A1 adenosine receptor.

Eur J Med Chem 2013 Sep 13;67:409-27. Epub 2013 Jul 13.

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

Allosteric enhancers for the A1 adenosine receptor represent a novel and unique drug design strategy to augment the response to endogenous adenosine in a site- and event-specific manner. We have previously investigated a detailed structure-activity relationship study around a wide series of 2-amino-3-aroyl-4-[(4-arylpiperazin-1-yl)methyl]thiophene derivatives as potent allosteric enhancers of the A1 adenosine receptor. In this manuscript we report our investigation on the influence on allosteric enhancer activity of further substitution at the 4-position of the 2-amino-3-(4-chlorobenzoyl)-thiophene system to explore bulk tolerance by replacement of the arylpiperazine moiety with a series of fused indole nuclei corresponding to 1,2,3,4-tetrahydropyrazino[1,2-a]indole, 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole, tetrahydro-γ-carboline, tetrahydroisoquinoline, spiro-1,3-benzodioxolepiperidine, aliphatic tertiary amine, N-alkylaniline, aryl ether and aryl thioether templates. The 1,2,3,4-tetrahydropyrazino[1,2-a]indole derivatives 3a-c and 3e 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. This study also shows that it is possible to obtain a good separation between allosteric enhancement and antagonistic activity at the A1 adenosine receptor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2013.07.002DOI Listing
September 2013

Discovery of 7-oxopyrazolo[1,5-a]pyrimidine-6-carboxamides as potent and selective CB(2) cannabinoid receptor inverse agonists.

J Med Chem 2013 Jun 4;56(11):4482-96. Epub 2013 Jun 4.

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

We recently described the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7-oxopyrimidines as CB2 receptor partial agonists, showing that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. We describe herein the design and synthesis of the 7-oxopyrazolo[1,5-a]pyrimidine-6-carboxamides, structural isomers of our previously reported pyrazolo[3,4-b]pyridines. All of the new compounds showed high affinity and selectivity for the CB2 receptor in the nanomolar range. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series shows stimulatory effects on forskolin-induced cAMP production acting as inverse agonists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm400182tDOI Listing
June 2013

Synthesis and biological evaluation of 2-(alkoxycarbonyl)-3-anilinobenzo[b]thiophenes and thieno[2,3-b]pyridines as new potent anticancer agents.

J Med Chem 2013 Mar 18;56(6):2606-18. Epub 2013 Mar 18.

Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.

Two new series of inhibitors of tubulin polymerization based on the 2-(alkoxycarbonyl)-3-(3',4',5'-trimethoxyanilino)benzo[b]thiophene and thieno[2,3-b]pyridine molecular skeletons were synthesized and evaluated for antiproliferative activity on a panel of cancer cell lines, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. Antiproliferative activity was strongly dependent on the position of the methyl group on the benzene portion of the benzo[b]thiophene nucleus, with the greatest activity observed when the methyl was located at the C-6 position. Also, in the smaller thieno[2,3-b]pyridine series, the introduction of the methyl group at the C-6 position resulted in improvement of antiproliferative activity to the nanomolar level. The most active compounds (4i and 4n) did not induce cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. Compound 4i significantly inhibited in vivo the growth of a syngeneic hepatocellular carcinoma in Balb/c mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm400043dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646584PMC
March 2013