RSC Medicinal Chemistry Blog

HOT: Inhibition of bromodomain-mediated protein–protein interactions as a novel therapeutic strategy

15 Nov 2011

This review from Manfred Jung and colleagues looks at the structural biology and inhibition of bromodomains, enzymatic domains which recognise acetylated lysines residues in modified histones in chromatin. Inhibiting the protein–protein interactions in bromodomains by using small molecules as epigenetic tools is an exciting new area of research, offering potential for new therapeutic approaches.

The review includes:

Structural features of bromodomains and acetyl-lysine recognition
Implication of bromodomains in pathological cellular states
Challenges by targeting protein–protein interactions with small molecules
Inhibitors of bromodomain-mediated protein–protein interactions
Inhibitors of the PCAF-BRD/HIV-TatK50ac interaction
Inhibitors of the CBP-BRD/p53K382ac interaction
Inhibitors of BET bromodomains

This hot review is part of our forthcoming themed issue on Epigenetics – keep checking back for more hot research in this theme:

Inhibition of bromodomain-mediated protein–protein interactions as a novel therapeutic strategy
Silviya D. Furdas, Luca Carlino, Wolfgang Sippl and Manfred Jung
DOI: 10.1039/C1MD00201E

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Development of second generation epigenetic agents

07 Nov 2011

By Francesca Burgoyne.

This hot review from Philip Jones, MD Anderson Cancer Center, Texas, examines our understanding of the structure and function of epigenetic enzymes, including lysine and arginine methyltransferases and demethylases, histone acetyl transferases and histone deacetylases, and the chemical probes and tools available to increase our understanding.

It focuses on the development of a second generation of epigenetic agents able to manipulate histone modifications responsible for aberrant epigenetic gene transcription associated with disease states.

Areas covered:

Class I and II HDAC inhibitors
HDAC 1-4, 6, 8 selective inhibitors
Class III HDAC inhibitors
Histone acetyl transferase inhibitors
Histone methyltransferase inhibitors
Lysine and arginine methyltransferase inhibitors
Histone demethylase inhibitors
Lysine specific demethylase 1 inhibitors
JmJ demethylase inhibitors

Development of second generation epigenetic agents
Philip Jones
DOI: 10.1039/C1MD00199J

This article is part of our forthcoming themed issue on Epigenetics – check back soon for more hot articles in this issue!

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HOT: A self-immolative strategy to enhance cancer chemotherapy selectivity

04 Nov 2011

By Marie Cote, Deputy Editor.

In this Hot article, scientists from France present a self-immolative dendritic glucuronide prodrug designed for the release of two doxorubicin molecules after a single triggering event.

‘While numerous glucuronide prodrugs have been studied so far, the efficiency of this targeting strategy is limited by the poor turnover of beta-glucuronidase in malignant tissues. Our novel dendritic prodrug which is programmed to release two molecules of doxorubicin after a single enzymatic activation step may permit to overcome this drawback’, the authors explain.

The biological experiments conducted have shown that this novel enzyme-responsive dendritic prodrug is twice more toxic than its monomeric counterpart against H661 lung cancer cells. It is hoped that this novel approach may open new avenues in selective cancer chemotherapy.

Selected as HOT, read this article for free now.

A self-immolative dendritic glucuronide prodrug of doxorubicin
Marion Grinda, Jonathan Clarhaut, Brigitte Renoux, Isabelle Tranoy-Opalinski and Sébastien Papot
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00193K, Concise Article

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HOT: acetylphosphonates inhibit DXP synthase in the MEP pathway

04 Nov 2011

By Francesca Burgoyne.

This hot article from Caren Freel Meyers and coworkers describes new inhibitors of DXP synthase, which catalyse an important precursor in the pathogen MEP pathway to isoprenoids. Butylacetylphosphonate was able to selectively inhibit E. coli DXP synthase.

Selective inhibition of E. coli 1-deoxy-D-xylulose-5-phosphate synthase by acetylphosphonates
Jessica M. Smith, Ryan J. Vierling and Caren Freel Meyers
Med. Chem. Commun., 2012, Advance Article
DOI: 10.1039/C1MD00233C

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New antimalarial compounds: the class of 2011

04 Nov 2011

By Francesca Burgoyne.

In another step to overcome bacterial resistance to antibiotics, scientists from India have made a new class of triazines. Sixteen compounds showed excellent activity against malaria, say the researchers, preserving the potency of their parent antimalarial drug chloroquine. IC₅₀ values ranged from 1.36 to 4.63ng ml^-1.

Synthesis of hybrid 4-anilinoquinoline triazines as potent antimalarial agents, their in silico modeling and bioevaluation as Plasmodium falciparum transketolase and β-hematin inhibitors
Moni Sharma, Kuldeep Chauhan, Shikha S. Chauhan, Ashok Kumar, Shiv Vardan Singh, Jitendra K. Saxena, Pooja Agarwal, Kumkum Srivastava, S. Raja Kumar, Sunil K. Puri, Priyanka Shah, M. I. Siddiqi and Prem M. S. Chauhan
DOI: 10.1039/C1MD00188D

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Tracking immune cell migration on the cover of Issue 11

04 Nov 2011

By Francesca Burgoyne.

On the cover of Issue 11 is a hot article from Mark Bradley and coworkers on a method to track innate immune cell migration in vivo using dye-labelled peptoids.

Far red and NIR dye-peptoid conjugates for efficient immune cell labelling and tracking in preclinical models
Kevin Dhaliwal, Géraldine Escher, Asier Unciti-Broceta, Neil McDonald, A. John Simpson, Chris Haslett and Mark Bradley
Med. Chem. Commun., 2011, 2, 1050-1053
DOI: 10.1039/C1MD00171J

Also in this issue is Ying-Wei Yang’s review on biocompatible nanovalves for drug delivery and release:

Towards biocompatible nanovalves based on mesoporous silica nanoparticles
Ying-Wei Yang
Med. Chem. Commun., 2011, 2, 1033-1049
DOI: 10.1039/C1MD00158B

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Hot Perspective: Reviewing current knowledge on DNA methylation aspects

31 Oct 2011

By Marie Cote, Deputy Editor.

In this MedChemComm article*, Nadine Martinet and colleagues at the Universities of Nice-Sophia Antipolis and Poitiers (France) provide a timely overview of the current knowledge concerning DNA methyltransferases (DNMT) biology and the two main classes of DNMT inhibtors, also highlighting epigenetic anti-cancer therapeutic strategies.

Read the article for FREE for the next 4 weeks!

Small molecules DNA methyltransferases inhibitors
Nadine Martinet, Benoît Y. Michel, Philippe Bertrand and Rachid Benhida
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00194A, Review

*This article will be part of MedChemComm’s web theme issue on Epigenetics, coming soon.

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New compound class for treating hepatitis C virus

31 Oct 2011

By Francesca Burgoyne.

Researchers from Biotica, UK have discovered a new compound class called sangamides with the potential to treat hepatitis C. Sangamides are amide derivatives of sanglifehrin A – a cyclophilin-binding polyketide natural product. Non-immunosuppressive analogues of sanglifehrin A are currently under development as hepatitis C virus therapies, but suffer from lengthy synthetic processes, and some adverse affects including drug-drug interactions.

The newly developed sangamides display improved potency and good pharmcokinetic properties that make them potentially suitable for once-a-day oral treatment of chronic hepatitis C infection. Download the article for the full details:

Sangamides, a new class of cyclophilin-inhibiting host-targeted antivirals for treatment of HCV infection
Steven J. Moss, Michael Bobardt, Pieter Leyssen, Nigel Coates, Udayan Chatterji, Xie Dejian, Teresa Foster, Jinlun Liu, Mohammad Nur-e-Alam, Dipen Suthar, Chen Yongsheng, Tony Warneck, Ming-Qiang Zhang, Johan Neyts, Philippe Gallay, Barrie Wilkinson and Matthew A. Gregory
Med. Chem. Commun., 2012, Advance Article
DOI: 10.1039/C1MD00227A

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Top ten accessed articles in September

26 Oct 2011

By Nathalie Horner.

This month sees the following articles in MedChemComm that are in the top ten most accessed:

2-Anilinonicotinyl linked 1,3,4-oxadiazole derivatives: Synthesis, antitumour activity and inhibition of tubulin polymerization
Ahmed Kamal, Y. V. V. Srikanth, Thokhir B. Shaik, M. Naseer A. Khan, Md. Ashraf, M. Kashi Reddy, K. Anil Kumar and Shasi V. Kalivendi
Med. Chem. Commun., 2011, 2, 819-823
DOI: 10.1039/C0MD00177E

Towards biocompatible nanovalves based on mesoporous silica nanoparticles
Ying-Wei Yang
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00158B

Minisci reactions: Versatile CH-functionalizations for medicinal chemists
Matthew A. J. Duncton
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00134E

Molecular obesity, potency and other addictions in drug discovery
Michael M. Hann
Med. Chem. Commun., 2011, 2, 349-355
DOI: 10.1039/C1MD00017A

Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space
Alexander Alex, David S. Millan, Manuel Perez, Florian Wakenhut and Gavin A. Whitlock
Med. Chem. Commun., 2011, 2, 669-674
DOI: 10.1039/C1MD00093D

The development of quinolone esters as novel antimalarial agents targeting the Plasmodium falciparum bc 1 protein complex
Robin Cowley, Suet Leung, Nicholas Fisher, Mohammed Al-Helal, Neil G. Berry, Alexandre S. Lawrenson, Raman Sharma, Alison E. Shone, Stephen A. Ward, Giancarlo A. Biagini and Paul M. O′Neill
Med. Chem. Commun., 2012, Advance Article
DOI: 10.1039/C1MD00183C

Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes
Jeffrey A. Pfefferkorn, Angel Guzman-Perez, Peter J. Oates, John Litchfield, Gary Aspnes, Arindrajit Basak, John Benbow, Martin A. Berliner, Jianwei Bian, Chulho Choi, Kevin Freeman-Cook, Jeffrey W. Corbett, Mary Didiuk, Joshua R. Dunetz, Kevin J. Filipski, William M. Hungerford, Christopher S. Jones, Kapil Karki, Anthony Ling, Jian-Cheng Li, Leena Patel, Christian Perreault, Hud Risley, James Saenz, Wei Song, Meihua Tu, Robert Aiello, Karen Atkinson, Nicole Barucci, David Beebe, Patricia Bourassa, Francis Bourbounais, Anne M. Brodeur, Rena Burbey, Jing Chen, Theresa D’Aquila, David R. Derksen, Nahor Haddish-Berhane, Cong Huang, James Landro, Amanda Lee Lapworth, Margit MacDougall, David Perregaux, John Pettersen, Alan Robertson, Beijing Tan, Judith L. Treadway, Shenping Liu, Xiayang Qiu, John Knafels, Mark Ammirati, Xi Song, Paul DaSilva-Jardine, Spiros Liras, Laurel Sweet and Timothy P. Rolph
Med. Chem. Commun., 2011, 2, 828-839
DOI: 10.1039/c1md00116g

Discovery of CP-866,087, a mu opioid receptor antagonist for the treatment of alcohol abuse and dependence
Stanton F. McHardy, Steven D. Heck, Sara Guediche, Monica Kalman, Martin P. Allen, Meihua Tu, Dianne K. Bryce, Anne W. Schmidt, Michelle Vanase-Frawley, Ernesto Callegari, Shawn Doran, Nicholas J. Grahame, Stafford McLean and Spiros Liras
Med. Chem. Commun., 2011, 2, 1001-1005
DOI: 10.1039/C1MD00164G

Synthesis and evaluation of novel 5-sulfonyl-indolin-2-ones as potent cytotoxic agents
Yu Luo, Feng Xiao, Shijing Qian, Qiaojun He, Wei Lu and Bo Yang
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00105A

Design, synthesis and antiproliferative activity of urocanic-chalcone hybrid derivatives
Alexander Ciupa, Natalie J. Griffiths, Stephanie K. Light, Pauline J. Wood and Lorenzo Caggiano
Med. Chem. Commun., 2011, 2,1011-1015
DOI: 10.1039/C1MD00155H

Why not take a look at the articles today and blog your thoughts and comments below.

Fancy submitting an article to MedChemComm? Then why not submit to us today or alternatively email us your suggestions.

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Current progress in inhibiting Stat5 protein signalling

14 Oct 2011

By Francesca Burgoyne.

This mini-review from Patrick Gunning et al. looks at progress made towards inhibiting Stat5, a member of the Stat family of signalling proteins, that is connected to many cancers, including acute myeloid leukemias and prostate cancer.

Areas covered include both direct and indirect inhibition:

Bcr/Abl inhibitors
FLT3 inhibitors
Jak2 inhibitors
truncation inhibitors
Binding to DNA
Disrupting dimerisation

Inhibitors of Stat5 protein signalling
Abbarna A. Cumaraswamy, Aleksandra Todic, Diana Resetca, Mark D. Minden and Patrick T. Gunning
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00175B

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RSC Medicinal Chemistry Blog

HOT: Inhibition of bromodomain-mediated protein–protein interactions as a novel therapeutic strategy

Development of second generation epigenetic agents

HOT: A self-immolative strategy to enhance cancer chemotherapy selectivity

HOT: acetylphosphonates inhibit DXP synthase in the MEP pathway

New antimalarial compounds: the class of 2011

Tracking immune cell migration on the cover of Issue 11

Hot Perspective: Reviewing current knowledge on DNA methylation aspects

New compound class for treating hepatitis C virus

Top ten accessed articles in September

Current progress in inhibiting Stat5 protein signalling

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