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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
- You have full text access to this OnlineOpen articleSynthesis, Anti-tubulin and Antiproliferative SAR of Steroidomimetic Dihydroisoquinolinones
Dr. Mathew P. Leese, Dr. Fabrice L. Jourdan, Dr. Meriel R. Major, Dr. Wolfgang Dohle, Dr. Mark P. Thomas, Dr. Ernest Hamel, Dr. Eric Ferrandis, Dr. Mary F. Mahon, Dr. Simon P. Newman, Dr. Atul Purohit and Prof. Dr. Barry V. L. Potter
Article first published online: 5 MAR 2014 | DOI: 10.1002/cmdc.201400017
Steroid-oids: Steroidomimetic dihydroisoquinolinones (DHIQs) were evaluated against two cancer cell lines. Carbonyl-linked DHIQs exhibit significant in vitro antiproliferative activity, show excellent activity against tubulin polymerisation, and compete at the colchicine binding site of tubulin. Crystal structure analysis and molecular modelling both suggest a preferred “steroid-like” conformation as a result of intramolecular electrostatic repulsion for this compound class.
- Bis-(1,2,3,4-tetrahydroisoquinolinium): A Chiral Scaffold for Developing High-Affinity Ligands for SK Channels
Prof. Jean-François Liégeois, Prof. Johan Wouters, Prof. Vincent Seutin and Dr. Sébastien Dilly
Article first published online: 5 MAR 2014 | DOI: 10.1002/cmdc.201400028
In the THIQ of things: A novel series of nonaromatic bis-(1,2,3,4-tetrahydroisoquinolinium) stereoisomers were synthesized and tested for their affinity for small-conductance calcium-activated potassium channel (SK/KCa2) subtypes in comparison with the corresponding bis-(1,2,3,4-tetrahydroisoquinoline) analogues. The results show that these compounds represent a new scaffold for the development of high-affinity ligands for SK channel subtypes.
- Efficient Acid-Catalyzed 18F/19F Fluoride Exchange of BODIPY Dyes
Dr. Edmund J. Keliher, Jenna A. Klubnick, Dr. Thomas Reiner, Dr. Ralph Mazitschek and Prof. Ralph Weissleder
Article first published online: 5 MAR 2014 | DOI: 10.1002/cmdc.201300506
A colorful exchange: In this study we explore acid-catalyzed 18F/19F exchange on a range of commercially available NHS ester and maleimide BODIPY fluorophores. We show this method to be a simple and efficient 18F-labeling strategy for a diverse range of fluorescent compounds, including a BODIPY-modified PARP-1 inhibitor, and amine- and thiol-reactive BODIPY fluorophores.
- Bis(pentafluorosulfanyl)phenyl Azide as an Expeditious Tool for Click Chemistry toward Antitumor Pharmaceuticals
Yu-Dong Yang, Etsuko Tokunaga, Prof. Hidehiko Akiyama, Norimichi Saito and Prof. Norio Shibata
Article first published online: 3 MAR 2014 | DOI: 10.1002/cmdc.201400059
Fluoro power! (5-Azido-1,3-phenylene)bis(pentafluoro-λ6-sulfane) is introduced as a powerful tool for the synthesis of pentafluorosulfanyl-containing arenes using click chemistry. A series of 13 pentafluorosulfanylarene-triazoles was synthesized and evaluated against a human leukemic monocyte lymphoma cell line. The results indicate their potential as building blocks for the further development of pentafluorosulfanyl-containing antitumor agents.
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Dr. Tanmaya Joshi, Vanessa Pierroz, Priv.-Doz. Dr. Stefano Ferrari and Prof. Dr. Gilles Gasser
Article first published online: 3 MAR 2014 | DOI: 10.1002/cmdc.201400029
The mitochondria count: Cytotoxicity and cellular localization studies reveal that structural modifications (lipophilicity, charge, and size-based) of a cytotoxic bis(dppz)-RuII complex [Ru(dppz)2(CppH)])PF6 (1) result in its cytotoxic potency being compromised. Overall, the results of this important structure–activity relationship strongly support our initial hypothesis that accumulation in mitochondria is crucial for 1 to exert its cytotoxic action.