RSC Medicinal Chemistry Blog

Type III secretion systems inhibitors – an updated comprehensive review

07 Nov 2012

Howard C. Hang (The Rockefeller University) et al.‘s review article reflects the latest updates on Type III secretion systems (T3SSs) inhibitors. ‘T3SSs are central to the virulence of many human Gram-negative pathogens such as Salmonella, Shigella, Pseudomonas, enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli,(EHEC), Vibrio, Yersinia, and Chlamydia’ explains Hang, and are exciting targets for anti-bacterial development.

The article not only provides the reader with a comprehensive view of the severall classes of small molecules that inhibit the secretion and translocation of bacterial effector proteins, their mode of action and prospects for clinical development, but also brings insights into the different methods developed to allow the screening of very large libraries of molecules.

A must-read for anyone interested in bacterial virulence and small molecule inhibitors.

Small molecules aimed at type III secretion systems to inhibit bacterial virulence
Lun K. Tsou, Paul D. Dossa and Howard C. Hang
Med. Chem. Commun., 2012, DOI: 10.1039/C2MD20213A

This review is part of MedChemComm’s New Talent themed issue:

Highlighting medicinal chemistry research in its broadest sense and showcasing the strength of research being carried out by tomorrow’s leaders in the field: view the collection grow

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TamiGold and tubulin polymerization inhibitors on MedChemComm’s covers this month

25 Oct 2012

By James Anson.

Wecome to MedChemComm Issue 11, 2012

Featuring on the front cover of this issue of MedChemComm is the work of Hansjörg Streicher and colleagues who report the strong and selective binding of 2 types of gold nanoparticles, decorated with the oseltamivir (aka TamifluTM) pharmacophore, to wild-type and resistant influenza virus strains. Streicher et al. describe how the particles interact with the virus neuraminidase rather than the hemagglutinin and could serve as a vantage point for novel influenza virus sensors.

‘TamiGold’: phospha-oseltamivir-stabilised gold nanoparticles as the basis for influenza therapeutics and diagnostics targeting the neuraminidase (instead of the hemagglutinin)
Mathew Stanley, Nicholas Cattle, John McCauley, Stephen R. Martin, Abdul Rashid, Robert A. Field, Benoit Carbain and Hansjörg Streicher
DOI: 10.1039/C2MD20034A

The inside front cover illustrates work by Ahmed Kamal et al. (CSIR-Indian Institute of Chemical Technology, Hyderabad), who have synthesized a new series of tetrazole based isoxazolines that show promising activity as tubulin polymerization inhibitors that could be developed for the treatment of cancer.

Synthesis of tetrazole–isoxazoline hybrids as a new class of tubulin polymerization inhibitors
Ahmed Kamal, A. Viswanath, M. Janaki Ramaiah, J. N. S. R. C. Murty, Farheen Sultana, G. Ramakrishna, Jaki R. Tamboli, S. N. C. V. L. Pushpavalli, Dhananjaya pal, Chandan Kishor, Anthony Addlagatta and Manika pal Bhadra
DOI: 10.1039/C2MD20085F

Enjoy FREE access to both articles for the next 6 weeks

Also in this issue, why not read the following 2 review articles:

Small molecules targeting phosphoinositide 3-kinases
Peng Wu and Yongzhou Hu
Med. Chem. Commun., 2012, 3, 1337-1355
DOI: 10.1039/C2MD20044A

Diaryl ether derivatives as anticancer agents – a review
Florence Bedos-Belval, Anne Rouch, Corinne Vanucci-Bacqué and Michel Baltas
Med. Chem. Commun., 2012, 3, 1356-1372
DOI: 10.1039/C2MD20199B

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Diaryl ether derivatives as anticancer agents – a review

22 Oct 2012

By James Anson.

This review article from Florence Bedos-Belval and co-workers at Université Paul Sabatier examines the possibility of diaryl ethers as a promising frame to design new anti-cancer agents.

Bedos-Belval et al. examine the diaryl ether scaffold found in natural products, related analogs and innovative molecules. Included in this examination is:

–   A look at encompassing synthesis,
–   Structure–activity relationships (SARs),
–   Studies on the biological action, namely in the context of anti-cancer activity.

Bedos-Belval et al. aim for this review is to show that the diaryl ether scaffold is an invaluable structure for the design of anticancer drugs.

Curious about diaryl ethers as anticancer agents? Read the full review today.

Diaryl ether derivatives as anticancer agents – a review
Florence Bedos-Belval, Anne Rouch, Corinne Vanucci-Bacqué and Michel Baltas
DOI: 10.1039/C2MD20199B

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Killing three parasites with one stone

19 Oct 2012

By James Anson.

Highlighting a MedChemComm article being featured in Chemistry World

Despite being the focus of much recent research, it is estimated that over 400 million people are currently infected with malaria, schistosomiasis or hookworm. As an attempt to help remedy this, scientists in the US have developed a hybrid drug that is active against all three of these parasitic diseases.

Over 400 million people are infected with malaria, schistosomiasis or hookworm (shown)

Although a variety of approaches have been developed for the treatment of these diseases, there are often toxic side effects associated with the drugs and widespread resistance to frequently used molecules has developed. To help improve the drugs on offer for those infected, Bryan Mott at the National Institutes of Health, and co-workers, have been investigating combined therapeutics, which can be especially useful for multiple parasites endemic in the same region.

The group developed a hybrid drug containing two heterocycles: furoxan and quinoline. The researchers had previously seen that furoxan had demonstrated significant anti-parasitic activity and quinoline has also shown promise in the chemotherapy of a variety of other diseases. It is likely that quninoline works by a different, perhaps complimentary, mechanism to furoxan, therefore the group’s rationale was that the combination of the two molecules could be beneficial.

Read the full story in Chemistry World

And read the full MedChemComm paper here:
A furoxan–amodiaquine hybrid as a potential therapeutic for three parasitic diseases
Bryan T. Mott et al.
DOI: 10.1039/C2MD20238G

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Understanding the stereochemistry of polyketide biosynthesis

16 Oct 2012

By Marie Cote, Deputy Editor.

Complex polyketides are a pharmaceutically important group of natural product compounds which present an elaborate stereochemistry, set up by ketoreductase enzymes that can control the the orientation of the substituents during polyketide biosynthesis.

One of the challenges ahead is the reliable engineering of modular polyketide synthases to produce new polyketides for drug development.

In this review, Jianting Zheng and Adrian Keatinge-Clay present a summary of the recent advances in understanding the stereocontrol of ketoreductases in modular polyketide synthases from biochemical, engineering and structural studies, providing a critical view on the mechanisms of ketoreductase stereocontrol. This timely review covers a number of outstanding questions surrounding their selectivity, activity, and engineering potential.

Curious? Why not read it now:

The status of type I polyketide synthase ketoreductases
Jianting Zheng and Adrian T. Keatinge-Clay
Med. Chem. Commun., 2012, Advance Article
DOI:10.1039/C2MD20191G, Review Article
From collection New Talent

This review is part of MedChemComm’s New Talent themed issue

Highlighting medicinal chemistry research in its broadest sense and showcasing the strength of research being carried out by tomorrow’s leaders in the field: view the collection grow

Interested in the Structural Aspects of Biosynthesis?

Why not view our sister journal Natural Product Reports‘ themed issue on the topic.

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Bacterial growth is inhibited by broccoli

08 Oct 2012

By James Anson.

Broccoli and Brussels sprouts contain compounds that can inhibit the growth of bacteria that cause disease

Chemists from Israel say that the isothiocyanates sulforaphane and erucin, found in brassicaceae vegetables such as broccoli, Brussels sprouts, cabbage and cauliflower, inhibit growth of the disease-causing bacteria Pseudomonas aeruginosa.

Bacterial quorum sensing (QS) is the method by which bacteria communicate. Instead of language, they release signalling molecules into the environment and a single cell can sense the number of other local bacteria. By using QS, bacteria can coordinate their behaviour through gene expression and adapt to changing environmental conditions. With bacteria such as MRSA and Pseudomonas aeruginosa developing antibiotic resistance, alternative strategies to inhibit bacterial growth are necessary and QS inhibition has been suggested as a new strategy to prevent bacterial growth.

The team, led by Michael Meijler from Ben-Gurion University of the Negev, Be’er-Sheva, found that isothiocyanates from broccoli inhibit quorum sensing. ‘This might signal to the bacteria that conditions for colonisation are not optimal,’ he explains. ‘The benefits of eating vegetables to human health in general have been known for quite some time now. At the molecular level, not a great deal is known yet, providing a fertile ground for fundamental research.’

Read the entire Chemistry World story

And then read the full MedChemComm paper:
Sulforaphane and erucin, natural isothiocyanates from broccoli, inhibit bacterial quorum sensing
Hadas Ganin, Josep Rayo, Neri Amara, Niva Levy, Pnina Krief and Michael M. Meijler
DOI: 10.1039/C2MD20196H

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Approaches to discover non-ATP site kinase inhibitors – a review by Lori Krim Gavrin

03 Oct 2012

By James Anson.

Major challenges currently exist in kinase research, such as being able to achieve selectivity between the large numbers of similarly structured family members all processing the same substrate. In addition to requiring this selectivity, ATP site inhibitors must also bind tightly to the kinase catalytic centre to overcome the high physiological concentration of ATP in the cell. And, as many ATP competitive scaffolds have already been discovered, the development of novel ATP site inhibitors is becoming increasingly more difficult.

In order to overcome these challenges and develop compounds with better selectivity among kinases, great interest is being paid to inhibitors that bind outside the ATP site. In this review Lori Krim Gavrin and Eddine Saiah, Pfizer, highlight the most commonly used methods to discover Type III (small molecule inhibitors that exclusively bind in a pocket adjacent to the ATP site) and IV kinase inhibitors (those that bind to a site remote from the ATP binding pocket). Included in the review are discussions on:

–Screens to identify non-ATP site kinase binders
-Computational methods to identify non-ATP site kinase binders
-Small molecule spin-labeled probes to identify non-ATP site kinase binders

This review is part of MedChemComm’s New Talent themed issue; read the full article and visit the MedChemComm webpage to see other articles from this collection.

Approaches to discover non-ATP site kinase inhibitors
Lori Krim Gavrin and Eddine Saiah
DOI: 10.1039/C2MD20180A

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MedChemComm issue 10 now available online

27 Sep 2012

By James Anson.

An overview of the latest issue of MedChemComm

The interesting image on the front cover of this month’s issue of MedChemComm is courtesy of Neil Vasdev and colleagues. Vasdev et al. present work which is aimed at developing a PET radiotracer based on a hydroxyquinoline chelator, and evaluates its potential for detecting amyloid plaques via imaging studies in transgenic rodent models.

Synthesis and PET imaging studies of [18F]2-fluoroquinolin-8-ol ([18F]CABS13) in transgenic mouse models of Alzheimer’s disease
Neil Vasdev et al.
DOI: 10.1039/C2MD20075A

The inside cover highlights the HOT article of Andreea R. Schmitzer and co-workers who report the factors intrinsic to imidazolium salts that are responsible for the salts’ ionophoric activity, allowing them to act as synthetic ion transporters.

An anion structure–activity relationship of imidazolium-based synthetic transporters
Claude-Rosny Elie, Mathieu Charbonneau and Andreea R. Schmitzer
DOI: 10.1039/C2MD20107K

Download both articles for free for the next 6 weeks.

Also in this issue is this HOT article from James S. Scott:

Reduction of acyl glucuronidation in a series of acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors: the discovery of AZD6925

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Reduction of acyl glucuronidation in a series of acidic 11β-HSD1 inhibitors: the discovery of AZD6925

27 Sep 2012

By James Anson.

This article is HOT as recommended by the referees, and is free to access for 4 weeks.

Metabolic syndrome is a combination of medical disorders that, when occurring together, increases the risk of developing cardiovascular disease and diabetes. It has been previously suggested that elevated levels of the hormone cortisol can contribute to the development of the metabolic syndrome.

11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) is an NADPH dependent reductase that converts the glucocorticoid inactive hormone cortisone to the glucocorticoid active hormone cortisol. As such, inhibition of this enzyme has been proposed as a potential target for the treatment of obesity and other contributors to the metabolic syndrome.

In this paper James S. Scott and colleagues report the optimisation of a carboxylic acid class of inhibitors from AZD4017 to the development candidate AZD6925. The novel acidic inhibitors of 11b-HSD1 show excellent pharmacokinetic profiles, and based on the reduced acyl glucuronidation liability and the overall profile, Scott et al. select one compound selected for development as AZD6925 which is to be progressed into toxicity studies.

Reduction of acyl glucuronidation in a series of acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors: the discovery of AZD6925
James S. Scott et al.
DOI: 10.1039/C2MD20154B

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RSC Medicinal Chemistry Blog

Type III secretion systems inhibitors – an updated comprehensive review

Top 5 most downloaded articles

TamiGold and tubulin polymerization inhibitors on MedChemComm’s covers this month

Diaryl ether derivatives as anticancer agents – a review

Killing three parasites with one stone

Understanding the stereochemistry of polyketide biosynthesis

Bacterial growth is inhibited by broccoli

Approaches to discover non-ATP site kinase inhibitors – a review by Lori Krim Gavrin

MedChemComm issue 10 now available online

Reduction of acyl glucuronidation in a series of acidic 11β-HSD1 inhibitors: the discovery of AZD6925

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