2,611 results match your criteria ACS medicinal chemistry letters[Journal]


Factor H-Inspired Design of Peptide Biomarkers of the Complement C3d Protein.

ACS Med Chem Lett 2020 May 28;11(5):1054-1059. Epub 2020 Feb 28.

Department of Bioengineering and Department of Chemistry, University of California Riverside, 900 University Avenue, Riverside California 92507, United States.

C3d is a hallmark protein of the complement system, whose presence is critical to measure the progression of several immune diseases. Here, we propose to directly target C3d through small peptides mimicking the binding of its natural ligand, the complement regulator Factor H (FH). Through iterative computational analysis and binding affinity experiments, we establish a rationale for the structure-based design of FH-inspired peptides, leading to low-micromolar affinity for C3d and stable binding over microsecond-length simulations. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236534PMC

HOPPI-NMR: Hot-Peptide-Based Screening Assay for Inhibitors of Protein-Protein Interactions by NMR.

ACS Med Chem Lett 2020 May 20;11(5):1047-1053. Epub 2020 Feb 20.

Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.

Protein-protein interactions (PPIs) contribute to the onset and/or progression of several diseases, especially cancer, and this discovery has paved the way for considering disruption of the PPIs as an attractive anti-tumor strategy. In this regard, simple and efficient biophysical methods for detecting the interaction of the inhibitors with the protein counterpart are still in high demand. Herein, we describe a convenient NMR method for the screening of putative PPI inhibitors based on the use of "hot peptides" (HOPPI-NMR). Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236535PMC

Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry.

ACS Med Chem Lett 2020 May 28;11(5):1041-1046. Epub 2020 Feb 28.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.

Protein-protein interactions (PPIs) play an important role in numerous biological processes such as cell-cycle regulation and multiple diseases. The family of 14-3-3 proteins is an attractive target as they serve as binding partner to various proteins and are therefore capable of regulating their biological activities. Discovering small-molecule modulators, in particular stabilizers, of such complexes via traditional screening approaches is a challenging task. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236542PMC

Artemisinin Derivatives with Antimelanoma Activity Show Inhibitory Effect against Human DNA Topoisomerase 1.

ACS Med Chem Lett 2020 May 10;11(5):1035-1040. Epub 2020 Apr 10.

Dipartimento di Biologia, Università di Padova Distaccato presso il "Centro Linceo Beniamino Segre" Accademia Nazionale dei Lincei, Palazzo Corsini, Via della Lungara 10, 00165 Rome, Italy.

Artesunic acid and artemisinin are natural substances with promiscuous anticancer activity against different types of cancer cell lines. The mechanism of action of these compounds is associated with the formation of reactive radical species by cleavage of the sesquiterpene pharmacophore endoperoxide bridge. Here we suggested topoisomerase 1 as a possible molecular target for the improvement of the anticancer activity of these compounds. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.0c00131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236541PMC

Novel Dithiolane-Based Ligands Combining Sigma and NMDA Receptor Interactions as Potential Neuroprotective Agents.

ACS Med Chem Lett 2020 May 3;11(5):1028-1034. Epub 2020 Apr 3.

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

Sigma receptors (SRs) are recognized as valuable targets for the treatment of neurodegenerative disorders. A series of novel SRs ligands were designed by combining key pharmacophoric amines (i.e. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.0c00129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236556PMC

Benzofuran-Based Carboxylic Acids as Carbonic Anhydrase Inhibitors and Antiproliferative Agents against Breast Cancer.

ACS Med Chem Lett 2020 May 18;11(5):1022-1027. Epub 2020 Mar 18.

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

Pursuing our effort for developing effective inhibitors of the cancer-related hCA IX isoform, here we describe the synthesis of novel benzofuran-based carboxylic acid derivatives, featuring the benzoic (-) or hippuric () acid moieties linked to 2-methylbenzofuran or 5-bromobenzofuran tails via an ureido linker. The target carboxylic acids were evaluated for the potential inhibitory action against hCAs I, II, IX, and XII. Superiorly, benzofuran-containing carboxylic acid derivatives , , and acted as submicromolar hCA IX inhibitors with KIs = 0. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.0c00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236537PMC

Characterization of an Alginate Encapsulated LS180 Spheroid Model for Anti-colorectal Cancer Compound Screening.

ACS Med Chem Lett 2020 May 3;11(5):1014-1021. Epub 2020 Apr 3.

Pharmacen, Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.

Colorectal cancer is one of the leading causes of cancer-related deaths. A main problem for its treatment is resistance to chemotherapy, requiring the development of new drugs. The success rate of new candidate cancer drugs in clinical trials remains dismal. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.0c00076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236536PMC

Phenolic Compounds from Regulate Viability and Apoptosis of Pancreatic β-Cells Possibly via SERCA Activity.

ACS Med Chem Lett 2020 May 26;11(5):1006-1013. Epub 2020 Mar 26.

Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine SAS, Dubravska cesta 9, 841 01 Bratislava, Slovakia.

The ability of phenolic compounds from to modulate sarco-endoplasmic Ca-ATPase (SERCA1) activity was analyzed. Enzyme activity decrease correlated with the binding energy of agents to SERCA1. Results from theoretical and experimental approaches were coherent in identifying binding sites to SERCA1. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.0c00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236539PMC

Looking toward the Rim of the Active Site Cavity of Druggable Human Carbonic Anhydrase Isoforms.

ACS Med Chem Lett 2020 May 4;11(5):1000-1005. Epub 2020 Mar 4.

Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali (CHIBIOFARAM), Università degli Studi di Messina, Viale Palatucci, Polo Didattico SS. Annunziata, 98168 Messina, Italy.

We report the synthesis and biochemical evaluation of a series of substituted 4-(4-aroylpiperazine-1-carbonyl)benzenesulfonamides (-) developed as inhibitors of druggable carbonic anhydrase (CA) isoforms, as tools for the identification of new therapeutics. X-ray crystallography confirmed that this class of benzenesulfonamides binds CAs through the canonical anchoring of the benzenesulfonamide moiety to the metal ion and a recognition of the middle/top area of the active site cavity. Compound (R = 2-Cl) demonstrated relevant selectivity toward brain-expressed hCA VII. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.0c00062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236538PMC

Substituted Naphthalenediimide Compounds Bind Selectively to Two Human Quadruplex Structures with Parallel Topology.

ACS Med Chem Lett 2020 May 30;11(5):991-999. Epub 2020 Mar 30.

UCL School of Pharmacy, University College London, London WC1N 1AX, U.K.

Interactions are reported of three representative naphthalenediimide derivatives with three quadruplex targets, from the promoter region of the telomerase (hTERT) gene, a human telomeric DNA quadruplex, and a telomeric RNA quadruplex (TERRA). Thermal melting studies showed that these compounds strongly stabilize the quadruplexes, with weak stabilization of a duplex DNA. Binding studies by surface plasmon resonance and fluorescence spectroscopy found that the compounds bind to the quadruplexes with nanomolar equilibrium dissociation constants. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.0c00041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236248PMC

Synthesis and Selective Functionalization of Thiadiazine 1,1-Dioxides with Efficacy in a Model of Huntington's Disease.

ACS Med Chem Lett 2020 May 20;11(5):984-990. Epub 2020 Feb 20.

Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.

The scope of the acid-mediated 3-component synthesis of thiadiazines was investigated. A selective functionalization of the six-membered heterocyclic core structure was accomplished by sequential alkylations, saponifications, and coupling reactions. Several new analogs of a dihydropyrimidinone Hsp70 chaperone agonist, MAL1-271, showed promising activity in a cell based model of Huntington's disease. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.0c00018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236266PMC

Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells.

ACS Med Chem Lett 2020 May 19;11(5):977-983. Epub 2020 Mar 19.

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.

Since the histone modifying enzymes EZH2 and HDACs control a number of epigenetic-dependent carcinogenic pathways, we designed the first-in-class dual EZH2/HDAC inhibitor displaying (sub)micromolar inhibition against both targets. When tested in several cancer cell lines, the hybrid impaired cell viability at low micromolar level and in leukemia U937 and rhabdomyosarcoma RH4 cells provided G1 arrest, apoptotic induction, and increased differentiation, associated with an increase of acetyl-H3 and acetyl-α-tubulin and a decrease of H3K27me3 levels. In glioblastoma U87 cells, hampered epithelial to mesenchymal transition by increasing the E-cadherin expression, thus proposing itself as a useful candidate for anticancer therapy. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.0c00014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236245PMC

Structure-Guided Identification of DNMT3B Inhibitors.

ACS Med Chem Lett 2020 May 7;11(5):971-976. Epub 2020 Feb 7.

Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.

Methyltransferase 3 beta (DNMT3B) inhibitors that interfere with cancer growth are emerging possibilities for treatment of melanoma. Herein we identify small molecule inhibitors of DNMT3B starting from a homology model based on a DNMT3A crystal structure. Virtual screening by docking led to purchase of 15 compounds, among which 5 were found to inhibit the activity of DNMT3B with IC values of 13-72 μM in a fluorogenic assay. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.0c00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236258PMC

Progress in the Field of Aldehyde Dehydrogenase Inhibitors: Novel Imidazo[1,2-]pyridines against the 1A Family.

ACS Med Chem Lett 2020 May 25;11(5):963-970. Epub 2020 Mar 25.

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

Members of the aldehyde dehydrogenase 1A family are commonly acknowledged as hallmarks of cancer stem cells, and their overexpression is significantly associated with poor prognosis in different types of malignancies. Accordingly, treatments targeting these enzymes may represent a successful strategy to fight cancer. In this work we describe a novel series of imidazo[1,2-]pyridines, designed as aldehyde dehydrogenase inhibitors by means of a structure-based optimization of a previously developed lead. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236222PMC

Exploring the Implication of DDX3X in DENV Infection: Discovery of the First-in-Class DDX3X Fluorescent Inhibitor.

ACS Med Chem Lett 2020 May 9;11(5):956-962. Epub 2020 Apr 9.

Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy.

In the absence of effective drugs or vaccines for the treatment of the five Dengue Virus serotypes, the search for novel antiviral drugs is of primary importance for the scientific community. In this context, drug repurposing represents the most used strategy; however, the study of host targets is now attracting attention since it allows identification of broad-spectrum drugs endowed with high genetic barrier. In the last ten years our research group identified several small molecules DDX3X inhibitors and proved their efficacy against different viruses including novel emerging ones. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236276PMC

Multiple Inhibition of HIV-1 Proteins by 2,6-Dipeptidyl-anthraquinone Conjugates Targeting the PBS RNA.

ACS Med Chem Lett 2020 May 23;11(5):949-955. Epub 2020 Mar 23.

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

We recently reported a series of 2,6-dipeptidyl-anthraquinone conjugates (AQs) as Trans-Activation Response element (TAR) RNA-binding agents able to inhibit the HIV-1 nucleocapsid (NC) protein-mediated processes. Because NC is a highly adaptable nucleic acid chaperone assisting several crucial steps along reverse transcription, in this study we investigate the ability of AQs to interact with other virus-derived nucleic acid structures thus potentially inhibiting multiple NC functions. Focusing on the HIV-1 Primer Binding Site (PBS) RNA sequence, we demonstrate that properly substituted dipeptidyl-anthraquinone conjugates efficiently inhibit the NC-mediated primer annealing in the low micromolar range. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236229PMC

Highly Promising Antitumor Agent of a Novel Platinum(II) Complex Bearing a Tetradentate Chelating Ligand.

ACS Med Chem Lett 2020 May 12;11(5):940-948. Epub 2020 Mar 12.

Department of Clinical Biochemistry, Medical School of Istinye University, 34010 Istanbul, Turkey.

A new mononuclear cationic platinum(II) coordination compound with 6,6'-bis(NH-benzimidazol-2-yl)-2,2'-bipyridine () ligand having N-tetradentate binding pocket [Pt()]Cl·2HO () was synthesized and characterized by FT-IR(ATR), UV-vis, H NMR, APCI and MALDI MS, and CHN analysis. The antigrowth effect of was tested in breast cancer (MDA-MB-231), lung cancer (A549), colorectal cancer (HCT-116), prostate cancer (PC-3) cell lines, and bronchial epithelial cell line (BEAS-2B) by the SRB and ATP cell viability assays. Apoptosis was detected with Annexin V, mitopotential, BCL-2 inactivation, and γH2AX assays by flow cytometry. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236228PMC

[F]ZCDD083: A PFKFB3-Targeted PET Tracer for Atherosclerotic Plaque Imaging.

ACS Med Chem Lett 2020 May 19;11(5):933-939. Epub 2020 Feb 19.

Kosterlitz Centre for Therapeutics, University of Aberdeen, AB25 2ZD Foresterhill, Aberdeen, U.K.

PFKFB3, a glycolysis-related enzyme upregulated in inflammatory conditions and angiogenesis, is an emerging target for diagnosis and therapy of atherosclerosis. The fluorinated phenoxindazole [F] was synthesized, radiolabeled in 17 ± 5% radiochemical yield and >99% radiochemical purity, and formulated for preclinical PET/CT imaging in mice. stability analysis showed no significant metabolite formation. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236280PMC

Predictive Gene Signature for Pyrazolopyrimidine Derivative c-Src Inhibitor 10a Sensitivity in Melanoma Cells.

ACS Med Chem Lett 2020 May 18;11(5):928-932. Epub 2020 Feb 18.

Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.

Melanoma is a highly aggressive cancer with poor prognosis. Although more than 80% of melanomas harbor an activating mutation in genes within the MAPK pathway, which are mutually exclusive, usefulness of therapies targeting MAPK pathway are impeded by innate and/or acquired resistance in most patients. In this study, using melanoma cells, we report the efficacy of a recently developed pyrazolo[3,4-]pyrimidine derived c-Src inhibitor 10a and identify a molecular signature which is predictive of 10a chemosensitivity. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236227PMC

Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity.

ACS Med Chem Lett 2020 May 24;11(5):921-927. Epub 2020 Mar 24.

Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, Patras GR-26504, Greece.

A series of novel hybrids of artemisinin (ART) with either a phytormone endoperoxide G factor analogue (GMeP) or chloroquine (CQ) and conjugates of the same compounds with the polyamines (PAs), spermidine (Spd), and homospermidine (Hsd) were synthesized and their antiplasmodial activity was evaluated using the CQ-resistant FcB1/Colombia strain. The ART-GMeP hybrid and compounds and which are conjugates of Spd and Hsd with two molecules of ART and one molecule of GMeP, were the most potent with IC values of 2.6, 8. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236259PMC

Glycans Meet Sphingolipids: Structure-Based Design of Glycan Containing Analogues of a Sphingosine Kinase Inhibitor.

ACS Med Chem Lett 2020 May 30;11(5):913-920. Epub 2020 Mar 30.

Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, FI, Italy).

Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator associated with diverse homeostatic and signaling roles. Enhanced biosynthesis of S1P, mediated by the sphingosine kinase isozymes (SK1 and SK2), is implicated in several pathophysiological conditions and diseases, including skeletal muscle fibrosis, inflammation, multiple sclerosis, and cancer. Therefore, therapeutic approaches that control S1P production have focused on the development of SK1/2 inhibitors. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236250PMC

Identification of 2-(4-(Phenylsulfonyl)piperazine-1-yl)pyrimidine Analogues as Novel Inhibitors of Chikungunya Virus.

ACS Med Chem Lett 2020 May 5;11(5):906-912. Epub 2020 Mar 5.

University of Vienna, Department of Pharmaceutical Chemistry, Althanstraße 14, A-1090 Vienna, Austria.

The chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus, and it is the causative agent of chikungunya fever (CHIKF). Although it has re-emerged as an epidemic threat, so far there are neither vaccines nor pharmacotherapy available to prevent or treat an infection. Herein, we describe the synthesis and structure-activity relationship studies of a class of novel small molecule inhibitors against CHIKV and the discovery of a new potent inhibitor (compound ). Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236252PMC

Screen of Unfocused Libraries Identified Compounds with Direct or Synergistic Antibacterial Activity.

ACS Med Chem Lett 2020 May 6;11(5):899-905. Epub 2020 Mar 6.

Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena, Viale Bracci 16, 53100 Siena, Italy.

Antibiotic resistance is an increasingly important global public health issue, as major opportunistic pathogens are evolving toward multidrug- and pan-drug resistance phenotypes. New antibiotics are thus needed to maintain our ability to treat bacterial infections. According to the WHO, carbapenem-resistant , , and are the most critical targets for the development of new antibacterial drugs. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236257PMC

New Class of Betulinic Acid-Based Nanoassemblies of Cabazitaxel, Podophyllotoxin, and Thiocolchicine.

ACS Med Chem Lett 2020 May 28;11(5):895-898. Epub 2020 Feb 28.

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

Betulinic acid is validated as a new self-assembly inducer for the formation of nanoparticles (NPs) in combination with different drugs. The target compounds are characterized by the presence of anticancer drugs acting on tubulin dynamics and of a linker that could be a carbon chain or a triazole-based one. Nanoparticles formed are characterized and their biological activity is evaluated. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236225PMC

Sigma Receptor Ligands Carrying a Nitric Oxide Donor Nitrate Moiety: Synthesis, In Silico, and Biological Evaluation.

ACS Med Chem Lett 2020 May 9;11(5):889-894. Epub 2020 Apr 9.

Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria, 95125 Catania, Italy.

We report the development of molecular hybrids in which a nitrate group serving as nitric oxide (NO) donor is covalently joined to σ receptor ligands to give candidates for double-targeted cancer therapy. The compounds have been evaluated in radioligand binding assay at both σ receptors and selected compounds tested for NO release. Compounds , , , , and were subjected to MTT test. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236233PMC

BOPC1 Enantiomers Preparation and HuR Interaction Study. From Molecular Modeling to a Curious DEEP-STD NMR Application.

ACS Med Chem Lett 2020 May 28;11(5):883-888. Epub 2020 Jan 28.

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

The Hu family of RNA-binding proteins plays a crucial role in post-transcriptional processes; indeed, Hu-RNA complexes are involved in various dysfunctions (i.e., inflammation, neurodegeneration, and cancer) and have been recently proposed as promising therapeutic targets. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236254PMC

ProBiS H2O MD Approach for Identification of Conserved Water Sites in Protein Structures for Drug Design.

ACS Med Chem Lett 2020 May 19;11(5):877-882. Epub 2020 Mar 19.

University of Maribor, Faculty of Chemistry and Chemical Engineering, Laboratory of Physical Chemistry and Chemical Thermodynamics, Smetanova ulica 17, SI-2000 Maribor, Slovenia.

The ProBiS H2O MD approach for identification of conserved waters and water sites of interest in macromolecular systems, which is becoming a typical step in a structure-based drug design or macromolecular study in general, is described. This work explores an extension of the ProBiS H2O approach introduced by Jukič et al. Indeed, water molecules are key players in the interaction mechanisms of macromolecules and small molecules and play structural roles. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236268PMC

Chiral Separation, X-ray Structure, and Biological Evaluation of a Potent and Reversible Dual Binding Site AChE Inhibitor.

ACS Med Chem Lett 2020 May 7;11(5):869-876. Epub 2020 Feb 7.

Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy.

Acetylcholinesterase (AChE) inhibitors (AChEIs) still remain the leading therapeutic options for the symptomatic treatment of cognitive deficits associated with mild-to-moderate Alzheimer's disease. The search for new AChEIs benefits from well-established knowledge of the molecular interactions of selective AChEIs, such as donepezil and related dual binding site inhibitors. Starting from a previously disclosed coumarin-based inhibitor (±)--, active as racemate in the nanomolar range toward AChE, we proceeded on a double track by (i) achieving chiral resolution of the enantiomers of by HPLC and (ii) preparing two close achiral analogues of , i. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236231PMC

From PARP1 to TNKS2 Inhibition: A Structure-Based Approach.

ACS Med Chem Lett 2020 May 3;11(5):862-868. Epub 2020 Feb 3.

Department of Chemistry and Technology of Drugs, ″Sapienza" University of Rome, 00185 Rome, Italy.

Tankyrases (TNKSs) have recently gained great consideration as potential targets in Wnt/β-catenin pathway-dependent solid tumors. Previously, we reported the 2-mercaptoquinazolin-4-one MC2050 as a micromolar PARP1 inhibitor. Here we show how the resolution of the X-ray structure of PARP1 in complex with MC2050, combined with the computational investigation of the structural differences between TNKSs and PARP1/2 active sites, provided the rationale for a structure-based drug design campaign that with a limited synthetic effort led to the discovery of the bis-quinazolinone as a picomolar and selective TNKS2 inhibitor, endowed with antiproliferative effects in a colorectal cancer cell line (DLD-1) where the Wnt pathway is constitutively activated. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236224PMC

Inhibition of Human Immunodeficiency Virus-1 Integrase by β-Diketo Acid Coated Gold Nanoparticles.

ACS Med Chem Lett 2020 May 20;11(5):857-861. Epub 2020 Mar 20.

Department of Chemistry and Pharmacy, Laboratory of Drug Design and Nanomedicine, University of Sassari, 07100 Sassari, Italy.

Gold nanoparticles (GNPs) have been proposed as carriers for drugs to improve their intrinsic therapeutic activities and to overcome pharmacokinetic problems. In this study, novel nanosystems constituted by a model β-diketo acid (DKA) grafted to the surface of GNPs were designed and synthesized following the "multivalent high-affinity" binding strategy. These first nanoscale DKA prototypes showed improved inhibition of HIV-1 integrase (HIV-1 IN) catalytic activities as compared with free DKA ligands. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236234PMC

New Dihydrothiazole Benzensulfonamides: Looking for Selectivity toward Carbonic Anhydrase Isoforms I, II, IX, and XII.

ACS Med Chem Lett 2020 May 13;11(5):852-856. Epub 2020 Feb 13.

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

In the present study we investigated the structure-activity relationships of a new series of 4-[(3-ethyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides (-). All synthesized compounds, with the exception of compound , preferentially inhibit off-target hCA II isoform. Within the series, compound , bearing a 2,4-dichorophenyl substituent in position 4 of the dihydrothiazole ring, was the most potent and selective toward hCA II with an inhibitory activity in the low nanomolar range. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236253PMC

Synthesis and Antiproliferative Activity of Nitric Oxide-Donor Largazole Prodrugs.

ACS Med Chem Lett 2020 May 7;11(5):846-851. Epub 2020 Feb 7.

Promidis, Via Olgettina 60, 20132 Milano, Italy.

The marine natural product Largazole is the most potent Class I HDAC inhibitor identified to date. Since its discovery, many research groups have been attracted by the structural complexity and the peculiar anticancer activity, due to its capability to discriminate between tumor cells and normal cells. Herein, we discuss the synthesis and the biological profile of hybrid analogues of Largazole, as dual HDAC inhibitor and nitric oxide (NO) donors, potentially useful as anticancer agents. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236235PMC

Molecular Docking Studies of Royleanone Diterpenoids from spp. as P-Glycoprotein Inhibitors.

ACS Med Chem Lett 2020 May 12;11(5):839-845. Epub 2020 Mar 12.

Center for Research in Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, 1749-024 Lisboa, Portugal.

The development of multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. Several abietane diterpenes with antitumoral activities have been isolated from spp. such as 6,7-dehydroroyleanone (DHR, ) and 7α-acetoxy-6β-hydroxyroyleanone (AHR, ). Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236232PMC

Pharmacophore-Based Virtual Screening for Identification of Negative Modulators of GLI1 as Potential Anticancer Agents.

ACS Med Chem Lett 2020 May 25;11(5):832-838. Epub 2020 Mar 25.

Dipartimento di Biotecnologie Chimica e Farmacia, Università di Siena, via Aldo Moro 2, I-53100 Siena, Italy.

Starting from known GLI1 inhibitors, a pharmacophore-based virtual screening approach was applied to databases of commercially available compounds with the aim of identifying new GLI1 modulators. As a result, three different chemical scaffolds emerged that were characterized by a significant ability to reduce the transcriptional activity of the endogenous Hedgehog-GLI pathway and GLI1 protein level in murine NIH3T3 cells. They also showed a micromolar antiproliferative activity in human melanoma (A375) and medulloblastoma (DAOY) cell lines, without cytotoxicity in non-neoplastic mammary epithelial cells. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236221PMC

Optimization of Indazole-Based GSK-3 Inhibitors with Mitigated hERG Issue and Activity in a Mood Disorder Model.

ACS Med Chem Lett 2020 May 24;11(5):825-831. Epub 2020 Mar 24.

Angelini Pharma S.p.A., Viale Amelia, 70, 00181 Rome, Italy.

Bipolar disorders still represent a global unmet medical need and pose a requirement for novel effective treatments. In this respect, glycogen synthase kinase 3β (GSK-3β) aberrant activity has been linked to the pathophysiology of several disease conditions, including mood disorders. Therefore, the development of GSK-3β inhibitors with good efficacy and safety profile associated with high brain exposure is required. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236279PMC

GPBAR1 Activation by C6-Substituted Hyodeoxycholane Analogues Protect against Colitis.

ACS Med Chem Lett 2020 May 2;11(5):818-824. Epub 2020 Mar 2.

Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, Perugia CH-6900, Italy.

GPBAR1 agonists have been identified as potential leads for the treatment of diseases related to colon inflammation such as Crohn's and ulcerative colitis. In this paper, we report the discovery of a small library of hyodeoxycholane analogues, decorated at C-6 with different substituents, as potent and selective GPBAR1 agonists. pharmacological assays showed that compound selectively activates GPBAR1 (EC = 0. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236273PMC

Peptides Mimicking the β7/β8 Loop of HIV-1 Reverse Transcriptase p51 as "Hotspot-Targeted" Dimerization Inhibitors.

ACS Med Chem Lett 2020 May 24;11(5):811-817. Epub 2020 Jan 24.

Instituto de Química Médica (IQM, CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain.

A conformationally constrained short peptide designed to target a protein-protein interaction hotspot in HIV-1 reverse transcriptase (RT) disrupts p66-p51 interactions and paves the way to the development of novel RT dimerization inhibitors. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236230PMC

Drug Synergism: Studies of Combination of RK-52 and Curcumin against Rhodesain of .

ACS Med Chem Lett 2020 May 15;11(5):806-810. Epub 2020 Jan 15.

Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168 Messina, Italy.

Rhodesain is an enzyme essential for the life of a parasite causing a rapid-onset form of Human African Trypanosomiasis. is a synthetic inhibitor of rhodesain, characterized by an impressive value ( = 67000 × 10 M min) and by a picomolar affinity toward the trypanosomal protease ( = 38 pM). Differently, curcumin, the golden multitarget nutraceutical obtained from L. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236278PMC

Pyrrolyl Pyrazoles as Non-Diketo Acid Inhibitors of the HIV-1 Ribonuclease H Function of Reverse Transcriptase.

ACS Med Chem Lett 2020 May 5;11(5):798-805. Epub 2020 Mar 5.

Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, p.le Aldo Moro 5, I-00185 Roma, Italy.

Due to the biological liability of diketo acid (DKA) chain, we transferred this element of our previously reported anti-HIV-1 pyrrolyl derivatives to a non-DKA scaffold, obtaining a series of pyrrolyl-pyrazole carboxylic acids as new RNase H inhibitors. Among the newly synthesized derivatives, oxyphenylpyrrolyl-pyrazoles demonstrated inhibitory activities within the low micromolar/submicromolar range with compound being the most potent. Interestingly, all tested compounds showed up to 2 orders of magnitude of selectivity for RNase H vs integrase. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236236PMC

Inhibition of Nonessential Bacterial Targets: Discovery of a Novel Serine -Acetyltransferase Inhibitor.

ACS Med Chem Lett 2020 May 13;11(5):790-797. Epub 2020 Feb 13.

P4T group and Laboratory of Biochemistry and Molecular Biology, Department of Food and Drug, University of Parma, 43124 Parma, Italy.

In ϒ-proteobacteria and Actinomycetales, cysteine biosynthetic enzymes are indispensable during persistence and become dispensable during growth or acute infection. The biosynthetic machinery required to convert inorganic sulfur into cysteine is absent in mammals; therefore, it is a suitable drug target. We searched for inhibitors of serine acetyltransferase (SAT), the enzyme that catalyzes the rate-limiting step of l-cysteine biosynthesis. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236226PMC

Targeting mPGES-1 by a Combinatorial Approach: Identification of the Aminobenzothiazole Scaffold to Suppress PGE Levels.

ACS Med Chem Lett 2020 May 5;11(5):783-789. Epub 2020 Mar 5.

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

Microsomal prostaglandin E synthase-1 (mPGES-1), the terminal enzyme responsible for the production of inducible prostaglandin E, has become an attractive target for the treatment of inflammation and cancer pathologies. Starting from an aminobenzothiazole scaffold, used as an unprecedented chemical core for mPGES-1 inhibition, a Combinatorial Virtual Screening campaign was conducted, using the X-ray crystal structure of human mPGES-1. Two combinatorial libraries (6 × 10) were obtained by decorating the aminobenzothiazole scaffold with all acyl chlorides and boronates available at the Merck database. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236256PMC

Pyridobenzothiazolones Exert Potent Anti-Dengue Activity by Hampering Multiple Functions of NS5 Polymerase.

ACS Med Chem Lett 2020 May 19;11(5):773-782. Epub 2020 Mar 19.

Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1-06123 Perugia, Italy.

Treatment of dengue virus (DENV) and other flavivirus infections is an unmet medical need. The highly conserved flaviviral NS5 RNA-dependent RNA polymerase (RdRp) is an attractive antiviral target that interacts with NS3 and viral RNA within the replication complex assembly. Biochemical and cell-based evidence indicate that targeting cavity B may lead to dual RdRp and NS5-NS3 interaction inhibitors. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236247PMC

5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein.

ACS Med Chem Lett 2020 May 19;11(5):766-772. Epub 2020 Mar 19.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

The HIV-1 nucleocapsid (NC) protein is a small basic DNA and RNA binding protein that is absolutely necessary for viral replication and thus represents a target of great interest to develop new anti-HIV agents. Moreover, the highly conserved sequence offers the opportunity to escape the drug resistance (DR) that emerged following the highly active antiretroviral therapy (HAART) treatment. On the basis of our previous research, nordihydroguaiaretic acid acts as a NC inhibitor showing moderate antiviral activity and suboptimal drug-like properties due to the presence of the catechol moieties. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236274PMC

Structural Elucidation and Antimicrobial Characterization of Novel Diterpenoids from var. .

ACS Med Chem Lett 2020 May 30;11(5):760-765. Epub 2020 Jan 30.

Department of Biochemical Sciences, Laboratory Affiliated to Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, P.le Aldo Moro 5 00185, Rome, Italy.

Novel diterpenoids were isolated from the extracts of var. and found to display a selective activity against Gram-positive bacterial strains with negligible cytotoxicity toward human keratinocytes. This study highlighted the role played by the acidic group at C18 of the tetracyclic ent-beyerene scaffold for antibacterial effects and how the length and flexibility of the alkyl chain between the two carbonyl groups are crucial factors to increase the antimicrobial activity of the molecules, supporting the development of natural products from and their derivatives for treatment of microbial infections. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236223PMC

Discovery of Reversible Inhibitors of KDM1A Efficacious in Acute Myeloid Leukemia Models.

ACS Med Chem Lett 2020 May 13;11(5):754-759. Epub 2020 Feb 13.

Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy.

Lysine-specific demethylase 1 (LSD1 or KDM1A) is a FAD-dependent enzyme that acts as a transcription corepressor or coactivator by regulating the methylation status of histone H3 lysines K4 and K9, respectively. KDM1A represents an attractive target for cancer therapy. While, in the past, the main medicinal chemistry strategy toward KDM1A inhibition was based on the optimization of ligands that irreversibly bind the FAD cofactor within the enzyme catalytic site, we and others have also identified reversible inhibitors. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236255PMC

Pharmacophore-Based Design of New Chemical Scaffolds as Translational Readthrough-Inducing Drugs (TRIDs).

ACS Med Chem Lett 2020 May 18;11(5):747-753. Epub 2020 Feb 18.

Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi, 90123-Palermo, Italy.

Translational readthrough-inducing drugs (TRIDs) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we report a computational study to identify new TRID scaffolds. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236267PMC

Combined Peptide and Small-Molecule Approach toward Nonacidic THIQ Inhibitors of the KEAP1/NRF2 Interaction.

ACS Med Chem Lett 2020 May 3;11(5):740-746. Epub 2020 Apr 3.

IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.

The NRF2-ARE pathway is an intrinsic mechanism of defense against oxidative stress. Inhibition of the interaction between NRF2 and its main negative regulator KEAP1 is an attractive strategy toward neuroprotective agents. We report here the identification of nonacidic tetrahydroisoquinolines (THIQs) that inhibit the KEAP1/NRF2 protein-protein interaction. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236277PMC

Targeting Orthosteric and Allosteric Pockets of Aromatase via Dual-Mode Novel Azole Inhibitors.

ACS Med Chem Lett 2020 May 23;11(5):732-739. Epub 2020 Mar 23.

CNR-IOM Democritos c/o International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy.

Breast cancer (BC) is the most diffused cancer type in women and the second leading cause of death among the female population. Effective strategies to fight estrogen responsive (ER+) BC, which represents 70% of all BC cases, rely on estrogen deprivation, via the inhibition of the aromatase enzyme, or the modulation of its cognate estrogen receptor. Current clinical therapies significantly increased patient survival time. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236249PMC

Glycomimetic Based Approach toward Selective Carbonic Anhydrase Inhibitors.

ACS Med Chem Lett 2020 May 11;11(5):727-731. Epub 2020 Mar 11.

Dipartimento di Chimica "Ugo Schiff", Università di Firenze, via della Lastruccia n. 3-13, Sesto Fiorentino, 50019 Firenze, Italy.

The synthesis of selective inhibitors of human carbonic anhydrases (hCAs) is of paramount importance to avoid side effects derived from undesired interactions with isoforms not involved in the targeted pathology, and this was partially addressed with the introduction of a sugar moiety (the so-called "sugar approach"). Since glycomimetics are considered more selective than the parent sugars in inhibiting carbohydrate-processing enzyme, we explored the possibility of further tuning the selectivity of hCAs inhibitors by combining the sulfonamide moiety with a sugar analogue residue. In particular, we report the synthesis of two novel hCAs inhibitors and which feature the presence of a piperidine iminosugar and an additional carbohydrate moiety derived from levoglucosenone (), a key intermediate derived from cellulose pyrolysis. Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236246PMC

Developing Cyclic Opioid Analogues: Fluorescently Labeled Bioconjugates of Biphalin.

ACS Med Chem Lett 2020 May 8;11(5):720-726. Epub 2020 Jan 8.

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

The development of bioconjugates is of pivotal importance in medicinal chemistry due to their potential applications as therapeutic agents to improve the targeting of specific diseases, decrease toxicity, or control drug release. In this work we achieved the synthesis and characterization of three novel opioid peptides fluorescently labeled, analogues of cyclic biphalin derivatives, namely , , and . Among them, compound , containing a dansyl-maleimide motif, exhibited an excellent binding affinity and functional potency for the δ-opioid receptor (DOR). Read More

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http://dx.doi.org/10.1021/acsmedchemlett.9b00569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236251PMC