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Get your hands on MedChemComm issue 7 today!

27 Jun 2012

This striking cover brings the work of Patrick T. Gunning and co-workers to the forefront of issue 7.

In this Concise article Gunning et al. discuss the design and synthesis of a novel class of ditopic coordination complex-based SH2 domain mimetics using de novo rational and computational design. In addition Gunning et al. identify several lead compounds that bind selectively to target phosphopeptides via the same bivalent binding mechanism employed by SH2 domains in a cell.

Access this article for FREE for 6 weeks!

Src homology 2 domain proteomimetics: developing phosphopeptide selective receptors
Joel A. Drewry, Steven Burger, Amir Mazouchi, Eugenia Duodu, Paul Ayers, Claudiu C. Gradinaru and Patrick T. Gunning

Also in this issue are the following 2 reviews:

The use of phosphate bioisosteres in medicinal chemistry and chemical biology
Thomas S. Elliott, Aine Slowey, Yulin Ye and Stuart J. Conway

M1 muscarinic cetylcholine receptor allosteric modulators as potential therapeutic opportunities for treating Alzheimer’s disease
Michael Decker and Ulrike Holzgrabe

Check out all this and more in the complete online issue

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The use of phosphate bioisosteres in medicinal chemistry and chemical biology

25 Jun 2012

This review from Stuart J. Conway and colleagues at University of Oxford and University of St Andrews, presents the major functional groups that have been employed as phosphate bioisoteres and the context of their use and deployment explained, including:

Phosphorus-based phosphate bioisosteres
Sulfur-based bioisosteres
Carboxylate-based bioisosteres
Heterocyclic-based bioisosteres
Squaric acid and squaramide-based phosphate bioisosteres
Phosphate bioisosteres containing other heteroatoms

Conway et al. hope that this review will provide a useful reference to medicinal chemists and chemical biologists alike who are involved in designing molecules that target phosphate-binding proteins.

The use of phosphate bioisosteres in medicinal chemistry and chemical biology
Thomas S. Elliott, Aine Slowey, Yulin Ye and Stuart J. Conway
Med. Chem. Commun., 2012
DOI: 10.1039/C2MD20079A

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Review: M1 muscarinic cetylcholine receptor allosteric modulators as potential therapeutic opportunities for treating Alzheimer’s disease

18 Jun 2012

Despite the tremendous advances in investigating the molecular mechanisms of Alzheimer’s disease and its relevance for society there is an alarming lack of drugs for clinical treatment. Apart from the NMDA antagonist memantine, several acetylcholinesterase inhibitors have been approved for symptomatic treatment of early stages of Alzheimer’s disease.

In this MedChemComm review Michael Decker and Ulrike Holzgrabe present a review of the different chemical structures of allosteric agonists and modulators of the muscarinic acetylcholine receptor subtype 1 (mAChR₁ or M₁) and their relevance for possible treatment of Alzheimer’s disease. The discussion also focuses on:

Their design principles,
Common structural properties,
Unique features with regard to structure–activity relationships (SARs)

M₁ muscarinic cetylcholine receptor allosteric modulators as potential therapeutic opportunities for treating Alzheimer’s disease
Michael Decker and Ulrike Holzgrabe
DOI: 10.1039/C2MD20025B

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MedChemComm issue 6 published online

01 Jun 2012

The front cover of this issue of MedChemComm highlights the work of Philip J. Johnson, Mikhail Y. Berezin and colleagues. As part of the long term goal of developing nerve specific near infrared (NIR) molecular probes capable of non-invasively assessing peripheral nerve damage, in this concise article Berezin et al. present a study on the identification of a NIR dye suitable for such probes, focusing on a novel highly hydrophilic and functionalisable polymethine dye, and its more hydrophobic analogue indocyanine green.

A NIR dye for development of peripheral nerve targeted probes
Tiffany P. Gustafson, Ying Yan, Piyaraj Newton, Daniel A. Hunter, Samuel Achilefu, Walter J. Akers, Susan E. Mackinnon, Philip J. Johnson and Mikhail Y. Berezin
DOI: 10.1039/C2MD00297C

Also in this issue is the review by Georges Vauquelin on:
Determination of drug–receptor residence times by radioligand binding and functional assays: experimental strategies and physiological relevance
DOI: 10.1039/C2MD20015E

View the entire issue here….

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Review: Determination of drug–receptor residence times by radioligand binding and functional assays: experimental strategies and physiological relevance

29 May 2012

Previously drug–receptor interactions have only been quantified in terms of their affinity and efficacy but recently the residence time has also been recognized to affect the clinical performance.

In this review Georges Vauquelin aims to try and help chemists to better evaluate the relevance of the kinetic data that may be obtained from compounds by discussing, with the aid of simulations, the different approaches to measure drug binding kinetics that are currently used to measure and calculate ligand–receptor dissociation kinetics, as well as covering some of the potential pitfalls associated with these methods.

To find out more about the finer points of drug–receptor residence times and see how this can help you, read the review now!

Determination of drug–receptor residence times by radioligand binding and functional assays: experimental strategies and physiological relevance
Georges Vauquelin
DOI: 10.1039/C2MD20015E

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Review: Labile natural products

28 May 2012

Natural product isolation has developed as techniques have advanced e.g. improvements in chromatographic methodologies, however isolating labile natural products remains a large difficulty due to their inherent instability. Such is their instability that even the removal of solvents in vacuo, a common step during isolation, can destroy them. As such new careful isolation techniques are needed to offer access to new natural products and their biosynthetic intermediates.

In this review Toshiyuki Wakimoto and Ikuro Abe discuss the current success in isolating labile natural products. Examples highlighted by Wakimoto and Abe include:
–Red pigments from a hippopotamus
-Labile polyketides from filamentous fungi
-Cyclopropene carboxylic acids from mushrooms
-Aziridine carboxylic acids from mushrooms
-Furan fatty acids from mussels

Labile natural products
Toshiyuki Wakimoto and Ikuro Abe
DOI: 10.1039/C2MD20016C

This review is part of MedChemComm’s Natural Products themed issue. Check out the rest of the articles appearing in this issue today…..

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Review: Latent antibiotics and the potential of the arylomycins for broad-spectrum

18 May 2012

Antibiotic resistance in bacterial pathogens is becoming increasingly common and so there is a need for the development of new antibiotics, which act in novel ways, to counter-act this. In this review, featuring in MedChemComm‘s Natural Products themed issue, Yun Xuan Tan and Floyd E. Romesberg (The Scripps Research Institute) review the arylomycins, the recently discovered class of natural product antibiotics that inhibit bacterial type I signal peptidase (SPase), an endoprotease that is required for the translocation of most proteins across the cytoplasmic membrane.

Tan and Romesberg assess how the total synthesis of several members of this family of natural products has allowed studies which show that their spectrum of activity is broader than previously thought. The discussion goes on to how the arylomycins may represent “latent” antibiotics, antibiotics that have scaffolds that once had potent and broard-spectrum activity, and how these are more likely to be optimised to regain this activity than other scaffolds that have never been antibiotics.

Read the full review to find out all the facts

If you liked that, then take a look at the other published articles. We’re sure you will find something that will grab your attention.

Latent antibiotics and the potential of the arylomycins for broad-spectrum antibacterial activity
Yun Xuan Tan and Floyd E. Romesberg
Med. Chem. Commun., 2012, DOI: 10.1039/C2MD20043K

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Potent inhibition of Ca2+-dependent activation of calpain-1 on the cover of issue 5

03 May 2012

The cover of MedChemComm issue 5 is by Rudolf K. Allemann et al., whose concise article presents the synthesis of a series of monohalide mercaptoacrylic acid derivatives, and looks at the structure activity relationship in order to investigate the ability of these molecules to inhibit the Ca²⁺ activation of calpain-1, which is linked with tissue inflammation.

Potent inhibition of Ca²⁺-dependent activation of calpain-1 by novel mercaptoacrylates
Sarah E. Adams, Christian Parr, David J. Miller, Rudolf K. Allemann and Maurice B. Hallett
Med. Chem. Commun., 2012,
DOI: 10.1039/C2MD00280A

As with all our covers, this work will be free to access for the next 6 weeks.

You may also be interested in the 3 reviews in the issue on how enantiomeric pairs reveal that key medicinal chemistry parameters vary more than simple physical property based models can explain, small-molecule inhibitors of dimeric transcription factors and Gd(III) chelates for MRI contrast agents.

Find the entire issue right here

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Review: Aminoacyl tRNA synthetases as targets for antibiotic development

30 Apr 2012

In this review from MedChemComm‘s forthcoming Natural Product themed issue, Vinayak Agarwal and Satish K. Nair (University of Illinois at Urbana-Champaign) review a number of small molecule natural products, that target aminoacyl tRNA synthetases, which are available for development into useful antibiotics. In particular Agarwal and Nair focus on three different chemical classes:

Molecules derived from polyketide precursors
Molecules that occur as phosphoramidate conjugates
Promising synthetic molecules with distinct modes of action to molecules of class 1 and 2

The factors that undermine the broad-based use of some of these molecules as effective antibiotics in humans are also discussed, as well as strategies to aid in directing development of derivatives with improved pharmacological properties.

Aminoacyl tRNA synthetases as targets for antibiotic development
Vinayak Agarwal and Satish K. Nair
Med. Chem. Commun., 2012,
DOI: 10.1039/C2MD20032E

We will be bringing you more examples of work from this themed issue, guest edited by Professor Christopher T. Walsh andDr Sylvie Garneau-Tsodikova, over the next few weeks so make sure you check back for more.

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Review: Discrete acyltransferases involved in polyketide biosynthesis

18 Apr 2012

In this review Ewa Maria Musiol and Tilmann Weber at Eberhard Karls University, Tübingen present a summary of genetically and biochemically characterized in trans active ATs, which supply polyketide synthases assembly lines with building blocks and thus, might influence the polyketide structure by their substrate selectivity.

Included in this review are discussions on:

MmpC involved in mupirocin biosynthesis
OzmM and OzmC involved in oxazolomycin biosynthesis
RhiG involved in rhizoxin biosynthesis
VirI involved in virginiamycin biosynthesis
TaV involved in myxovirescin biosynthesis
BryP involved in bryostatin biosynthesis

…. and many more.

Discrete acyltransferases involved in polyketide biosynthesis
Ewa Maria Musiol and Tilmann Weber
Med. Chem. Commun., 2012,
DOI: 10.1039/C2MD20048A

This review is part of our forthcoming themed issue on Natural Products, guest edited by Professor Christopher T. Walsh and Dr Sylvie Garneau-Tsodikova – keep checking back for more hot research in this theme.

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