Cover Pictures

Free Access

Cover Picture: Studies on Cycloheptathiophene-3-carboxamide Derivatives as Allosteric HIV-1 Ribonuclease H Inhibitors (ChemMedChem 16/2016)

  • Pages: 1669
  • First Published: 22 August 2016
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The front cover picture shows the heterodimeric structure of the HIV-1 reverse transcriptase (RT) complexed with the RNA:DNA duplex. RT is a multifunctional enzyme endowed with several different functions, including the ribonuclease H (RNase H) activity responsible for the RNA strand hydrolysis of the RNA:DNA replication intermediate. Compounds able to interfere with this pivotal RT-associated function could represent an innovative anti-HIV-1 strategy. The cycloheptathiophene-3-carboxamide catechol derivative is a new RNase H nanomolar inhibitor, which is able to recognize an allosteric site (yellow) located below the catalytic site (light blue) as suggested by computational studies. More information can be found in the Full Paper by Oriana Tabarrini, et al. on page 1709 in Issue 16, 2016 (DOI: 10.1002/cmdc.201600015). Artwork by Serena Massari.

Free Access

Back Cover: Hit Identification of a Novel Dual Binder for h-telo/c-myc G-Quadruplex by a Combination of Pharmacophore Structure-Based Virtual Screening and Docking Refinement (ChemMedChem 16/2016)

  • Pages: 1875
  • First Published: 22 August 2016
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The back cover picture shows a high-throughput in silico screening of commercial libraries from several different vendors by means of a combined structure-based pharmacophore model approach followed by docking simulations. The compounds selected by the virtual screening procedure were then tested for their ability to interact with human telomeric G-quadruplex folding by circular dichroism, fluorescence spectroscopy, and fluorescence intercalator displacement. Our workflow was successful in retrieving a novel promising ligand, characterized by a peculiar chemical scaffold, able to well stabilize both human telomeric and c-myc promoter G4 structures. More information can be found in the Full Paper by Giosuè Costa et al. on page 1721 in Issue 16, 2016 (DOI:10.1002/cmdc.201600053).

Editorials

Free Access

The 23rd National Meeting of the Medicinal Chemistry Division of the Italian Chemical Society (DCF-SCI) in Salerno (NMMC 2015)

  • Pages: 1670-1675
  • First Published: 22 August 2016
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Top-notch Italian medicinal chemistry: Guest editors Pietro Campiglia and Gianluca Sbardella look back at the 2015 National Meeting of the Medicinal Chemistry Division of the Italian Chemical Society. They recall the history of the society and this annual conference and provide highlights of last year′s events, as well as key papers and posters presented, which are now collected in this Special Issue.

News

Minireviews

Progress in the Development of Lysine Methyltransferase SETD8 Inhibitors

  • Pages: 1680-1685
  • First Published: 14 July 2016
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Quest for SETD8 inhibitors: Lysine methyltransferase SETD8/SET8/Pr-SET7/KMT5A plays a key role in the regulation of transcriptional activity and is implicated in many human diseases comprising cancer. However, the development of SETD8 inhibitors is still in its infancy. This review covers the progress made in inhibiting the activity of SETD8 by small molecules, with an emphasis on their discovery, selectivity over other methyltransferases, and cellular activity.

TRPV1–FAAH–COX: The Couples Game in Pain Treatment

  • Pages: 1686-1694
  • First Published: 31 May 2016
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Double the action: Pain management remains an intriguing research topic, and despite the innovative analgesic drugs that are available, very few of them are therapeutically efficient without serious side effects. The simultaneous modulation of two key targets involved in pain transduction by a single molecule seems to be a useful approach. This strategy has the dual aim of decreasing both the doses and side effects of the single drugs.

Communications

Indazole, Pyrazole, and Oxazole Derivatives Targeting Nitric Oxide Synthases and Carbonic Anhydrases

  • Pages: 1695-1699
  • First Published: 05 July 2016
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Double agent! This study involved the design, synthesis, and in vitro biological evaluation of a cluster of new nitrogen-based heterocyclic compounds. Compound 10 b was revealed to be a potent dual agent, able to act as a selective neuronal nitric oxide synthase inhibitor and activator of the human carbonic anhydrase I isoform. It is a promising lead for the design of therapies for neurological diseases.

3-Arylidene-N-hydroxyoxindoles: A New Class of Compounds Endowed with Antitumor Activity

  • Pages: 1700-1704
  • First Published: 17 June 2016
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Exploring new scaffolds: A series of 3-arylidene-N-hydroxyoxindoles show potent antiproliferative and pro-apoptotic activity against wild-type p53 IGROV-1 ovarian carcinoma cells and a considerably lower efficacy against the mutant IGROV-1/Pt1 subline lacking p53 function. These results support a role for this transcription factor as a determinant of cytotoxicity. Treatment of an IGROV-1 xenograft growing as an ascitic tumor produced a significant delay in the onset of ascites.

Synthesis and Biological Evaluation of N2-Substituted 2,4-Diamino-6-cyclohexylmethoxy-5-nitrosopyrimidines and Related 5-Cyano-NNO-azoxy Derivatives as Cyclin-Dependent Kinase 2 (CDK2) Inhibitors

  • Pages: 1705-1708
  • First Published: 29 June 2016
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Say yes to NNO! Starting from compound NU6027, a series of 2,4-diamino-5-nitrosopyrimidines were synthesized. Structure–activity relationship studies of this compound class led to an improved understanding of the criteria for inhibitory activity toward cyclin-dependent kinase 2. The cyano-NNO-azoxy substituent was confirmed to be a valuable alternative to a 5-nitroso group.

Full Papers

Studies on Cycloheptathiophene-3-carboxamide Derivatives as Allosteric HIV-1 Ribonuclease H Inhibitors

  • Pages: 1709-1720
  • First Published: 16 March 2016
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A site to see: By screening an in-house library of cycloheptathiophene-3-carboxamide derivatives and synthesizing a new series of analogues, catechol derivative 33 was identified as a nanomolar inhibitor of HIV-1 RNase H. Mechanistic studies suggest its interaction with an innovative allosteric site entailing p66 residue Q500, a key residue for the binding of reverse transcriptase to the RNA:DNA duplex substrate.

Hit Identification of a Novel Dual Binder for h-telo/c-myc G-Quadruplex by a Combination of Pharmacophore Structure-Based Virtual Screening and Docking Refinement

  • Pages: 1721-1733
  • First Published: 23 March 2016
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Pushing through: A high-throughput in silico screening of libraries by a structure-based pharmacophore model approach was undertaken. Docking simulations and biophysical tests of selected compounds were carried out to determine their capacity to interact with the human telomeric G-quadruplex (G4). Hit 56, a 13-[(dimethylamino)methyl]-12-hydroxy-8H-benzo[c]indolo[3,2,1-ij][1,5]naphthyridin-8-one derivative, was identified as a promising stabilizer of G4 structures.

Cationic Supramolecular Vesicular Aggregates for Pulmonary Tissue Selective Delivery in Anticancer Therapy

  • Pages: 1734-1744
  • First Published: 08 March 2016
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What a GEM: Gemcitabine hydrochloride (GEM) was trapped in cationic supramolecular vesicular aggregates (SVAs) using a pH gradient remote loading procedure, increasing the amount of precipitated GEM inside the aqueous compartment. The GEM-loaded SVAs were found to target lung tissues selectively, with decreased anticancer activity in both A549 and CaCo-2 cells, and pulmonary tissue showing a different response before and after treatment.

Enhanced Efficacy of Artemisinin Loaded in Transferrin-Conjugated Liposomes versus Stealth Liposomes against HCT-8 Colon Cancer Cells

  • Pages: 1745-1751
  • First Published: 21 March 2016
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Express delivery: A novel decorated liposome (L) was developed for selective artemisinin (ART) delivery and activation in cancer tissues, given their overexpression of transferrin (Tf) receptors (PEG: polyethylene glycol). Liposomes were characterized for size, drug-entrapment efficiency, transferrin coupling moieties, and stability. Cell uptake and cytotoxicity were tested in the HCT-8 cell line. We found enhanced selectivity and improved cytotoxicity, resulting in concomitant synergism.

Cyclic Ketoximes as Estrogen Receptor β Selective Agonists

  • Pages: 1752-1761
  • First Published: 02 May 2016
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What a nice cycle tour! A new class of ERβ-selective agonists was developed by introducing a cyclic portion in the salicylketoxime scaffold. This structural modification gives rise to potent and selective ligands for ERβ. Cell-free coactivator binding and recruitment assays prove that ERβ is able to recruit co-regulator proteins upon ligand activation, which confirms the agonist functional properties of these compounds.

Molecular Basis for Differential Recognition of G-Quadruplex versus Double-Helix DNA by Bis-Phenanthroline Metal Complexes

  • Pages: 1762-1769
  • First Published: 24 May 2016
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Preferential treatment: Nickel(II) coordination by bis-phenanthroline derivatives effectively increases affinity for G-quadruplex DNA and decreases affinity for double-stranded DNA as a result of distinct binding modes on the two templates.

Targeting Steroidogenic Cytochromes P450 (CYPs) with 6-Substituted 1-Imidazolylmethylxanthones

  • Pages: 1770-1777
  • First Published: 13 April 2016
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Curbing corticosteroids: 6-substituted-1-imidazolylmethylxanthones provide new insight into the role of an appropriately decorated scaffold in the modulation of steroidogenic cytochromes P450 (CYPs). As regards CYP11B isoforms, the establishment of an additional hydrogen bond seems to be crucial for high potency. Two potent inhibitors of these enzymes emerged, active in the low nanomolar range, as well as a relatively good and selective inhibitor of CYP19.

Reactivity, Selectivity, and Reaction Mechanisms of Aminoguanidine, Hydralazine, Pyridoxamine, and Carnosine as Sequestering Agents of Reactive Carbonyl Species: A Comparative Study

  • Pages: 1778-1789
  • First Published: 17 February 2016
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Carbonyl quenchers: A protein carbonylation assay is used to quantify the extent of modification of a model protein upon its in vitro incubation with fixed concentrations of different reactive carbonyl species (RCS) and increasing concentrations of sequestering agents. The assay shows preferential reactivity of some sequestering agents versus given RCS. The reaction products obtained from the RCS and the sequestering agents are identified by HRMS.

Design, Synthesis, and Evaluation of Acrylamide Derivatives as Direct NLRP3 Inflammasome Inhibitors

  • Pages: 1790-1803
  • First Published: 17 March 2016
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CAPS block is on! Cryopyrin-associated periodic syndromes (CAPS) are rare genetic diseases caused by gain-of-function mutations in NLRP3. Overactivation of the NLRP3 inflammasome is also involved in other metabolic diseases. Herein, a series of acrylamides that inhibit NLRP3-dependent pyroptosis and IL-1β release from CAPS-mutant macrophages are reported. Direct inhibition of NLRP3 ATPase in human isolated NLRP3 has emerged as a potential target for this compound class.

A Series of COX-2 Inhibitors Endowed with NO-Releasing Properties: Synthesis, Biological Evaluation, and Docking Analysis

  • Pages: 1804-1811
  • First Published: 27 May 2016
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Conjugating a COX-2-selective diarylpyrrole scaffold with various nitrooxyalkyl side chains endowed them with NO-releasing properties. These compounds have high in vitro potencies at COX-2 inhibition, NO-vasorelaxing responses, and good antinociceptive activity. They are promising candidates as a new class of analgesic drugs.

In Vivo Evaluation of Selective Carbonic Anhydrase Inhibitors as Potential Anticonvulsant Agents

  • Pages: 1812-1818
  • First Published: 24 February 2016
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Something on the brain: We evaluated the anticonvulsant effects of sulfonamide derivatives showing high selectivity toward the human carbonic anhydrase VII isoform. The most active compound is a potentially useful lead structure for further development of anticonvulsants.

A Novel Class of Dopamine D4 Receptor Ligands Bearing an Imidazoline Nucleus

  • Pages: 1819-1828
  • First Published: 15 March 2016
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That's pretty dope(amine): Focusing on dopamine D2-like receptors, we identified novel imidazoline ligands based on a bioversatile scaffold. The most interesting compounds were selective for D4 over D2 and D3 receptors and behaved as competitive D4 antagonists. These results provide useful information for further optimization of this novel class of compounds.

The Length and Flexibility of the 2-Substituent of 9-Ethyladenine Derivatives Modulate Affinity and Selectivity for the Human A2A Adenosine Receptor

  • Pages: 1829-1839
  • First Published: 01 April 2016
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Size matters: Substituted 9-ethyladenine derivatives were synthesised and tested for affinity to the human A2A adenosine receptor. The new adenine derivatives behave as A2A adenosine receptor antagonists with half-maximal inhibitory concentration values in the nanomolar range. Molecular modelling studies provide a description of the possible binding mode of the compounds and an interpretation of the affinity data.

Albumin Nanoparticles for Brain Delivery: A Comparison of Chemical versus Thermal Methods and in vivo Behavior

  • Pages: 1840-1849
  • First Published: 07 March 2016
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Coming together: Human serum albumin nanoparticles (NPs) were prepared through two different cross-linking methods. The NPs were optimized in terms of size, homogeneity, and stability in order to generate carriers able to cross the blood–brain barrier. Their capacity to do so was evaluated after systemic administration in healthy rats. The distribution, cellular uptake, and fate were investigated in vivo. Toxicity was estimated by behavioral tests.

Serpin A1 C-Terminal Peptides as Collagen Turnover Modulators

  • Pages: 1850-1855
  • First Published: 30 November 2015
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Time to heal: A) Synthesis of overlapping peptides of serpin A1 C-terminal portion: SA1-I, SA1-II, SA1-III. B) Biological screening on cultured normal human dermal fibroblasts: dose–response curve for peptide SA1-III. Our data highlight that this decapeptide is a promising lead compound for further development in the search for wound-healing agents to be included in future pharmaceutical formulas.

Structure–Activity Study of the Peptides P5U and Urantide by the Development of Analogues Containing Uncoded Amino Acids at Position 9

  • Pages: 1856-1864
  • First Published: 09 April 2016
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The key position 9: Derivatives of urotensin-II were generated by replacing the tyrosine residue in the sequences of both P5U and urantide peptides with various aromatic and nonaromatic bulky groups. These modifications helped us to determine the influence of such residues on the binding affinity for and biological activity at the human urotensin receptor.

Targeting Different Transthyretin Binding Sites with Unusual Natural Compounds

  • Pages: 1865-1874
  • First Published: 09 May 2016
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Help from the plant kingdom for TTR amyloidosis: We used an in-house library of unexplored natural compounds to target different TTR binding sites. We found that various unusual natural scaffolds are able to interact with the traditional thyroxine (T4) binding pocket. Some further interesting results have also emerged for the accessibility of the EGCG binding site.