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Archive for the ‘Reviews’ Category

Have you seen our recent review articles? Papers on molecular obesity, telomeres targetted with natural products and minisci reactions

03 Feb 2012

During 2011 we published a number of topical reviews on a wide range of topics by expert researchers in their fields. We’ve collected them below and we hope you’ll find something interesting in your area!

Molecular obesity, potency and other addictions in drug discovery
Michael M. Hann
DOI: 10.1039/C1MD00017A

Proteochemometric modeling as a tool to design selective compounds and for extrapolating to novel targets
Gerard J. P. van Westen, Jörg K. Wegner, Adriaan P. IJzerman, Herman W. T. van Vlijmen and A. Bender
DOI: 10.1039/C0MD00165A

Impact of ion class and time on oral drug molecular properties
Paul D. Leeson, Stephen A. St-Gallay and Mark C. Wenlock
DOI: 10.1039/C0MD00157K

Novel, unifying mechanism for aromatic primary-amines (therapeutics, carcinogens and toxins): electron transfer, reactive oxygen species, oxidative stress and metabolites
Peter Kovacic and Ratnasamy Somanathan
DOI: 10.1039/C0MD00233J

Natural products targeting telomere maintenance
Jack Li-Yang Chen, Jonathan Sperry, Nancy Y. Ip and Margaret A. Brimble
DOI: 10.1039/C0MD00241K

The p53-MDM2/MDMX axis – A chemotype perspective
Kareem Khoury, Grzegorz M. Popowicz, Tad A. Holak and Alexander Dömling
DOI: 10.1039/C0MD00248H

Computational ligand-based rational design: role of conformational sampling and force fields in model development
Jihyun Shim and Alexander D. MacKerell, Jr.
DOI: 10.1039/C1MD00044F

Expanding the horizon of chemotherapeutic targets: From MDM2 to MDMX (MDM4)
Antonio Macchiarulo, Nicola Giacchè, Andrea Carotti, Fabiola Moretti and Roberto Pellicciari
DOI: 10.1039/C0MD00238K

Progress on lamellarins
Daniel Pla, Fernando Albericio and Mercedes Álvarez
DOI: 10.1039/C1MD00003A

Are pyridazines privileged structures?
Camille G. Wermuth
DOI: 10.1039/C1MD00074H

Towards biocompatible nanovalves based on mesoporous silica nanoparticles
Ying-Wei Yang
DOI: 10.1039/C1MD00158B

Minisci reactions: Versatile CH-functionalizations for medicinal chemists
Matthew A. J. Duncton
DOI: 10.1039/C1MD00134E

If you have an idea for a review article that hasn’t been covered and you would like to see included, contact the Editorial Office – we’d love to hear from you.

You can also find the collection here.

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Themed issue on epigenetics just published

31 Jan 2012

The web-based issue in MedChemComm termed “Epigenetics” is a timely collection of articles covering recent developments in epigenetic medicinal chemistry research in the broadest sense, including reviews of the field, original articles, and perspectives looking in to the future.

Epigenetics is the study of changes in phenotype or gene expression that cannot be related to a change in gene sequence. From being seen as a fringe science looking at strange phenomena, it is today very clear that epigenetic mechanisms are crucial for cell development and a cause of many diseases. In particular, many cancers have been shown to have an epigenetic component, and cancer research provided epigenetic compounds before the proteins involved were known, as exemplified by Breslow’s pioneering work on hydroxamic acids. Today several histone deacetylase (HDAC) inhibitors have reached the market, and this area is the most established part of the research field. Similarly, many other enzymes involved in epigenetic regulation are potential drug targets and development of new tool compounds to validate these targets and understanding the dynamics of epigenetic marks is a key requirement in the field. Fortunately, this need is balanced by increasing activity and interest from the medicinal chemistry community as we hope this issue clearly demonstrates.

It is therefore highly appropriate that MedChemComm has decided to gather a web-based issue on epigenetic medicinal chemistry research. This issue contains more than 10 papers on epigenetic research with contributions as concise articles as well as reviews from leading groups in the field. These papers demonstrate the broadness of the field including inhibitors of HDACs, DNA methyltransferases, protein-protein interactions of reader domains, and looking at the enzymatic action of lysyl hydroxylases.

We are very pleased with this issue describing and demonstrating state-of-art within epigenetic medicinal chemistry and hope the readers of MedChemComm will enjoy it.

–Rasmus Prætorius Clausen (University of Copenhagen) and Mark Bunnage (Pfizer), Guest Editors

View the issue

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Mini-review on aminoglycoside resistance caused by N-6′-acetyltransferase

18 Jan 2012

Kenward Vong and Karine Auclair, McGill University, discuss the mechanism of AAC(6′)s – N-acetyltransferase enzymes that confer resistance to aminoglycoside resistance by catalysing the addition of an acetyl group from acetyl coenzyme A (AcCoA) to the 6′-N of aminoglycosides. They also discuss aminoglycoside analogues designed to overcome AAC(6′)s and strategies for blocking AAC(6′)s.

Understanding and overcoming aminoglycoside resistance caused by N-6′-acetyltransferase
Kenward Vong and Karine Auclair
DOI: 10.1039/C2MD00253A

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Review: Advances in design and drug discovery of antimalarial peroxides

11 Jan 2012

In this MedChemComm review article Professor Gary H. Posner and coworkers at The Johns Hopkins Malaria Research Institute (Baltimore, MD, USA) provide an up-to-date review of the design and antimalarial activity of cyclic peroxides.

The review covers:

antimalarial monomeric and dimeric derivatives of artemisinin
peroxides not derived from artemisinin
hybrides containing one peroxide unit covalently linked to a non-peroxide unit.

… and highlights the effectiveness and the symplicity of synthesis of these diverse cyclic peroxides.

Reference
Antimalarial peroxides: advances in drug discovery and design
Rachel D. Slack, Alexander M. Jacobine and Gary H. Posner
Med. Chem. Commun., 2012, Advance Article
DOI: 10.1039/C2MD00277A, Review

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Review: a unified mechanism for amphotericin B

11 Jan 2012

Peter Kovacic and Andrew Cooksy examine the multiple modes of action and toxicity of this important antifungal antibiotic.

Areas covered:

Autoxidation and metabolism
Electron affinity
Pro-oxidant action
Drug activity and ROS-OS
Antifungal mechanism: ET-ROS-OS
Physiological action
Antioxidant activity
Toxicity
Conjugated dicarbonyls

Novel, unifying mechanism for amphotericin B and other polyene drugs: electron affinity, radicals, electron transfer, autoxidation, toxicity, and antifungal action.
Peter Kovacic and Andrew Cooksy
DOI: 10.1039/C2MD00267A

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Reviewing the pros and cons of protein structure-based pharmacophore modelling

20 Dec 2011

Pharmacophore modelling is a useful tool for medicinal chemists to identify novel ligands to bind to a receptor. This review from Chris de Graaf and colleagues describes the advantages, and challenges, of using 3D protein structures to predict pharmacophores (rather than using a ligand-based approach, which involves searching for similarities based on previously known active ligands).

The review covers (i) protein structure preparation, (ii) binding site detection, (iii) pharmacophore feature definition, and (iv) pharmacophore feature selection, concluding that ‘SBPs are valuable tools for hit and lead optimization, compound library design and target hopping, especially in cases where ligand information is scarce‘.

Epigenetics: a highly promising source of new drug targets

12 Dec 2011

As an introduction to the web theme issue on Epigenetics published in MedChemComm (guest-edited by Dr Mark Bunnage – Pfizer – and Professor Rasmus Prætorius Clausen -University of Copenhagen), Nessa Carey (Head of Epigenetics ERDI, Pfizer) provides a concise summary of the current thinking in the ever expanding field of epigenetics.

Read Nessa’s review:
Epigenetics – an emerging and highly promising source of new drug targets
Nessa Carey
Med. Chem. Commun., 2012, Advance Article
DOI: 10.1039/C1MD00264C

…and view the collection of articles that makes for a timely and essential web theme issue in the emerging field of epigenetics research.

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HOT Review: Epigenetic modulators for cancer chemotherapy

21 Nov 2011

In this Hot review article Professor Patrick Woster and a team of international collaborators provide insights into the design, synthesis and biological activity of a range of chromatin remodeling enzymes inhibitors that promote the re-expression of aberrantly silenced genes of importance in human cancer.

Interested in Epigenetic therapeutics? Why not read the article now:

Polyamine-based small molecule epigenetic modulators
DOI: 10.1039/C1MD00220A, Review

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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

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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