RSC Medicinal Chemistry Blog

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.

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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

By James Anson.

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

By James Anson.

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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Themed issue: still time to submit to the Drugs in Middle Space themed issue

14 Jun 2012

By Richard Kelly.

There’s still time to submit to the MedChemComm web themed issue on Drugs in Middle Space. Guest edited by David Rees (Astex Therapeutics, UK) and Nick Terrett (Ensemble Therapeutics, USA) this issue will feature research and review articles focussing on non-traditional drug molecules that occupy the ‘middle space’ between ‘Rule of 5’ compliant small molecules and biologicals.

Deadline for submission: 30th September 2012

Appropriate topics include the design, synthesis, optimization, modelling, analysis and profiling of peptides, peptidomimetics, macrocycles, natural products, natural product mimetics, and any other molecule in range of approximately 500 to 3000 Daltons. We will seek an emphasis on how this range of structural classes is providing novel approaches to address challenging disease targets and in particular those that might hitherto have been categorised as ‘undruggable’.

Submissions for this issue can be submitted anytime from now until 30th September 2012 using the journal’s online submission system. Please add the phrase ‘Invited article for Drugs in Middle Space’ in the comments to the editor field. All manuscripts will undergo strict peer review and will be assessed using the same criteria as for regular MedChemComm articles.

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Review: Natural products inhibitors of glucose-6-phosphate translocase

07 Jun 2012

By Marie Cote, Deputy Editor.

This mini-review authored by Prof. Chaitan Khosla and coworkers at Stanford University (CA, USA) provides a
concise overview of natural product inhibitors of the glucose-6-phosphate translocase (G6P T1) system.

Non-insulin dependant diabetes (type II) and carcinogenesis are two major diseases in which abberant glucose levels are observed, and for which glucose-6-phosphate translocase could be a promising therapeutic target. Enzyme G6P T1 hydrolyses glucose-6-phosphate to glucose, which is then released into the bloodstream: modulating its activity may prove an attractive therapeutic strategy.

Following an overview of the role of glucose-6-phosphate translocase in human physiology and its potential as a therapeutic target, the review covers its Natural Product inhibitors, including:

Chlorogenic acid and chlorogenic acid derivatives
Phloretin
Salicilic acid derived G6P T1 inhibitors
Kodaistatins
Mumbaistatins and Mumbaistatins derivatives

Natural product inhibitors of glucose-6-phosphate translocase
Louise K. Charkoudian, Bailey P. Farrell and Chaitan Khosla
Med. Chem. Commun., 2012

Access the article by Chaitan Khosla et al. – Access the full collection on Natural Products

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MedChemComm issue 6 published online

01 Jun 2012

By James Anson.

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

By James Anson.

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

By James Anson.

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

By James Anson.

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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RSC Medicinal Chemistry Blog

Get your hands on MedChemComm issue 7 today!

The use of phosphate bioisosteres in medicinal chemistry and chemical biology

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

Themed issue: still time to submit to the Drugs in Middle Space themed issue

Review: Natural products inhibitors of glucose-6-phosphate translocase

Top ten most accessed article in April

MedChemComm issue 6 published online

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

Review: Labile natural products

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

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