key: cord-0041561-n62up39u authors: nan title: Graphical Abstract: ChemMedChem 8/2013 date: 2013-07-29 journal: ChemMedChem DOI: 10.1002/cmdc.201390032 sha: 76c7cd562c2b50d6a5694854535c47879ab5d24e doc_id: 41561 cord_uid: n62up39u nan Recent Developments of 19-Nor-1,25dihydroxyvitamin D 3 Analogues Vital analogues: The use of 1,25(OH) 2 D 3 for the treatment of a wide variety of diseases was limited by the parallel induction of hypercalcemic effects. There is an urgent need to find novel agents with greater selectivity. This review highlights recent advances in the research of 19-nor-1,25-dihydroxyvitamin D 3 analogues, paying special attention to their activities and structureactivity relationships. Antiproliferative Activity, Cell Cycle, and Apoptosis Studies of a Series of 6-Substituted 9H-Purin-9-yl-pyridinium Derivatives on a Human Cervical Carcinoma Cell Line Better by benzylthio: A series of 6-substituted 9H-purin-9-yl-pyridinium derivatives was synthesized and evaluated for their antitumor activity. Compounds included in this study elicit variations in cell-cycle progression and an increase of apoptotic cells in a caspase-3-dependent process. Z. Zhao, Z. Zhang, Y. Li, M. Zhou, X. Li, B. Yu, R. Wang* Probing the Key Interactions between Human Atg5 and Atg16 Proteins: A Prospective Application of Molecular Modeling Breaking things down: Disruption of the Atg5-Atg16 protein-protein interaction is a potential strategy for the development of effective inhibitors of autophagy. Using a structural model of the human Atg5-Atg16 complex, a total of 30 Atg16-based peptides were designed and tested for their binding affinity to Atg5. A number of these peptides exhibited binding affinities in the low micromolar range. Furthermore, three Atg16 residues were identified as the key factors in Atg5 binding. The Bivalent Ligand Approach as a Tool for Improving the in vitro Anti-Alzheimer Multitarget Profile of Dimebon Inspired by the concept of bivalent ligands, we prepared a small set of analogues of the drug candidate dimebon. They were shown to inhibit AChE, Ab 42 aggregation, and NMDA receptor activation to a greater extent than dimebon. Some of these compounds also enhanced the survival of chicken neurons under apoptosis-inducing conditions. ]tetradeca-2,4,6-trien-1-yl}phenol (10) was found to be 1000-fold selective for ERb over ERa. This compound exhibits~10 nm potency and appears to be the first to take advantage of both conservative amino acid differences found in the aand b-faces of the binding cavities of ERa and ERb. Selective and Brain-Permeable Pololike Kinase-2 (Plk-2) Inhibitors That Reduce a-Synuclein Phosphorylation in Rat Brain Gets into your head: By using a structure-guided drug discovery approach, highly selective brain-penetrant Plk-2 inhibitors were designed with the use of an interesting aromatic edge-face interaction as a potency-selectivity determinant. An analogue from this work lowered phosphorylated a-synuclein levels in vivo on oral dosing, demonstrating successful target engagement in the rat brain and paving the way for proof-ofconcept studies in rodent models of Parkinson's disease. Structure-Based Design of Small-Molecule Ligands of Phosphofructokinase-2 Activating or Inhibiting Glycolysis Fruct-o so good! Using a structurebased approach, potential small-molecule regulators of phosphofructokinase-2, a bifunctional enzyme and regulator of glycolytic flux, were discovered. The most potent inhibitors of kinase activity in the series also inhibited the proliferation of HeLa, lung adenocarcinoma, colon adenocarcinoma, and breast cancer cells at concentrations in the low micromolar range. Synthesis and Radiopharmacological Characterisation of a Fluorine-18-Labelled Azadipeptide Nitrile as a Potential PET Tracer for in vivo Imaging of Cysteine Cathepsins Visualising cathepsins in tumours: Cysteine cathepsins are key players in tumour pathology. An azadipeptide nitrile with high affinity for cathepsins L, S, B, and K was labelled with fluorine-18 and investigated for its pharmacokinetic properties. PET imaging studies with tumour-bearing mice indicate the tumour accumulation of the probe and the potential of tumour targeting for this inhibitor class. 2013 Binding Affinities for Anti-apoptotic Bcl-2 Family Proteins Ambidexterity! The compounds reported herein were characterized as inhibitors of anti-apoptotic Bcl-2 family proteins. Structures in this compound class contain a chiral center (C4 atom) on the pyrimidine ring. Interestingly, our study revealed that the R and S enantiomers of this compound class have similar binding affinities for Bcl-x L , Bcl-2, and Mcl-1. Discovery of an Acyclic Nucleoside Phosphonate that Inhibits Mycobacterium tuberculosis ThyX Based on the Binding Mode of a 5-Alkynyl Substrate Analogue Rational design: The selective ThyX A C H T U N G T R E N N U N G inhibitor 5-alkynyl 2'-deoxyuridine 5'monophosphate was modeled in its target active site, and NMR was used to support the predicted binding mode. To increase the stability of the lead compound, some acyclic nucleoside phosphonate (ANP) derivatives were synthesized and tested in vitro for ThyX inhibition. A modestly active inhibitor was identified, further optimization of which could lead to antibacterial thymidylate synthase inhibitors. Design, Synthesis and Biological Evaluation of Rose Bengal Analogues as SecA Inhibitors The simpler the better: We report the synthesis and structure-activity relationship (SAR) studies of 23 rose bengal analogues that were designed by systematical dissections. Evaluation of these analogues allowed us to establish an A C H T U N G T R E N N U N G initial SAR for SecA inhibition. The anti-A C H T U N G T R E N N U N G microbial effects of these SecA inhibitors are confirmed in experiments using E. coli and B. subtilis. N. Bionda, R. M. Fleeman, L. N. Shaw, P. Cudic* Effect of Ester to Amide or N-Methylamide Substitution on Bacterial Membrane Depolarization and Antibacterial Activity of Novel Cyclic Lipopeptides To be or not to be active: A cyclic lipodepsipeptide and its amide analogue can depolarize the cytoplasmic membranes of Gram-positive bacteria, whereas the N-methylamide analogue is inactive. Membrane depolarization does not correlate with bacterial cell lethality, suggesting that membrane-targeting activity is not the main mode of action for this class of antibacterial peptides. Design, Synthesis, and Evaluation of WC5 Analogues as Inhibitors of Human Cytomegalovirus Immediate-Early 2 Protein, a Promising Target for Anti-HCMV Treatment Immediate, early effects: >The quinolone scaffold of the potent and selective anti-HCMV compound WC5 was investigated in depth, furnishing new SAR insight and identifying novel potent analogues, the anti-HCMV activity of which is brought about by inhibition of IE2mediated transactivation. These quinolone derivatives are therefore particularly well suited for treating patients that do not respond to the DNA polymerase inhibitors in current use. * Author to whom correspondence should be addressed. Supporting information on the WWW (see article for access details). A video clip is available as Supporting Information on the WWW (see article for access details). This is an open-access article, published under the terms and conditions of a Creative Commons license; the specific license and details about the permitted reuse can be found on the first page of the article. Contributions labeled with this symbol have been judged as "Very Important Papers" by the referees. New Therapeutic Strategies for Type 2 Diabetes Efficient Preparations of Fluorine SERVICE All the Tables of Contents may be found on the WWW under In particular, co-funding by FEDER through the COMPETE program (ref. FCOMP-01-0124-FEDER-020963) was not mentioned FCOMP-01-0124-FEDER-020963) and by Portuguese national funds through Fundażo para a CiÞncia e Tecnologia -FCT (ref. PTDC/QUI-QUI/116864/2010). C.T. and J.R.B.G. thank FCT for a postdoctoral grant (SFRH/BPD/62967/2009) and Programa CiÞncia CORRIGENDUM Due to a typesetting error, Scheme 1 was incorrectly printed. The correct scheme is given below Adamantyl Arotinoids That Inhibit IkB Kinase a and IkB Kinase b ChemMedChem