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Archive for the ‘Hot articles’ Category

HOT Article: A step forward in the fight against cancer

01 Apr 2011

Novel water soluble bis(1,10-phenanthroline)octanedioate Cu²⁺ and Mn²⁺ complexes synthesised by researchers in Ireland and the US show extremely high cytotoxicity, encouraging cytoselectivity against cancer cells.

Mononuclear [Cu(phen)₂(phthalate)] complexes have been shown to display excellent chemotherapeutic potential against colon, breast and prostate cancer lines, but their water solubility is poor making them difficult to deliver in the body. This inspired Andrew Kellett, Michael Devereux and colleagues to build upon the most active chemotherapeutic agents in this class of compounds and develop more potent water soluble versions.

Both complexes displayed greater in vivo drug tolerance compared to cisplatin, a commonly used chemotherapy drug, when examined using the insect Galleria mellonella.

Read more now in the MedChemComm article that is free to download!

Water-soluble bis(1,10-phenanthroline) octanedioate Cu2+ and Mn2+ complexes with unprecedented nano and picomolar in vitro cytotoxicity: promising leads for chemotherapeutic drug development
Andrew Kellett, Mark O’Connor, Malachy McCann, Orla Howe, Alan Casey, Pauraic McCarron, Kevin Kavanagh, Mary McNamara, Sean Kennedy, Donald D. May, Philip S. Skell, Denis O’Shea and Michael Devereux
Med. Chem. Commun., 2011, DOI: 10.1039/C0MD00266F

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HOT article: anionic gold nanoparticles for multi-strain flu virus inhibition

15 Mar 2011

One of the difficulties in vaccinating against annual flu pandemics is the myriad of different virus strains and the ability of the virus to rapidly mutate – which occurs so much faster than vaccine development.

Excitingly, however, Aharon Gedanken from Bar-Ilan University and colleagues from the Israeli Ministry of Health have developed a method of virus inhibition effective against several different strains, including H1N1 (swine flu). By using gold nanoparticles with anionic surface functional groups mercaptoethanesulfonate or mercaptosuccinic acid, the researchers were able to inhibit infection in MDCK cells, with no cytotoxic side effects. They believe the mode of action is due to the nanoparticles preventing the virus from attaching to the cell surface, but further research is currently under way to determine the exact mechanism.

This HOT article is currently free to access – download it today!

Effective multi-strain inhibition of influenza virus by anionic gold nanoparticles
Matias Sametband, Sourabh Shukla, Tal Meningher, Shira Hirsh, Ella Mendelson, Ronit Sarid, Aharon Gedanken and Michal Mandelboim
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C0MD00229A

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HOT perspective: drug discovery – overweight and in need of a psychologist?

09 Mar 2011

In this interesting review Michael Hann from GSK gives his take on why it is becoming harder and harder to bring drugs to market. The finger of blame, he suggests, points not just towards regulatory hurdles but to our ideas about the drug discovery process itself.

As well as examining the causes of failure in drug discovery in terms of lead candidate properties, he also takes a look at the behavioural psychology of the medicinal chemist. Hann suggests that the quest for the potency borders on addiction, and that while potency is an important aspect of drug design, it should not necessarily be the overarching goal. His reason – that the search for potency can lead to molecules that are too large and liphophilic to make it to market. He ironically coins the term ‘molecular obesity‘ to describe the risk that this presents to the fitness of lead compounds.

Whether you agree with Hann on the cause of failure or not, the 95% attrition rate of pharma R&D is indisputable; it would appear that drug discovery is in need of a check-up.

Download this though-provoking review today – it’s free to access until April:

Molecular obesity, potency and other addictions in drug discovery
Michael M. Hann
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00017A

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HOT: mending broken hearts – with water soluble flavonols

03 Mar 2011

Current treatments for heart attacks usually involve restoring blood flow to the heart and and removing the blockage that caused it in the first place. But what treatments are there for the oxygen-starved muscle? Well, currently, none.

The correct name for the damage caused to tissue by a lack of oxygen and nutrients is reperfusion injury, largely caused by the production of reactive oxygen species. Naturally occurring flavonoids – antioxidants found in fruit, tea, wine and chocolate – have been shown to have a positive effect on cardiovascular health and have been highlighted as promising treatments for heart disease. To date however, the poor aqueous solubility of the most promising flavonol candidates has prevented further therapeutic development – probably because the FDA has strong views on DMSO as an injecting solvent.

Now, researchers from Melbourne, Australia have synthesised water soluble prodrugs of some of those flavonols. Owen Woodman and co-workers synthesised phosphate and hemiadipate derivatives of flavonol, 4′-hydroxyflavonol and 3′,4′-dihydroxyflavonol which were shown to significantly decrease reperfusion injury in two distinct animal models. The group hopes this work will make a meaningful step towards the clinical application of hydroxylated flavonols.

Read the full details of this interesting study online – the article is currently free to access:

Water soluble flavonol prodrugs that protect against ischaemia-reperfusion injury in rat hindlimb and sheep heart
Spencer J. Williams, Colleen J. Thomas, Mirna Boujaoude, Carlie T. Gannon, Shannon D. Zanatta, Bevyn Jarrott, Clive N. May and Owen L. Woodman
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C0MD00240B

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HOT: Novel photocytotoxic glycosylated porphyrins to combat cancer

15 Feb 2011

Novel glycosylated porphyrins have recently been synthesised by researchers from Nanyang Technological University with increased cellular uptake and and photocytotoxicity towards human cancer cells. The groups, led by Ho Sup Yoon and Xue-Wei Liu, have demonstrated that the new compounds locate in the lysosomes of the cancer cells. This is in contrast to previously reported sugar-phorphyrin conjugates – which usually locate in the mitochondria or endoplasmic reticulum – and could provide a new angle for treating multidrug-resistant phenotype tumor cells.

The researchers attribute the enhanced cellular uptake and lysosomal location of the glycosylated porphyrins to the sugar moiety. The location of the compounds allowed the researchers to trigger cell death via apoptosis by selectively disrupting the lysosome. Studies are currently being undertaken to investigate the photodynamic activity in vivo on the most promising drug candidate.

The referees thought this paper was of ‘high technical merit’, read the full article online today – it’s free to access!

Glycosylated porphyrin derivatives and their photodynamic activity in cancer cells
Seenuvasan Vedachalam, Bo-Hwa Choi, Kalyan Kumar Pasunooti, Kun Mei Ching, Kijoon Lee, Ho Sup Yoon and Xue-Wei Liu
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C0MD00175A

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HOT: Silencing the threat of HIV

10 Feb 2011

HIV has proved a difficult disease to treat, constantly mutating to evade the drugs used to treat it. An alternative line of research to traditional drug therapies is the use of siRNA techniques, in which carefully crafted segments of genetic code interfere with the viral genetic code directly, disrupting the infection.

Prof. Jyoti Chattopadhyaya from Uppsala University and colleagues from India have synthesised modified siRNAs targetting the TAR region of HIV-1, some of which exhibit a four-fold enhanced half-life in serum over the native unmodified siRNA. The best compound synthesised had an IC50 more than three-fold lower than that of the native and two-fold lower than that of the existing locked nucleic acid (LNA) modified counterpart.

The strategy to chemically modify the native siRNAs by substitution with the jcLNA can be considered as a significant development, leading to both enhanced siRNA efficiency and serum stability over that of the native.

Read this HOT article for free in MedChemComm today!

Carba-LNA modified siRNAs targeting HIV-1 TAR region downregulate HIV-1 replication successfully with enhanced potency
Suman Dutta, Nipa Bhaduri, Neha Rastogi, Sunita G. Chandel, Jaya Kishore Vandavasi, Ram Shankar Upadhayaya and Jyoti Chattopadhyaya
Med. Chem. Commun., 2011, Advance Article

DOI: 10.1039/C0MD00225A

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Virtually sieving for new antibiotics

01 Feb 2011

The pesky ability of bacteria to develop resistance towards carefully constructed antibiotics constantly pushes researchers to develop novel compounds to annihilate them. Identifying new active compounds from the myriad of possibilities is a task made easier by computer-assisted ‘virtual screening‘, and now researchers from Germany and Switzerland have upped the ante once again with an even better process.

Gisbert Schneider and co-workers have developed a two-step screening process which they use to find small molecular aminoglycoside mimetics to inhibit bacterial protein biosynthesis. They screened a compound database using the pseudoreceptor approach with ‘fuzzy pharmacophore’ representations – which allows ‘scaffold-hopping’ to different ligand structures with retention of bioactivity – to find alternative chemotypes with lower structural complexity and greater synthetic accessibility.

Read how they did it here – the article’s free to access

Scaffold-hopping from aminoglycosides to small synthetic inhibitors of bacterial protein biosynthesis using a pseudoreceptor model
Dorota A. Urbanek, Ewgenij Proschak, Yusuf Tanrikulu, Steffi Becker, Michael Karas and Gisbert Schneider
Med. Chem. Commun. , 2011
DOI: 10.1039/C0MD00207K

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HOT: Understanding the biological activity of polysulfanes

26 Jan 2011

Polysulfanes are best for their importance in the vulcanisation of rubber, but certain naturally occurring polysulfanes, such as those in garlic, have generated interest due to their biological activity. In recent years it has been realised that many polysulfanes undergo a myriad of complex reactions in vivo, few of which are fully understood – or have even been investigated yet.

Claus Jacob from Saarland University and team have investigated previously unknown biochemical modes of action of a number of naturally occurring polysulfanes. Using an assay based on the haemolysis of red blood cells as a simple biological model they looked at hydrophobic interactions of the polysulfanes with cell membranes, interactions with metalloproteins and metal-ligand interactions.

Interestingly, the study found (contrary to some previous reports) that redox processes involving thiol/disulfide exchange and S-thiolation of proteins and enzymes were not the sole explanation for the biological activity of polysulfanes. Instead, a combination of redox activity, superoxide generation, hydrophobic interactions with membranes and combined ligand-metal/hydrophobic interactions with certain proteins were together concluded to explain the complex and often selective biological activity. The authors hope that their findings will provide a strong basis for future research in selective cytotoxicity and drug development.

To read more download the article which is currently free to access:

Interactions of polysulfanes with components of red blood cells
Thomas Schneider, Lalla A. Ba, Khairan Khairan, Clemens Zwergel, Nguyen Duc Bach, Ingolf Bernhardt, Wolfgang Brandt, Ludger Wessjohann, Marc Diederich and Claus Jacob
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C0MD00203H

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New antibiotics repair faulty genes

19 Jan 2011

Many genetic diseases, such as cystic fibrosis and muscular dystrophy, are caused by DNA mutations that terminate protein synthesis in the mutant gene. Aminoglycoside based antibiotics have been shown to stop these mutations but are often toxic and cause unpleasant side-effects in patients.

Now Timor Baasov and colleagues have designed and synthesised new aminoglycoside derivatives that show enhanced targeting and reduced cell toxicity, compared with the leading antibiotic gentamicin. Baasov’s compounds contain a chiral methyl group at the side-chain of the ribosamine ring, which they claim could be an essential feature responsible for the compound’s biological activity.

These findings could have immediate therapeutic applications for the treatment of many genetic diseases and could also aid treatment of several types of cancer caused by DNA mutations.

Download this paper for free now!

Repairing faulty genes by aminoglycosides: Identification of new pharacophore with enhanced suppression of disease-causing nonsense mutations.
Jeyakumar Kandasamy, Dana Atia-Gilkin, Valery Belakhov and Timor Baasov
Med.Chem. Commun, 2011, Advance Article, DOI: 10.1039/C0md00195c

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Hybrid ligands targeting Aβ fibrillization for Alzheimer

17 Dec 2010

Alzheimer disease is the most common form of dementia. It is a neurodegenerative disorder characterized by a progression from episodic memory problems to a slow global decline of cognitive function and it affects 10% of the people over the age of 65.

Unfortunately, the current treatments are purely symptom-relieving and an actual treatment or prevention of Alzheimer is still lacking.

Ilona B. Bruinsma and her team at Nijmegen, The Netherlands, have designed bifunctional “β -sheet breakers” that interfere with the portions of the Aβ peptide known to contribute to aggregation and GAG interaction.

Read this interesting paper free to access from MedChemComm

A rational design to create hybrid β-sheet breaker peptides to inhibit aggregation and toxicity of amyloid-β
Ilona B. Bruinsma, Anna Karawajczyk, Gijs Schaftenaar, Robert M. W. de Waal, Marcel M. Verbeek and Floris L. van Delft
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C0MD00213E

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