key: cord-0041571-2mzsqm4d authors: nan title: Graphical Abstract: ChemMedChem 6/2010 date: 2010-05-31 journal: ChemMedChem DOI: 10.1002/cmdc.201090022 sha: a652323950b505567571057cdb5435f635cfff78 doc_id: 41571 cord_uid: 2mzsqm4d nan Chairmen Giorgio Tarzia Guarding the grey matter: This paper reports the discovery of sulfonamide derivatives as carbonic anhydrase inhibitors that selectively act against the hCA VII over the hCA II isoform. These compounds represent potentially useful lead structures for the further development of neuroprotective agents targeting the hCA VII isoform. Conformationally Constrained Spiro C-Arylglucosides as Potent and Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitors Sodium glucose co-transporter 2 (SGLT2) is an emerging target for the treatment of type 2 diabetes mellitus (DM2). Here, the synthesis and preliminary biological evaluation of a series of potent, selective SGLT2 inhibitors, derived from a rigid spiro C-arylglucoside scaffold, is described. Lead Optimization of Diarylpyrimidines as Non-nucleoside Inhibitors of HIV-1 Reverse Transcriptase Antiviral agents: A series of CN-CH 2 -DAPY analogues were identified as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) against HIV-1. Most of the newly synthesized compounds exhibited strong activity against wild-type HIV-1. Electrocyclization-Based Labeling Allows Efficient In Vivo Imaging of Cellular Trafficking Labeling the living! New synthetic chemistry allows living cells to be labeled for 10 min at extremely low concentrations without deactivating cell functions; lymphocyte trafficking was visualized with high-contrast fluorescence imaging at the whole-body level. A. M. Wassermann, L. Peltason, J. Bajorath* Computational Analysis of Multitarget Structure-Activity Relationships to Derive Preference Orders for Chemical Modifications toward Target Selectivity Selectivity: A computational methodology is presented for the analysis of multi-target structure-activity relationships of compound series that ultimately aims at the identification of selectivity determinants. The approach provides a basis for the formulation of intuitive rules for the design of target-selective compounds. Shown is the derivation of preference orders of pharmacophore features at a defined substitution site in an analogue series. Rendering Conventional Molecular Fingerprints for Virtual Screening Independent of Molecular Complexity and Size Effects Molecular complexity and size effects are known to complicate virtual screening with fingerprints. A methodology is introduced to render standard fingerprints independent of molecular complexity effects by merging a fingerprint with its complement. The resulting fingerprints show increased similarity search performance for optimized reference compounds, which is highly relevant for many practical virtual screening applications. Reactions between thiol-containing enzymes and Michael systems were studied to investigate new agents against viral proteases and to analyze the excess toxicity of Michael systems. Our results explain the trends in inhibition and toxicity and explain why some Michael systems are irreversible inhibitors of the SARS coronavirus main protease, whereas others are only reversible. Pentalysine b-Carbonylphthalocyanine Zinc: An Effective Tumor-Targeting Photosensitizer for Photodynamic Therapy A new unsymmetrical zinc phthalocyanine photosensitizer (pentalysine b-carbonylphthalocyanine zinc, ZnPc-(Lys) 5 ) was prepared in large quantity and high purity. This water-soluble cationic photosensitizer shows high tumor phototoxicity and significant inhibition of tumor growth. Q. Hu, M. Negri, S. Olgen, R. W. Hartmann* The Role of Fluorine Substitution in Biphenyl Methylene Imidazole-Type CYP17 Inhibitors for the Treatment of Prostate Carcinoma CYP17 inhibition is a promising approach for the treatment of prostate cancer. Modification of biphenyl methylene imidazoles by fluorine substitution significantly increases the inhibitory potency of this compound class and prolongs plasma half-life. Compound 9 (ball-and-stick structure) was found to be a potent CYP17 inhibitor (IC 50 = 131 nm) with good pharmacokinetic properties. Always similar to Epo A: The tubulinbound conformation of a series of C3and C15-modified epothilones was found to be similar to the NMR-derived structure of tubulin-bound Epo A, based on NMR spectroscopy and computational modeling. The results obtained for two isomeric quinoline-based Epo B analogues suggest that the aromatic side chain moieties contribute to tubulin binding through van der Waals interactions rather than hydrogen bonding. Gene Therapy in HIV-Infected Cells to Decrease Viral Impact by Using an Alternative Delivery Method The NN16 dendrimer is capable of transfecting genetic material to a wide array of cell types crucial for HIV infection, thereby resulting in low cytotoxicity. We monitored the cellular uptake of oligonucleotides transfected via NN16, identifying it as an efficient vector in gene therapy by its significant reduction of HIV protein release and specific inhibition of gene expression in HIV-infected cells. Fragment-Based Lead Discovery: Screening and Optimizing Fragments for Thermolysin Inhibition Virtual fragment-based screening has been applied to the metalloproteinase thermolysin. A protein-targeted library was screened by docking, and two fragments could be identified. For one, a crystal structure with the protein was determined. It was further optimized to improve affinity and keep its fragmentlike properties. Redesign of the zinc coordination group revealed novel micromolar fragments as a good starting point for further lead design. A Series of 18 F-Labelled Pyridinylphenyl Amides as Subtype-Selective Radioligands for the Dopamine D3 Receptor A series of D3 receptor ligands was developed based on 3D-QSAR models. The in vitro D3 affinities of the predicted biphenyl amide ligands revealed single-digit to sub-nanomolar potencies with substantial D3 selectivities. Ex vivo autoradiography of rat brain revealed high accumulation of two 18 F-labeled D3 radioligand candidates in the ventricles. Pushing back the frontiers of science: Conferences are an ideal way to share exciting and ground-breaking results with some of the world's foremost medicinal chemists, and this meeting was no exception. The 7th international conference, organized jointly by the DPhG and GDCh and held earlier this year (March 14-17) in Münster (Germany), featured presentations on hot topics in drug discovery, including ion channels, nanotechnology, neglected diseases and anticancer drugs. Select presentations delivered at the conference are described. 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). * Author to whom correspondence should be addressed. Carlomagno* Dynamic Combinatorial Chemistry in Drug Discovery EGFR Signaling Networks in Cancer Pharmaceutical Data Mining · K All the Tables of Contents may be found on the WWW under is not a corresponding author of this paper, rather L.B and I.N. contributed equally to this work