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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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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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Issue 2 now online including hot articles on epigenetics

06 Feb 2012

On the cover of this month’s issue is an article from our Epigenetics collection from Manfred Jung, looking at the potential of small molecule inhibitors of acetyl lysine–bromodomain interactions.

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

The issue also contains several other epigenetics articles on second generation epigenetic agents, epigenetics as a source of new drug targets and thiobarbiturates inhibitors. The epigenetics issue was guest edited by Rasmus Prætorius Clausen (University of Copenhagen) and Mark Bunnage (Pfizer) – read their introduction to the issue.

View Issue 2

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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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Chagas disease: selenosemicarbazones as new leads to beat drug resistant parasite

05 Jan 2012

Scientists from Uruguay and the US have made new compounds that could be used to treat Chagas disease. Chagas disease is a parastic disease caused by the protozoan Trypanosoma cruzi. It affects an estimated 10 million people in South and Central America and results in 20 000 deaths each year.

The cysteine protease cruzipain is an essential T. cruzi enzyme and is one of the few validated drug targets for the disease. Current treatments include Nifurtimox and Benznidazole, but the cruzipain is becoming resistant to them.

Thiosemicarbazones have been described as cruzipain inhibitors. Now, the team have replaced the sulfur in these compounds with selenium to make selenosemicarbazones to find new drug leads. The selenosemicarbazones showed enhanced cysteine protease inhibitory activity compared to the thiosemicarbazones and to Benznidazole, one of the two current drugs on the market.

Selenosemicarbazones as Potent Cruzipain Inhibitors and their Antiparasitic Properties against Trypanosoma cruzi
Chiara Pizzo, Paula Faral-Tello, Gustavo Salinas, Martín Fló, Carlos Robello, Peter Wipf and Graciela Mahler
Med. Chem. Commun., 2011, Accepted Manuscript
DOI: 10.1039/C2MD00283C

Research on the Chagas and neglected diseases was also recently the subject of MedChemComm‘s latest poster prize.

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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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