2,258 results match your criteria ACS medicinal chemistry letters[Journal]


Exploiting Chemical Toolboxes for the Expedited Generation of Tetracyclic Quinolines as a Novel Class of PXR Agonists.

ACS Med Chem Lett 2019 Apr 27;10(4):677-681. Epub 2018 Dec 27.

Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, I-06123 Perugia, Italy.

The discovery of lead compounds relies on the iterative generation of structure-activity relationship data resulting from the synthesis and biological evaluation of hit analogues. Using traditional approaches, a significant time delay may occur from compound design to results, leading to slow and expensive hit-to-lead explorations. Herein, we have exploited the use of chemical toolboxes to expedite lead discovery and optimization. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466813PMC

Novel Sustainable-by-Design HDAC Inhibitors for the Treatment of Alzheimer's Disease.

ACS Med Chem Lett 2019 Apr 29;10(4):671-676. Epub 2019 Mar 29.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy.

Alzheimer's disease (AD) represents a global problem, with an estimation of the majority of dementia patients in low- and middle-income countries by 2050. Thus, the development of sustainable drugs has attracted much attention in recent years. In light of this, taking inspiration from the HDAC inhibitor vorinostat (), we develop the first HDAC inhibitors derived from cashew nut shell liquid (CNSL), an inexpensive agro-food waste material. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466821PMC
April 2019
1 Read

Mechanisms of Metabolite Amyloid Formation: Computational Studies for Drug Design against Metabolic Disorders.

ACS Med Chem Lett 2019 Apr 15;10(4):666-670. Epub 2019 Feb 15.

Istituto di Chimica del Riconoscimento Molecolare, CNR, via Mario Bianco 9, Milano 20131, Italy.

Ordered self-organization of polypeptides into fibrillar assemblies has been associated with a number of pathological conditions linked to degenerative diseases. Recent experimental observations have demonstrated that even small-molecule metabolites can aggregate into supramolecular arrangements with structural and functional properties reminiscent of peptide-based amyloids. The molecular determinants of such mechanisms, however, are not clear yet. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466829PMC
April 2019
2 Reads

α,γ-Diketocarboxylic Acids and Their Esters Act as Carbonic Anhydrase IX and XII Selective Inhibitors.

ACS Med Chem Lett 2019 Apr 19;10(4):661-665. Epub 2019 Feb 19.

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.

Among human carbonic anhydrase (CA) inhibitors, the α,γ-diketocarboxylic acids and esters are still poorly investigated. Here, we report the first compounds of this class (-) acting as potent inhibitors at low nanomolar level against the cancer-related human CA IX and XII, and 2-3 magnitude orders selective toward the cytosolic isoforms hCA I and II. At enzymatic level, the α,γ-diketoacids - were more effective inhibitors compared to the corresponding ethyl esters -. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466837PMC

Replacement of the Thiosugar of Auranofin with Iodide Enhances the Anticancer Potency in a Mouse Model of Ovarian Cancer.

ACS Med Chem Lett 2019 Apr 7;10(4):656-660. Epub 2019 Feb 7.

Laboratory of Metals in Medicine (MetMed), Department of Chemistry "U. Schiff", University of Florence, via della Lastruccia 3, 50019 Sesto Fiorentino, Italy.

In recent years, a few successful attempts were made to repurpose the clinically approved antiarthritic gold drug, Auranofin (), as an anticancer agent. The present study shows that the iodido(triethylphosphine)gold(I) complex, ( hereafter)-an analogue where the thiosugar ligand is simply replaced by one iodide ligand-manifests a solution chemistry resembling that of and exerts similar cytotoxic and proapoptotic effects on A2780 human ovarian cancer cells . However, when evaluated in a preclinical orthotopic model of ovarian cancer, produces a far superior anticancer action than inducing a nearly complete tumor remission. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466815PMC

X-ray Crystallography Deciphers the Activity of Broad-Spectrum Boronic Acid β-Lactamase Inhibitors.

ACS Med Chem Lett 2019 Apr 27;10(4):650-655. Epub 2019 Mar 27.

Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy.

Recent decades have witnessed a dramatic increase of multidrug resistant (MDR) bacteria, compromising the efficacy of available antibiotics, and a continual decline in the discovery of novel antibacterials. We recently reported the first library of benzo[b]thiophen-2-ylboronic acid inhibitors sharing broad spectrum activity against β-lactamases (BLs). The ability of these compounds to inhibit structurally and mechanistically different types of β-lactamases has been here structurally investigated. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00607
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http://dx.doi.org/10.1021/acsmedchemlett.8b00607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466825PMC
April 2019
1 Read

Selective Inhibitors of T Cell Receptor Recognition of Antigen-MHC Complexes for Rheumatoid Arthritis.

ACS Med Chem Lett 2019 Apr 13;10(4):644-649. Epub 2019 Mar 13.

Institute of Chemistry of Molecular Recognition (ICRM) - CNR, Rome, Italy.

Autoreactive T cells specific to human collagen type II have a crucial role in the development of rheumatoid arthritis (RA) in the context of MHC class II allele HLA-DRB1-*04. The protein-protein interactions between the T cell receptor (TCR) and the type II collagen bound to the allele MHC of class II may thus represent the target for the development of new drugs against RA. In this study, a structure-based pharmacophore model for potential small molecule inhibitors was developed from protein-protein interface structure. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466834PMC

Chalcones and Chalcone-mimetic Derivatives as Notch Inhibitors in a Model of T-cell Acute Lymphoblastic Leukemia.

ACS Med Chem Lett 2019 Apr 26;10(4):639-643. Epub 2019 Feb 26.

Instituto de Química Médica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.

Based on hit-likeness and chemical diversity, a number of chalcones and chalcone-mimetic compounds were selected as putative Notch inhibitors. The evaluation of the antiproliferative effect combined with the inhibition of Notch1 expression in KOPTK1 cell line identified compound , featuring a tetrahydronaphthalene-based scaffold, as a new promising Notch-blocking agent. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466818PMC
April 2019
1 Read

Prediction of UGT-mediated Metabolism Using the Manually Curated MetaQSAR Database.

ACS Med Chem Lett 2019 Apr 12;10(4):633-638. Epub 2019 Feb 12.

Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, U.K.

Even though glucuronidations are the most frequent metabolic reactions of conjugation, both in quantitative and qualitative terms, they have rather seldom been investigated using computational approaches. To fill this gap, we have used the manually collected MetaQSAR metabolic reaction database to generate two models for the prediction of UGT-mediated metabolism, both based on molecular descriptors and implementing the Random Forest algorithm. The first model predicts the occurrence of the reaction and was internally validated with a Matthew correlation coefficient (MCC) of 0. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00603
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http://dx.doi.org/10.1021/acsmedchemlett.8b00603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466832PMC
April 2019
1 Read

Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS.

ACS Med Chem Lett 2019 Apr 7;10(4):627-632. Epub 2019 Feb 7.

Promidis, Via Olgettina 60, 20132 Milan, Italy.

Acid-sensing ion channels (ASICs) are a family of ion channels permeable to cations and largely responsible for the onset of acid-evoked ion currents both in neurons and in different types of cancer cells, thus representing a potential target for drug discovery. Owing to the limited attention ASIC2 has received so far, an exploratory program was initiated to identify ASIC2 inhibitors using diminazene, a known -ASIC inhibitor, as a chemical starting point for structural elaboration. The performed exploration enabled the identification of a novel series of ASIC2 inhibitors. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00591
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http://dx.doi.org/10.1021/acsmedchemlett.8b00591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466820PMC
April 2019
1 Read

Stereoselective Synthesis of C-2 Alkylated Trihydroxypiperidines: Novel Pharmacological Chaperones for Gaucher Disease.

ACS Med Chem Lett 2019 Apr 8;10(4):621-626. Epub 2019 Feb 8.

Department of Chemistry "Ugo Schiff", University of Firenze, via della Lastruccia n. 3-13, 50019 Sesto Fiorentino (FI), Italy.

Pharmacological chaperones (PCs) are small molecules that bind and stabilize enzymes. They can rescue the enzymatic activity of misfolded or deficient enzymes when they are used at subinhibitory concentration, thus with minimal side effects. Pharmacological Chaperone Therapy (PCT) is an emerging treatment for many lysosomal storage disorders (LSDs) including Gaucher disease, the most common, which is characterized by a deficiency in the GCase enzyme. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467014PMC

Novel Compounds Targeting the RNA-Binding Protein HuR. Structure-Based Design, Synthesis, and Interaction Studies.

ACS Med Chem Lett 2019 Apr 21;10(4):615-620. Epub 2019 Jan 21.

Department of Drug Sciences, Medicinal Chemistry and Technology Section, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy.

The key role of RNA-binding proteins (RBPs) in regulating post-transcriptional processes and their involvement in several pathologies (, cancer and neurodegeneration) have highlighted their potential as therapeutic targets. In this scenario, Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs have been gaining growing attention. Compounds able to modulate the complex stability could constitute an innovative pharmacological strategy for the treatment of numerous diseases. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466816PMC

Self-assembling Releasable Thiocolchicine-Diphenylbutenylaniline Conjugates.

ACS Med Chem Lett 2019 Apr 4;10(4):611-614. Epub 2019 Jan 4.

Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy.

The design and the synthesis of new self-assembling conjugates is reported. The target compounds are characterized by the presence of a self-immolative linker that secures a controlled release induced by lipase cleavage. 4-(1,2-Diphenylbut-1-en-1-yl)aniline is used as a self-assembling inducer and amino-thiocolchicine as prototype of drug. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00605
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http://dx.doi.org/10.1021/acsmedchemlett.8b00605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466830PMC
April 2019
1 Read

Identification of a Strigoterpenoid with Dual Nrf2 and Nf-κB Modulatory Activity.

ACS Med Chem Lett 2019 Apr 8;10(4):606-610. Epub 2019 Jan 8.

Maimonides Biomedical Research Institute of Córdoba, Avda Menendez Pidal s/n, 14004 Cordoba, Spain.

The sesquiterpene-coumarin ether samarcandone provided a suitable framework to replace the apocarotenoid A-C ring system of strigol (), replicating, after linking to a butenolide moiety, the activity of the natural phytohormone on Nrf2 and also showing potent NF-kB inhibitory activity, overall modulating two critical pathways of inflammation and cancer. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467025PMC

Identification of the 2-Benzoxazol-2-yl-phenol Scaffold as New Hit for JMJD3 Inhibition.

ACS Med Chem Lett 2019 Apr 25;10(4):601-605. Epub 2019 Feb 25.

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

JMJD3 is a member of the KDM6 subfamily and catalyzes the demethylation of lysine 27 on histone H3 (H3K27). This protein was identified as a useful tool in understanding the role of epigenetics in inflammatory conditions and in cancer as well. Guided by a virtual fragment screening approach, we identified the benzoxazole scaffold as a new hit suitable for the development of tighter JMJD3 inhibitors. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466828PMC

Polycyclic Maleimide-based Scaffold as New Privileged Structure for Navigating the Cannabinoid System Opportunities.

ACS Med Chem Lett 2019 Apr 26;10(4):596-600. Epub 2019 Feb 26.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.

The discovery of the relevant role played by a dysregulation of the endogenous cannabinoid system in several pathological conditions has prompted an extensive research in this field. In this Letter, a series of cannabinoid receptor ligands bearing a previously unexplored polycyclic scaffold was designed and synthesized, in order to evaluate the potential of a new easily affordable privileged structure. The new compounds showed an appreciable affinity and a significant selectivity for the CB2 receptor and are endowed with an intriguing noncompetitive antagonist behavior. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466824PMC

Covalent Inhibitors of Glyceraldehyde 3-Phosphate Dehydrogenase with Antimalarial Activity in Vitro.

ACS Med Chem Lett 2019 Apr 20;10(4):590-595. Epub 2019 Feb 20.

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

Covalent inhibitors of GAPDH characterized by a 3-bromoisoxazoline warhead were developed, and their mode of interaction with the target enzyme was interpreted by means of molecular modeling studies: some of them displayed a submicromolar antiplasmodial activity against both chloroquine sensitive and resistant strains of , with good selectivity indices. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00592
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http://dx.doi.org/10.1021/acsmedchemlett.8b00592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466836PMC
April 2019
1 Read

EC18 as a Tool To Understand the Role of HCN4 Channels in Mediating Hyperpolarization-Activated Current in Tissues.

ACS Med Chem Lett 2019 Apr 6;10(4):584-589. Epub 2019 Feb 6.

Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence 50139, Italy.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are membrane proteins encoded by four genes (HCN1-4) and widely distributed in the central and peripheral nervous system and in the heart. HCN channels are involved in several physiological functions, including the generation of rhythmic activity, and are considered important drug targets if compounds with isoform selectivity are developed. At present, however, few compounds are known, which are able to discriminate among HCN channel isoforms. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00587
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http://dx.doi.org/10.1021/acsmedchemlett.8b00587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466822PMC
April 2019
1 Read

Mass Spectrometry-based Label-free Quantitative Proteomics To Study the Effect of 3PO Drug at Cellular Level.

ACS Med Chem Lett 2019 Apr 11;10(4):577-583. Epub 2019 Jan 11.

Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milan, Italy.

Human endothelial cells (ECs) have been employed to monitor the protein changes induced by [3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one] (3PO), a compound able to inhibit the glycolytic flux partially and transiently and to reduce pathological angiogenesis in a variety of disease models. Normal and TNFα induced inflamed ECs were incubated with and without 3PO at a concentration (20 μM) able to inhibit cell proliferation without cell death. At the end of the incubation period, samples were submitted to the following steps: (a) whole protein extraction, reduction, alkylation, and digestion by trypsin; (b) peptide separation by nano-LC-MS/MS analysis using a high-resolution mass spectrometer; (c) data analysis including protein identification, quantification, and statistical analysis. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466823PMC

Investigating the Anticancer Activity of Isatin/Dihydropyrazole Hybrids.

ACS Med Chem Lett 2019 Apr 18;10(4):571-576. Epub 2018 Dec 18.

Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.

A series of isatin-dihydropyrazole hybrids have been synthesized in order to assess their potential as anticancer agents. In particular, 12 compounds were evaluated for their antiproliferative activity toward A549, IGR39, U87, MDA-MB-231, MCF-7, BT474, BxPC-3, SKOV-3, and H1299 cell lines, and human foreskin fibroblasts. Four compounds exhibited interesting antiproliferative activity and were further examined to determine their EC values toward a panel of selected tumor cell lines. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466827PMC

Inhibition Mechanism of Urease by Au(III) Compounds Unveiled by X-ray Diffraction Analysis.

ACS Med Chem Lett 2019 Apr 4;10(4):564-570. Epub 2019 Jan 4.

Laboratory of Bioinorganic Chemistry, Department of Pharmacy and Biotechnology, University of Bologna, Viale Giuseppe Fanin 40, I-40127 Bologna, Italy.

The nickel-dependent enzyme urease is a virulence factor for a large number of critical human pathogens, making this enzyme a potential target of therapeutics for the treatment of resistant bacterial infections. In the search for novel urease inhibitors, five selected coordination and organometallic Au(III) compounds containing NN or CN and CNN ligands were tested for their inhibitory effects against (jack bean) urease. The results showed potent inhibition effects with IC values in the nanomolar range. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00585
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http://dx.doi.org/10.1021/acsmedchemlett.8b00585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466819PMC
April 2019
1 Read

Scaffold Morphing Approach To Expand the Toolbox of Broad-Spectrum Antivirals Blocking Dengue/Zika Replication.

ACS Med Chem Lett 2019 Apr 23;10(4):558-563. Epub 2019 Jan 23.

Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy.

We have recently discovered a family of 2,6-diaminopurine derivatives acting as DENV inhibitors by targeting an allosteric pocket on the thumb of the viral NS5 polymerase. Although the following target-based optimization allowed conversion of the hits into broad-spectrum DENV/ZIKV inhibitors, no improvement of the antiviral potency was reached. Herein, we applied a phenotypic scaffold-morphing approach to explore additional biologically relevant chemical space around the original hits by converting the flat purine derivatives into more complex chemotypes characterized by a higher degree of saturation. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466831PMC

Behind the Mirror: Chirality Tunes the Reactivity and Cytotoxicity of Chloropiperidines as Potential Anticancer Agents.

ACS Med Chem Lett 2019 Apr 13;10(4):552-557. Epub 2019 Feb 13.

Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Francesco Marzolo 5, 35131 Padova, Italy.

The pressing demand for sustainable antitumor drugs prompted us to investigate 3-chloropiperidines as potential mustard-based anticancer agents. In this study, an explorative set of variously decorated monofunctional 3-chloropiperidines (M-CePs) was efficiently synthesized through a fast and affordable route providing high yields of pure racemates and enantiomers. Consistently with their reactivity, M-CePs were demonstrated to alkylate DNA . Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00580
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http://dx.doi.org/10.1021/acsmedchemlett.8b00580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466835PMC
April 2019
1 Read

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

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

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

The development of PPARα/γ dual or PPARα/γ/δ pan-agonists could represent an efficacious approach for a simultaneous pharmacological intervention on carbohydrate and lipid metabolism. Two series of new phenyldiazenyl fibrate derivatives of GL479, a previously reported PPARα/γ dual agonist, were synthesized and tested. Compound was identified as a PPAR pan-agonist with moderate and balanced activity on the three PPAR isoforms (α, γ, δ). Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466826PMC

Cannabinoids from L.: A New Tool Based on HPLC-DAD-MS/MS for a Rational Use in Medicinal Chemistry.

ACS Med Chem Lett 2019 Apr 29;10(4):539-544. Epub 2019 Jan 29.

Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.

L. represents one of the most widely used source of drugs and drugs of abuse worldwide. Its biologically active compounds are mainly cannabinoids, including Δ-tetrahydrocannabinol (THC), which is responsible for the psychoactive effects, tetrahydrocannabinolic acid (THCA), cannabinol (CBN), cannabidiol (CBD), and cannabidiolic acid (CBDA). Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00571
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http://dx.doi.org/10.1021/acsmedchemlett.8b00571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466817PMC
April 2019
1 Read

Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515.

ACS Med Chem Lett 2019 Apr 13;10(4):534-538. Epub 2019 Mar 13.

Oncology, Nerviano Medical Sciences S.r.l., Viale Pasteur 10, 20014 Nerviano, Milan, Italy.

Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD to modify substrate proteins via the attachment of poly(ADP-ribose) chains. PARP-1 is a well established target in oncology, as testified by the number of marketed drugs (e. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00569
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http://dx.doi.org/10.1021/acsmedchemlett.8b00569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466814PMC
April 2019
2 Reads

SAR Studies and Biological Characterization of a Chromen-4-one Derivative as an Anti- Agent.

ACS Med Chem Lett 2019 Apr 29;10(4):528-533. Epub 2019 Jan 29.

University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy.

Chemical modulation of the flavonol 2-(benzo[d][1,3]dioxol-5-yl)-chromen-4-one (), a promising anti-Trypanosomatid agent previously identified, was evaluated through a phenotypic screening approach. Herein, we have performed structure-activity relationship studies around hit compound . The pivaloyl derivative () showed significant anti- activity (EC = 1. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466517PMC

Deciphering the Nonsense Readthrough Mechanism of Action of Ataluren: An Compared Study.

ACS Med Chem Lett 2019 Apr 7;10(4):522-527. Epub 2019 Feb 7.

Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF) Università degli Studi di Palermo, via Archirafi 28 - viale delle Scienze, Edificio 16 & 17, 90100-Palermo-Italy.

Ataluren was reported to suppress nonsense mutations by promoting the readthrough of premature stop codons, although its mechanism of action (MOA) is still debated. The likely interaction of Ataluren with CFTR-mRNA has been previously studied by molecular dynamics. In this work we extended the modeling of Ataluren's MOA by complementary computational approaches such as induced fit docking (IFD), quantum polarized ligand docking (QPLD), MM-GBSA free-energy calculations, and computational mutagenesis. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00558
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http://dx.doi.org/10.1021/acsmedchemlett.8b00558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466511PMC
April 2019
1 Read

Proof-of-Concept Multistage Biomimetic Liposomal DNA Origami Nanosystem for the Remote Loading of Doxorubicin.

ACS Med Chem Lett 2019 Apr 31;10(4):517-521. Epub 2019 Jan 31.

Clinical and Experimental Pharmacology Unit, IRCCS CRO Aviano-National Cancer Institute, 33081 Aviano, Italy.

One of the most promising applications of DNA origami is its use as an excellent evolution of nanostructured intelligent systems for drug delivery, but short lifetime and immune-activation are still major challenges to overcome. On the contrary, stealth liposomes have long-circulation time and are well tolerated by the immune system. To overcome DNA origami limitations, we have designed and synthesized a compact short tube DNA origami (STDO) of approximately 30 nm in length and 10 nm in width. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466551PMC

Role of the NMDA Receptor in the Antitumor Activity of Chiral 1,4-Dioxane Ligands in MCF-7 and SKBR3 Breast Cancer Cells.

ACS Med Chem Lett 2019 Apr 28;10(4):511-516. Epub 2019 Jan 28.

School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy.

The potent -methyl-d-aspartate (NMDA) receptor antagonists - have been demonstrated to show antiproliferative and cytotoxic effects in MCF-7 and SKBR3 breast cancer cell lines. To improve the knowledge about the role played by the NMDA receptor in the antitumor activity of these compounds, the enantiomers of were prepared and evaluated for their affinity for the phencyclidine (PCP) site of the NMDA receptor and for their cytotoxic effect in MCF-7 and SKBR3 cell lines, both expressing the NMDA receptor. The ()- enantiomer, showing negligible affinity for the PCP site, exhibited antiproliferative activity higher than that of ()-, which instead bound the PCP site. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466546PMC
April 2019
1 Read

Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists.

ACS Med Chem Lett 2019 Apr 10;10(4):504-510. Epub 2019 Jan 10.

Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, Naples 80131, Italy.

Recent findings have shown that Farnesoid X Receptor (FXR) antagonists might be useful in the treatment of cholestasis and related metabolic disorders. In this paper, we report the discovery of a new chemotype of FXR antagonists featured by a 3,5-disubstituted oxadiazole core. In total, 35 new derivatives were designed and synthesized, and notably, compounds and , containing a piperidine ring, displayed the best antagonistic activity against FXR with promising cellular potency (IC = 0. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466555PMC

Drug Design and Synthesis of First in Class PDZ1 Targeting NHERF1 Inhibitors as Anticancer Agents.

ACS Med Chem Lett 2019 Apr 14;10(4):499-503. Epub 2019 Jan 14.

Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy.

Targeted approaches aiming at modulating NHERF1 activity, rather than its overall expression, would be preferred to preserve the normal functions of this versatile protein. We focused our attention on the NHERF1/PDZ1 domain that governs its membrane recruitment/displacement through a transient phosphorylation switch. We herein report the design and synthesis of novel NHERF1 PDZ1 domain inhibitors. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00532
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http://dx.doi.org/10.1021/acsmedchemlett.8b00532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466550PMC
April 2019
1 Read

Investigation on 2',3'--Substituted ATP Derivatives and Analogs as Novel P2X3 Receptor Antagonists.

ACS Med Chem Lett 2019 Apr 26;10(4):493-498. Epub 2018 Dec 26.

School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, MC, Italy.

Antagonists of the purinergic P2X3 receptors represent promising drugs for the treatment of inflammation and pain. The ATP derivative 2',3'--(2,4,6-trinitrophenyl)-ATP (TNP-ATP) has been described as a potent competitive inhibitor of this receptor. In this work, the design and synthesis of novel TNP-ATP analogues bearing alkyl groups in the 2',3'-position are reported. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466514PMC

Discovering New Casein Kinase 1d Inhibitors with an Innovative Molecular Dynamics Enabled Virtual Screening Workflow.

ACS Med Chem Lett 2019 Apr 13;10(4):487-492. Epub 2018 Dec 13.

Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, 10125 Torino, Italy.

The value of including protein flexibility in structure-based drug design (SBDD) is widely documented, and currently, molecular dynamics (MD) simulations represent a powerful tool to investigate protein dynamics. Yet, the inclusion of MD-derived information in pre-existing SBDD workflows is still far from trivial. We recently published an integrated MD-FLAP (Fingerprints for Ligands and Proteins) approach combining MD, clustering and Linear Discriminant Analysis (LDA) for enhancing accuracy, efficacy, and for protein conformational selection in virtual screening (VS) campaigns. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00523
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http://dx.doi.org/10.1021/acsmedchemlett.8b00523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466522PMC
April 2019
1 Read

Improved Selective Class I HDAC and Novel Selective HDAC3 Inhibitors: Beyond Hydroxamic Acids and Benzamides.

ACS Med Chem Lett 2019 Apr 27;10(4):481-486. Epub 2018 Nov 27.

IRBM Science Park, Via Pontina km 30,600, 00071 Pomezia, Rome, Italy.

The application of class I HDAC inhibitors as cancer therapies is well established, but more recently their development for nononcological indications has increased. We report here on the generation of improved class I selective human HDAC inhibitors based on an ethylketone zinc binding group (ZBG) in place of the hydroxamic acid that features the majority of HDAC inhibitors. We also describe a novel set of HDAC3 isoform selective inhibitors that show stronger potency and selectivity than the most commonly used HDAC3 selective tool compound RGFP966. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466521PMC

First-of-its-kind STARD Inhibitor: Identification and Biological Evaluation as Anticancer Agent.

ACS Med Chem Lett 2019 Apr 20;10(4):475-480. Epub 2019 Feb 20.

Department of Translational Research, Pathology Unit, National Cancer Institute-CRO-IRCSS, 33081 Aviano, Italy.

STARD3 is a cellular protein that represents an attractive target for cancer therapy, being overexpressed in breast cancer and implied in the development of colorectal, gastric, and prostate cancers. Unfortunately, no STARD3 inhibitor has been identified yet. In this work, an strategy was applied to predict a reliable binding mode of cholesterol into STARD3 and to develop a pharmacophore-based virtual screening protocol that allowed the identification of the first STARD3 inhibitor ever reported. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00509
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http://dx.doi.org/10.1021/acsmedchemlett.8b00509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466518PMC
April 2019
2 Reads

Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer's Disease.

ACS Med Chem Lett 2019 Apr 4;10(4):469-474. Epub 2019 Feb 4.

Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.

Several evidence pointed out the role of epigenetics in Alzheimer's disease (AD) revealing strictly relationships between epigenetic and "classical" AD targets. Based on the reported connection among histone deacetylases (HDACs) and glycogen synthase kinase 3β (GSK-3β), herein we present the discovery and the biochemical characterization of the first-in-class hit compound able to exert promising anti-AD effects by modulating the targeted proteins in the low micromolar range of concentration. Compound induces an increase in histone acetylation and a reduction of tau phosphorylation. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466523PMC

Synthesis and Evaluation of Bifunctional Aminothiazoles as Antiretrovirals Targeting the HIV-1 Nucleocapsid Protein.

ACS Med Chem Lett 2019 Apr 7;10(4):463-468. Epub 2018 Dec 7.

Department of Biotechnology, Chemistry and Pharmacy, "Department of Excellence 2018-2022", University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

Small molecule inhibitors of the HIV-1 nucleocapsid protein (NC) are considered as promising agents in the treatment of HIV/AIDS. In an effort to exploit the privileged 2-amino-4-phenylthiazole moiety in NC inhibition, here we conceived, synthesized, and tested 18 NC inhibitors (NCIs) bearing a double functionalization. In these NCIs, one part of the molecule is deputed to interact noncovalently with the NC hydrophobic pocket, while the second portion is designed to interact with the N-terminal domain of NC. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00506
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http://dx.doi.org/10.1021/acsmedchemlett.8b00506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466545PMC
April 2019
2 Reads

Discovery of Pyrido[3',2':5,6]thiopyrano[4,3-]pyrimidine-Based Antiproliferative Multikinase Inhibitors.

ACS Med Chem Lett 2019 Apr 17;10(4):457-462. Epub 2019 Jan 17.

Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.

Protein kinases dysregulation is extremely common in cancer cells, and the development of new agents able to simultaneously target multiple kinase pathways involved in angiogenesis and tumor growth may offer several advantages in the treatment of cancer. Herein we report the discovery of new pyridothiopyranopyrimidine derivatives (-) showing high potencies in VEGFR-2 KDR inhibition as well as antiproliferative effect on a panel of human tumor cell lines. Investigation on the selectivity profile of the representative 2-anilino-substituted compounds , , and revealed a multiplicity of kinase targets that should account for the potent antiproliferative effect produced by these pyridothiopyranopyrimidine derivatives. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466516PMC
April 2019
1 Read

Novel Cyclic Biphalin Analogues by Ruthenium-Catalyzed Ring Closing Metathesis: and Biological Profile.

ACS Med Chem Lett 2019 Apr 8;10(4):450-456. Epub 2019 Mar 8.

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

In this work we report the application of the ring-closing metathesis (RCM) to the preparation of two cyclic olefin-bridged analogues of biphalin (Tyr-d-Ala-Gly-Phe-NH-NH ← Phe ← Gly ← d-Ala ← Tyr), using the second generation Grubbs' catalyst. The resulting - and -cyclic isomers were identified, fully characterized, and tested at μ (ΜΟR), δ (DOR), and κ (KOR) opioid receptors and for antinociceptive activity. Both were shown to be full agonists at MOR and potential partial antagonists at DOR, with low potency KOR agonism. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466526PMC

Coupling Supervised Molecular Dynamics (SuMD) with Entropy Estimations To Shine Light on the Stability of Multiple Binding Sites.

ACS Med Chem Lett 2019 Apr 15;10(4):444-449. Epub 2019 Feb 15.

Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35122 Padova, Italy.

Exploring at the molecular level, all possible ligand-protein approaching pathways and, consequently, identifying the energetically favorable binding sites is considered crucial to depict a clear picture of the whole scenario of ligand-protein binding. In fact, a ligand can recognize a protein in multiple binding sites, adopting multiple conformations in every single binding site and inducing protein modifications upon binding. In the present work, we would like to present how it is possible to couple a supervised molecular dynamics (SuMD) approach to explore, from an unbound state, the most energetically favorable recognition pathways of the ligand to its protein, with an enthalpic and entropic characterization of the most stable ligand-protein bound states, using the protein kinase CK2α as a prototype study. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466520PMC

Bioisosteres of Indomethacin as Inhibitors of Aldo-Keto Reductase 1C3.

ACS Med Chem Lett 2019 Apr 28;10(4):437-443. Epub 2019 Jan 28.

Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125 Turin, Italy.

Aldo-keto reductase 1C3 (AKR1C3) is an attractive target in drug design for its role in resistance to anticancer therapy. Several nonsteroidal anti-inflammatory drugs such as indomethacin are known to inhibit AKR1C3 in a nonselective manner because of COX-off target effects. Here we designed two indomethacin analogues by proposing a bioisosteric connection between the indomethacin carboxylic acid function and either hydroxyfurazan or hydroxy triazole rings. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466513PMC

L-DOPA-quinone Mediated Recovery from GIRK Channel Firing Inhibition in Dopaminergic Neurons.

ACS Med Chem Lett 2019 Apr 9;10(4):431-436. Epub 2019 Jan 9.

Dipartimento di Scienze Ecologiche e Biologiche, Università della Tuscia, Via S. C. De Lellis 44, 01100 Viterbo, Italy.

The oxidative degeneration of dopamine-releasing (DAergic) neurons in the substantia nigra pars compacta (SNc) has attracted much interest in preclinical research, due to its involvement in Parkinson's disease manifestations. Evidence exists on the participation of quinone derivatives in mitochondrial dysfunction, alpha synuclein protein aggregation, and protein degradation. With the aim to investigate the role of L-DOPA-quinone in DAergic neuron functions, we synthesized L-DOPA-quinone by use of 2-iodoxybenzoic acid and measured its activity in recovery from dopamine-mediated firing inhibition of SNc neurons. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466524PMC

Inhibition of PCSK9/LDLR Protein-Protein Interaction by Computationally Designed T9 Lupin Peptide.

ACS Med Chem Lett 2019 Apr 3;10(4):425-430. Epub 2018 Dec 3.

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

The inhibition of the PCSK9/LDLR protein-protein interaction is a promising strategy for developing new hypocholesterolemic agents. Familial hypercholesterolemia is linked to specific PCSK9 mutations: the D374Y is the most potent gain-of-function (GOF) PCSK9 mutation among clinically relevant ones. Recently, a lupin peptide (T9) showed inhibitory effects on this mutant PCSK9 form, being also capable to increase liver uptake of low density lipoprotein cholesterol. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00464
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http://dx.doi.org/10.1021/acsmedchemlett.8b00464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466515PMC
April 2019
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Multifunctional Carrier Based on Halloysite/Laponite Hybrid Hydrogel for Kartogenin Delivery.

ACS Med Chem Lett 2019 Apr 22;10(4):419-424. Epub 2018 Oct 22.

Dipartimento STEBICEF, Sez. Chimica, Università degli Studi di Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy.

A novel carrier system based on halloysite nanotubes (HNT), for the potential intraarticular delivery of kartogenin (KGN) by means laponite (Lap) hydrogel (HNT/KGN/Lap), is developed. The drug was first loaded into HNT, and the hybrid composite obtained was used as filler for laponite hydrogel. Both the filler and the hydrogel were thoroughly investigated by several techniques and the hydrogel morphology was imaged by transmission electron microscopy. Read More

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http://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00465
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http://dx.doi.org/10.1021/acsmedchemlett.8b00465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466553PMC
April 2019
1 Read

-Nitrosulfonamides as Carbonic Anhydrase Inhibitors: A Promising Chemotype for Targeting Chagas Disease and Leishmaniasis.

ACS Med Chem Lett 2019 Apr 27;10(4):413-418. Epub 2018 Nov 27.

Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy.

and Leishmania spp. are protozoa of the Trypanosomatidae family, respectively, responsible of the neglected tropical disorders (NTDs) Chagas disease and leishmaniasis. The present pharmacotherapy is often ineffective and exhibits serious side effects. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466549PMC

Novel Isoxazole Derivatives with Potent FXR Agonistic Activity Prevent Acetaminophen-Induced Liver Injury.

ACS Med Chem Lett 2019 Apr 6;10(4):407-412. Epub 2018 Dec 6.

Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131 Naples, Italy.

Acetaminophen misuse is a leading cause of acute liver failure and liver transplantation for which therapy is poorly effective. FXR ligands have shown effective in reducing liver injury in several experimental and clinical settings. In this Letter, we have elaborated on the structure of GW4064, the first nonsteroidal agonist for FXR, to identify novel isoxazoles endowed with FXR agonistic activity and improved ADME properties. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466548PMC
April 2019
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Discovery of 1,4-Naphthoquinones as a New Class of Antiproliferative Agents Targeting GPR55.

ACS Med Chem Lett 2019 Apr 15;10(4):402-406. Epub 2019 Feb 15.

Department of Biotechnology, Chemistry and Pharmacy - Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.

A new series of 1,4-naphthoquinones, bearing various cyclic and aliphatic amines on C2, was designed and synthesized to identify antiproliferative agents for triple-negative breast cancer, which represents a clinical challenge without targeted therapies. Among naphthoquinones, and inhibited the proliferation of MDA-MB-231 cells (EC = 1.6 and 2. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466525PMC
April 2019
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Synthesis and Anti-HIV Profile of a Novel Tetrahydroindazolylbenzamide Derivative Obtained by Oxazolone Chemistry.

ACS Med Chem Lett 2019 Apr 15;10(4):398-401. Epub 2018 Dec 15.

Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, UZ St. Rafael, Kapucijnenvoer 33, BE-3000 Leuven, Belgium.

A new tetrahydroindazolylbenzamide derivative has been synthesized, characterized, and evaluated as HIV-inhibitor. The biological data revealed the ability to inhibit HIV proliferation with low cytotoxicity allowing for significant selectivity (EC 2.77 μM; CC 118. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.8b00511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466547PMC

Highlighting Medicinal Chemistry in Italy Special Issue.

Authors:
Maurizio Botta

ACS Med Chem Lett 2019 Apr 11;10(4):395. Epub 2019 Apr 11.

Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena 53100, Italy.

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http://dx.doi.org/10.1021/acsmedchemlett.9b00137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466519PMC