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Diaryl ether derivatives as anticancer agents – a review

22 Oct 2012

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

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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Bacterial growth is inhibited by broccoli

08 Oct 2012

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

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

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

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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An anion structure–activity relationship of imidazolium-based synthetic transporters

25 Sep 2012

The study of the mechanisms of transport of anions in general, and particularly those relating to Cl^–, has slowly been gaining significance, with a number of synthetic peptides with selective anionophoric properties on chloride being recently recently reported.

In a previous Communication Andreea R. Schmitzer and colleagues at University of Montréal demonstrated that imidazolium salts with low molecular weights have anionophoric properties, and that it was also possible to modulate the Cl^– transport across a bilayer by complexing the imidazolium salt with cyclodextrins and cucurbituril, i.e. the anionic diffusion through the membrane could be activated or inhibited.

In this MedChemComm article Schmitzer et al. report the factors intrinsic to the imidazolium salts that are responsible for the salts’ ionophoric activity by:

1)   Using the lucigenin method to demonstrate the influence of the nature of the imidazolium counter-anion on its anionophoric activity across the membrane of egg yolk phosphatidylcholine (EYPC) liposomes.
2)   Describing the efflux of different anions using the pH-sensitive HPTS (8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt) method.
3)   Presenting the kinetic parameters of the most active imidazolium salt, the EC₅₀ and the rate constant characterising the efflux of the Cl^–

Read the complete study by following the link below….

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

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Review: Amino-derivatives of the sesquiterpene lactone class of natural products as prodrugs

18 Sep 2012

The sesquiterpene lactone class of natural products displays a diverse array of biological activities due to the presence of the α-methylene-γ-lactone motif. One of the limitations of is the intrinsic reactivity of the α-methylene-γ-lactone- motif which represents an electrophilic Michael acceptor that reacts with thiol nucleophiles and leads to undesired and toxic side effects

This review by David A. Colby et al. provides an interesting overview about an emerging prodrug approach that has been developed to overcome these problems in which an amine is added into the α-methylene-γ-lactone to mask this group from nucleophiles and increase solubility.

Included is a concise description of the medicinal chemistry of amino-derivatives of the sesquiterpene lactones, from early development in synthesis, to application in medicinal chemistry, to its move to a clinical candidate.

For the complete picture on this prodrug approach download the review now by following the link below…

Amino-derivatives of the sesquiterpene lactone class of natural products as prodrugs
James R. Woods, Huaping Mo, Andrew A. Bieberich, Tanja Alavanja and David A. Colby
DOI: 10.1039/C2MD20172K

The review features as part of MedChemComm’s New Talent issue; view the expanding collection of articles for this issue HERE

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Recent applications of multicomponent reactions in medicinal chemistry

05 Sep 2012

Multicomponent reactions (MCRs) are defined as being a one-pot process that involves the reaction of at least three components to form a single product that retains the majority of the atoms from the starting materials.

These reactions are atom economic, step efficient, and owing to their flexibility, have found applications in many fields of medicinal chemistry, such as cancer therapy and infectious diseases, where MCRs are powerful tools for drug discovery and development. The application in these fields is quite broad, ranging from initial lead structure identification to the generation of large libraries of analogues.

In this Review Romano V. A. Orru and colleagues from VU University Amsterdam highlight recent applications (2005-present) of multicomponent reactions in medicinal chemistry, discussing these applications by therapeutic field.

Read the full review…. Here

Recent applications of multicomponent reactions in medicinal chemistry
Paul Slobbe, Eelco Ruijter and Romano V. A. Orru

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Phosphofructokinase: structural and functional aspects and design of selective inhibitors

29 Aug 2012

Human African trypanosomiasis, also commonly known as sleeping sickness, is a disease that leads to many deaths worldwide and is caused by protozoan parasites. When in the bloodstream these parasites can only produce the ATP (adenosine triphosphate) they need to survive via a glycolytic pathway, making this pathway essential for the parasite’s survival.

Phosphofructokinase is a kinase enzyme that phosphorylates fructose 6-phosphate in the glycolysis metabolic pathway, and is of central importance to carbohydrate metabolism. As such it is a very promising target for anti-trypanosomal drug design to treat sleeping sickness.

In this review Renata B. Oliveira et al. present a survey of recent literature regarding the structural and functional properties of phosphofructokinase as well as discussing its importance as a target in the development of selective therapeutics to treat Human African trypanosomiasis.

Read the full review here…

Phosphofructokinase: structural and functional aspects and design of selective inhibitors
Stefânia N. Lavorato, Saulo F. Andrade, Thaïs H. A. Silva, Ricardo J. Alves and Renata B. Oliveira
DOI: 10.1039/C2MD20122D

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