Archive for the ‘Hot articles’ Category

Synthesis of novel thiadiazole derivatives as selective COX-2 inhibitors – a new HOT article

New, effective and selective COX-2 inhibitors that prevent inflammation have been reported in MedChemComm, in a new HOT article.

Cyclo-oxygenases are enzymes responsible for production of key inflammation-promoting molecules. Most drugs that target COX are non-selective and inhibit both COX-2, present in inflamed tissues, and COX-1, which has important regulatory functions in normal tissues. This can lead to gastro-intestinal side-effects such as ulcers.

Dr Marwa El-Gazzar’s group at the National Centre for Radiation Research and Technology in Cairo synthesized new derivatives of celecoxib, a recently discovered COX-2 selective inhibitor. They tested their effect on COX-2 in vitro to study their structure-activity relationship. Several of the compounds – many of which had sulfonamide moieties – were as effective as celecoxib at inhibiting COX-2, while having no effect on COX-1. These compounds were also the most effective at reducing paw oedema in rat models of inflammation, and had significant analgesic effects – importantly, they were non-toxic and did not cause ulceration.

The designed 1,3,4-thiadiazole derivatives and their proposed orientation into the selectivity site of COX-2.

The group also performed a molecular docking study to gain insight into the compounds’ inhibition mechanism. The compounds were found to strongly bind to the COX-2 active site, making them more effective. They could also enter a small pocket found only in COX-2 to bind to specific residues there – this gave them their selectivity.

The promising results for the reported compounds, as well as the mechanistic insights gained, could prove invaluable in developing new, selective drugs that can successfully treat inflammation without adverse side effects.


Read the full article here:

Synthesis of novel thiadiazole derivatives as selective COX-2 inhibitors
Fatma A. Ragab, Helmi I. Heiba, Marwa G. El-Gazzar,* Sahar M. Abou-Seri, Walaa A. El-Sabbagh and Reham M. El-Hazek
Med. Chem. Commun., 2016, Advance Article
DOI10.1039/C6MD00367B




Susannah May is a guest web writer for the RSC Journal blogs. She currently works in the Publishing Department of the Royal Society of Chemistry, and has a keen interest in biology and biomedicine, and the frontiers of their intersection with chemistry. She can be found on Twitter using @SusannahCIMay.

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PNA-encoded libraries can selectively identify covalently bound molecules – HOT article

A new way of screening for small molecules using PNA-encoded libraries has been reported in MedChemComm. The technique, by Nicolas Winssinger’s group at the University of Geneva, identifies molecules that bind covalently to specific proteins. It could help to find new potent drugs in future.

DNA or PNA-encoded libraries are becoming a popular technique to easily screen large numbers of small molecules. However, it is often difficult to distinguish covalently binding molecules from those that bind non-covalently but with high affinity. Researchers are especially interested in covalent inhibitors as they permanently deactivate proteins and can make powerful drugs, with examples including aspirin and omeprazole.

Winssinger’s group synthesised two libraries of small molecules that were tagged with PNA “barcodes” and immobilised on a surface to form microarrays. These were incubated with a kinase solution and then washed. The group used a washing procedure which removed kinase bound with high-affinity non-covalent bonds, but left any kinase that was covalently bound to molecules. The DNA-PNA bonds were undamaged by the washing, and allowed easy identification and discrimination of the covalently bound and non-covalently bound molecules.

The method could be combined with other techniques such as next-generation sequencing in future. It promises to be the next step in efficient and rapid drug discovery.


Read the full article here:

Screening for covalent inhibitors using DNA display of small molecule libraries functionalized with cysteine reactive moieties
C. Zambaldo, J.-P. Daguer, J. Saarbach, S. Barluenga and N. Winssinger
Med. Chem. Commun. 2016, 7, 1340-1351

Part of the DNA Encoded Libraries themed collection in MedChemComm.




Susannah May is a guest web writer for the RSC Journal blogs. She currently works in the Publishing Department of the Royal Society of Chemistry, and has a keen interest in biology and biomedicine, and the frontiers of their intersection with chemistry. She can be found on Twitter using @SusannahCIMay.

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Recent HOT MedChemComm articles

The following MedChemComm articles have all been recommened by the reviewers of the articles as being particularly interesting or particularly significant research. These have all been made free to access until 12th December 2014. The order they appear in the list holds no special meaning or ranking.

Imidazole derivatives show anticancer potential by inducing apoptosis and cellular senescence
Gangavaram V. M. Sharma, Adepu Ramesh, Ashita Singh, Gourishetty Srikanth, Vankudoth Jayaram, Divya Duscharla, Jung Ho Jun, Ramesh Ummanni and Sanjay V. Malhotra  
DOI: 10.1039/C4MD00277F, Concise Article

C4MD00277F


Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor
Katherine S. England, Anthony Tumber, Tobias Krojer, Giuseppe Scozzafava, Stanley S. Ng, Michelle Daniel, Aleksandra Szykowska, KaHing Che, Frank von Delft, Nicola A. Burgess-Brown, Akane Kawamura, Christopher J. Schofield and Paul E. Brennan  
DOI: 10.1039/C4MD00291A, Concise Article
From themed collection Epigenetics

C4MD00291A GA


Computationally motivated synthesis and enzyme kinetic evaluation of N-(β-D-glucopyranosyl)-1,2,4-triazolecarboxamides as glycogen phosphorylase inhibitors
Jaida Begum, Gergely Varga, Tibor Docsa, Pál Gergely, Joseph M. Hayes, László Juhász and László Somsák  
DOI: 10.1039/C4MD00335G, Concise Article

C4MD00335G GA


Synthesis and biological evaluation of a series of aryl triazoles as firefly luciferase inhibitors
Haixiu Bai, Peng Zhu, Wenxiao Wu, Jing Li, Zhao Ma, Wei Zhang, Yanna Cheng, Lupei Du and Minyong Li  
DOI: 10.1039/C4MD00368C, Concise Article

C4MD00368C GA


Rational design of protein–protein interaction inhibitors
Didier Rognan  
DOI: 10.1039/C4MD00328D, Review Article

C4MD00328D GA

 

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Recent HOT MedChemComm articles

The following are HOT articles, as recommened by the reviewers of the articles. These have all been made free to access until 24th October:

Structure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomain
Apirat Chaikuad, Andrew M. Petros, Oleg Fedorov, Jing Xu and Stefan Knapp
Med. Chem. Commun., DOI: 10.1039/C4MD00237G, Concise Article
From themed collection Epigenetics


Gold compounds as aquaporin inhibitors: new opportunities for therapy and imaging
Andreia de Almeida, Graça Soveral and Angela Casini
Med. Chem. Commun., DOI: 10.1039/C4MD00265B, Review Article


A novel surface-coated nanocarrier for efficient encapsulation and delivery of camptothecin to cells
Rie Wakabayashi, Ryutaro Ishiyama, Noriho Kamiya and Masahiro Goto
Med. Chem. Commun., DOI: 10.1039/C4MD00179F, Concise Article
From themed collection In celebration of Seiji Shinkai’s 70th Birthday


Peptide HIV fusion inhibitors: modifications and conjugations
Wei Liu, Jianjun Tan, Mohammadreza Mohammadzad Mehryar, Zhiping Teng and Yi Zeng
Med. Chem. Commun., 2014, Advance Article
DOI: 10.1039/C4MD00214H, Review Article


3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors
Craig J. Kutz, Steven L. Holshouser, Ethan A. Marrow and Patrick M. Woster
Med. Chem. Commun., 2014, Advance Article
DOI: 10.1039/C4MD00283K, Concise Article
From themed collection Epigenetics

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Recent HOT MedChemComm articles

Check out the following HOT articles, these have been made free to access for a limited time:

Recognition of diazirine-modified O-GlcNAc by human O-GlcNAcase
Andrea C. Rodriguez and Jennifer J. Kohler
Med. Chem. Commun., 2014,5, 1227-1234
DOI: 10.1039/C4MD00164H

Recognition of diazirine-modified O-GlcNAc by human O-GlcNAcase

Free to access until 21st August 2014


Evaluation of functional groups as acetyl-lysine mimetics for BET bromodomain inhibition
Phillip P. Sharp, Jean-Marc Garnier, David C. S. Huang and Christopher J. Burns
Med. Chem. Commun., 2014, Advance Article
DOI: 10.1039/C4MD00182F

Evaluation of functional groups as acetyl-lysine mimetics for BET bromodomain inhibition

Free to access until 21st August 2014


Beyond substrate analogues: new inhibitor chemotypes for glycosyltransferases
Lauren Tedaldi and Gerd K. Wagner
Med. Chem. Commun., 2014,5, 1106-1125
DOI: 10.1039/C4MD00086B

Beyond substrate analogues: new inhibitor chemotypes for glycosyltransferases

Free to access until 21st August 2014

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Some HOT MedChemComm articles for March

Emerging classes of armed antibody therapeutics against cancer
Christian Hess, Dario Venetz and Dario Neri  
Med. Chem. Commun., 2014,5, 408-431
DOI: 10.1039/C3MD00360D

Emerging classes of armed antibody therapeutics against cancer

Free to access until 25th April


Cysteine-reactive chemical probes based on a modular 4-aminopiperidine scaffold
Shalise M. Couvertier and Eranthie Weerapana
Med. Chem. Commun., 2014,5, 358-362
DOI: 10.1039/C3MD00289F

Cysteine-reactive chemical probes based on a modular 4-aminopiperidine scaffold

Free to access until 25th April

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HOT MedChemComm articles for November

Design, synthesis, and preliminary ex vivo and in vivo evaluation of cationic magnetic resonance contrast agent for rabbit articular cartilage imaging
Takayoshi Irie, Kazuhiro Oda, Akihiko Shiino, Mitsuhiko Kubo, Shigehiro Morikawa, Noboru Urushiyama, Shuji Aonuma, Takahide Kimura, Toshiro Inubushi, Toshitaka Oohashi and Naoki Komatsu  
Med. Chem. Commun., 2013, DOI: 10.1039/C3MD00229B

Free to access until 13th December

Design, synthesis, and preliminary ex vivo and in vivo evaluation of cationic magnetic resonance contrast agent for rabbit articular cartilage imaging

 


 

Small-molecule Inhibitors of SREBP Activation – Potential for New Treatment of Metabolic Disorders
Mizuki Watanabe and Motonari Uesugi  
Med. Chem. Commun., 2013, DOI: 10.1039/C3MD00177F

Free to access until 13th December

Small-molecule Inhibitors of SREBP Activation – Potential for New Treatment of Metabolic Disorders

 


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HOT: A critical assessment of modeling safety-related drug attrition

In this HOT perspective, Hasselgreen and co-workers at AstraZeneca R&D Mölndal, reflect on the tough crisis that has afflicted the pharmaceutical industry in recent years, where the increased R&D budgets have not translated into new valuable products. This review offers an excellent overview of aspects and practicalities involved in preclinical toxicity prediction and analysis. The authors inspect commonly used guidelines/rules in medicinal chemistry aimed at reducing toxicity wondering if a simple distinction between compounds that have safety liabilities and “clean” compounds really exists. And crucially, they reflect on the impact of applying such guidelines on compounds progressing to clinical phases or even further and becoming approved drugs.

A critical assessment of modeling safety-related drug attrition

A critical assessment of modeling safety-related drug attrition
Daniel Muthas, Scott Boyer and Catrin Hasselgren
DOI: 10.1039/C3MD00072A

Free to access for 4 weeks

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Drug discovery: on the origins of drug polypharmacology – a review

‘The ability of many drugs, unintended most often, to interact with multiple proteins is commonly referred to as polypharmacology. Could this be a reminiscent chemical signature of early protein evolution?’ asks Jordi Mestres.

In this review article, Xavier Jalencas and Jordi Mestres (Chemogenomics Laboratory, Hospital del Mar Research Institute, Barcelona) explore the origins of drug polypharmacology and provide clues as to why most drugs hit multiple targets. Covering both the chemical (including molecular properties and fragment composition of the drug themselves) and the biological sources of polypharmacology (describing target phylogeny and binding site similarity), the article also provides some direct key implications of polypharmacology for drug discovery, while questioning whether this multitarget ability could have come from adaptative mechanisms…

Take this fascinating journey and read the full review today!

On the origins of drug polypharmacology
Xavier Jalencas and Jordi Mestres
Med. Chem. Commun, 2013, Advance Article
DOI:10.1039/C2MD20242E

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

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Type III secretion systems inhibitors – an updated comprehensive review

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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