Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
March 06, 2014
VIP: Synthesis, Anti-tubulin and Antiproliferative SAR of Steroidomimetic Dihydroisoquinolinones
Mathew P. Leese, Fabrice L. Jourdan, Meriel R. Major, Wolfgang Dohle, Mark P. Thomas, Ernest Hamel, Eric Ferrandis, Mary F. Mahon, Simon P. Newman, Atul Purohit, Barry V. L. Potter*
Tubulin is a well-validated cancer drug target, and vinca alkaloids, taxanes, and other taxane site binders have found wide therapeutic application. Nevertheless, significant problems associated with existing drugs remain, with issues of limited therapeutic window, acquired resistance, lack of oral bioavailability, and problematic formulation. Together with colleagues at the NCI (USA), Ipsen (France), and at Imperial College London, Barry Potter’s group at the University of Bath (UK) focused on a natural steroidal lead, designing a partial surrogate of the steroidal core with new structural elements added, and also building in a motif they pioneered earlier in clinical translation that confers attractive oral activity and delivery and imbues resistance to metabolism. Read more...
Recently Published Articles
- Methyl, Ethyl, Propyl, Butyl: Futile But Not for Water, as the Correlation of Structure and Thermodynamic Signature Shows in a Congeneric Series of Thermolysin Inhibitors
Stefan G. Krimmer, Michael Betz, Prof. Dr. Andreas Heine and Prof. Dr. Gerhard Klebe
Article first published online: 13 MAR 2014 | DOI: 10.1002/cmdc.201400013
Water matters! Water is ubiquitously present in any biological system and has to be regarded as an additional binding partner in the protein–ligand binding process. A new solvent-exposed surface is generated and water molecules from the first solvation layer arrange around it. In conclusion, the quality of a water network assembled around a protein–ligand complex influences the enthalpy/entropy signature and can even modulate affinity.
- Synthesis and Anti-HCV Entry Activity Studies of β-Cyclodextrin–Pentacyclic Triterpene Conjugates
Dr. Sulong Xiao, Dr. Qi Wang, Longlong Si, Yongying Shi, Han Wang, Fei Yu, Prof. Yongmin Zhang, Yingbo Li, Yongxiang Zheng, Chuanling Zhang, Prof. Chunguang Wang, Lihe Zhang and Demin Zhou
Article first published online: 12 MAR 2014 | DOI: 10.1002/cmdc.201300545
An awesome CD collection: A series of water-soluble triazole-bridged β-cyclodextrin (CD)–pentacyclic triterpene conjugates were synthesized, and their hydrophobicity, anti-HCV entry activities, and toxicity were studied. Easy access to such conjugates may provide a way to obtain a new class of anti-HCV entry inhibitors.
- In silico Design, Synthesis, and Screening of Novel Deoxyhypusine Synthase Inhibitors Targeting HIV-1 Replication
Dr. Marcus Schroeder, Adrian Kolodzik, Katharina Pfaff, Dr. Poornima Priyadarshini, Dr. Marcel Krepstakies, Prof. Dr. Joachim Hauber, Prof. Dr. Matthias Rarey and Prof. Dr. Chris Meier
Article first published online: 11 MAR 2014 | DOI: 10.1002/cmdc.201300481
Combating drug resistance: The in silico design, synthesis, and biological evaluation of deoxyhypusine synthase (DHS) inhibitors are described. DHS is involved in post-translational modification of the protein eIF-5A, which is needed for the translocation of HIV RNA from the nucleus into the cytosol. A newly designed inhibitor showed dose-dependent inhibition of DHS in vitro and suppression of HIV replication in cell cultures without cytotoxic effects.
- Targeting Cystalysin, a Virulence Factor of Treponema denticola-Supported Periodontitis
Dr. Francesca Spyrakis, Dr. Barbara Cellini, Dr. Stefano Bruno, Dr. Paolo Benedetti, Dr. Emanuele Carosati, Prof. Gabriele Cruciani, Dr. Fabrizio Micheli, Dr. Antonio Felici, Prof. Pietro Cozzini, Prof. Glen E. Kellogg, Prof. Carla Borri Voltattorni and Prof. Andrea Mozzarelli
Article first published online: 11 MAR 2014 | DOI: 10.1002/cmdc.201300527
Biting back: Cystalysin from Treponema denticola has been proposed as a potential antimicrobial target, because it is a virulence factor in adult periodontitis. Specific inhibitors of cystalysin activity were identified and assayed by complementary in silico and in vitro methods. Compounds found by these techniques might be suitable for the treatment of periodontitis after further optimization.
- The DiPPro Approach: Synthesis, Hydrolysis, and Antiviral Activity of Lipophilic d4T Diphosphate Prodrugs
Dr. Tilmann Schulz, Prof. Dr. Jan Balzarini and Prof. Dr. Chris Meier
Article first published online: 11 MAR 2014 | DOI: 10.1002/cmdc.201300500
NDPs delivered! A structure–activity relationship of bioreversibly protected DiPPro–d4TDP was performed. The stability of the compounds was studied in various media such as cell extracts. Stability increased with increasing lipophilicity of the acyl chain. D4TDP was released as main product. Compounds with long acyl residues showed good anti-HIV activities in TK-deficient cells, proving intracellular uptake of the compounds.