Archive for February, 2011

Repairing faulty genes

Israeli scientists have developed compounds that could be better treatments for genetic diseases than current drugs.

Timor Baasov and his colleagues at the Israel Institute of Technology have improved compounds used to suppress faults in genes called nonsense mutations.

Nonsense mutations, which cause more than 1800 human diseases, are alterations in the genetic code that stop protein production prematurely, leading to truncated or nonfunctional proteins. Gene therapy is one treatment, but it’s had limited success. With suppression therapy, small molecules allow cells’ protein producing equipment to skip over nonsense mutations to restore the proteins. Aminoglycosides – antibiotic amine-modified sugars – are the only clinically available drug family known to be effective in suppression therapy, but at effective doses, the compounds have high human toxicity.


Two aminoglycoside derivatives were found to suppress alterations in the genetic code called nonsense mutations

Read the full story in Chemistry World
¬
Link to journal article
Repairing faulty genes by aminoglycosides: Identification of new pharmacophore with enhanced suppression of disease-causing nonsense mutations
Jeyakumar Kandasamy, Dana Atia-Glikin, Valery Belakhov and Timor Baasov,
Med. Chem. Commun., 2011, DOI: 10.1039/c0md00195c

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Top ten most accessed articles in January

This month sees the following articles in MedChemComm that are in the top ten most accessed:-

Silver nanoparticles – the real ‚Äúsilver bullet‚ÄĚ in clinical medicine?¬
Kenneth K. Y. Wong and Xuelai Liu¬
Med. Chem. Commun., 2010,¬†1, 125-131, DOI: 10.1039/C0MD00069H, Review¬

Targeting epigenetic modifiers: Inhibitors of histone methyltransferases
Elisabeth-Maria Bissinger, Ralf Heinke, Wolfgang Sippl and Manfred Jung¬†¬
Med. Chem. Commun., 2010, 1, 114-124, DOI: 10.1039/C0MD00062K, Review¬

Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04691502 through structure based drug design¬
Hengmiao Cheng, Shubha Bagrodia, Simon Bailey, Martin Edwards, Jacqui Hoffman, Qiyue Hu, Robert Kania, Daniel R. Knighton, Matthew A. Marx, Sacha Ninkovic, Shaoxian Sun and Eric Zhang¬
Med. Chem. Commun., 2010, 1, 139-144 , DOI: 10.1039/C0MD00072H, Concise Article¬

Boronic acids in medicinal chemistry: anticancer, antibacterial and antiviral applications¬
Paul C. Trippier and Christopher McGuigan¬
Med. Chem. Commun., 2010,¬†1, 183-198, DOI: 10.1039/C0MD00119H, Review¬

Small molecule modulation of stem cells in regenerative medicine: recent applications and future direction¬
Timothy E. Allsopp, Mark E. Bunnage and Paul V. Fish¬
Med. Chem. Commun., 2010,¬†1, 16-29, DOI: 10.1039/C0MD00055H, Review¬

Synthesis and biological evaluation of novel ferrocenyl curcuminoid derivatives¬
Anusch Arezki, Guy G. Chabot, Lionel Quentin, Daniel Scherman, G√©rard Jaouen and Emilie Brul√©¬
Med. Chem. Commun., 2011, Advance Article, DOI: 10.1039/C0MD00231C, Concise Article¬

Chemical space as a source for new drugs¬
Jean-Louis Reymond, Ruud van Deursen, Lorenz C. Blum and Lars Ruddigkeit¬
Med. Chem. Commun., 2010,¬†1, 30-38, DOI: 10.1039/C0MD00020E, Review¬

Novel indolizine compounds as potent inhibitors of phosphodiesterase IV (PDE4): structure-activity relationship¬
Shoujun Chen, Zhiqiang Xia, Masazumi Nagai, Rongzhen Lu, Elena Kostik, Teresa Przewloka, Minghu Song, Dinesh Chimmanamada, David James, Shijie Zhang, Jun Jiang, Mitsunori Ono, Keizo Koya and Lijun Sun¬
Med. Chem. Commun., 2011, Advance Article, DOI: 10.1039/C0MD00215A, Concise Article¬

Aromatic chloride to nitrile transformation: medicinal and synthetic chemistry¬
Lyn H. Jones, Nicholas W. Summerhill, Nigel A. Swain and James E. Mills¬
Med. Chem. Commun., 2010,¬†1, 309-318, DOI: 10.1039/C0MD00135J, Review¬

Biofunctional TiO2 nanoparticle-mediated photokilling of cancer cells using UV irradiation¬
Kazusa Matsui, Miki Karasaki, Maiko Segawa, Sang Youn Hwang, Tsutomu Tanaka, Chiaki Ogino and Akihiko Kondo¬
Med. Chem. Commun., 2010,¬†1, 209-211, DOI: 10.1039/C0MD00027B, Concise Article¬

Why not take a look at the articles today and blog your thoughts and comments below.

Fancy submitting an article to MedChemComm? Then why not submit to us today or alternatively email us your suggestions.

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MedChemComm in The Korea Herald

MedChemComm article by Chung Sung-kee and co-workers has been highlighted in The Korea Herald.

A group of South Korean researchers said Monday that they found a way to use drugs to fight brain tumors that are currently treated with only surgery and chemotherapy.

You can read the whole story here and also download the article which is free to access here.

Preparation of blood-brain barrier-permeable paclitaxel-carrier conjugate and its chemotherapeutic activity in the mouse glioblastoma model
Juyoun Jin, Woo Sirl Lee, Kyeung Min Joo, Kaustabh K. Maiti, Goutam Biswas, Wanil Kim, Kyong-Tai Kim, Se Jeong Lee, Kang-Ho Kim, Do-Hyun Nam and Sung-Kee Chung
Med. Chem. Commun., 2011
DOI: 10.1039/C0MD00235F

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Repairing faulty genes – Baasov and MedChemComm in Chemistry World

Israeli scientists have developed compounds that could be better treatments for genetic diseases than current drugs.

Timor Baasov and his colleagues at the Israel Institute of Technology have improved compounds used to suppress faults in genes called nonsense mutations.

‘Treating genetic disorders is one of the biggest challenges of modern medicine. The likelihood that suppression therapy could be used clinically is very feasible,’ says Baasov.

Read the whole story in Chemistry World.

The full paper is free to access here:

Repairing faulty genes by aminoglycosides: Identification of new pharmacophore with enhanced suppression of disease-causing nonsense mutations
Jeyakumar Kandasamy, Dana Atia-Glikin, Valery Belakhov and Timor Baasov,
Med. Chem. Commun., 2011
DOI: 10.1039/c0md00195c

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HOT: Novel photocytotoxic glycosylated porphyrins to combat cancer

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 Рwhich usually locate in the mitochondria or endoplasmic reticulum Рand 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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New hepatitis C drug

Scientists in the UK have developed a compound to combat the hepatitis C virus that could be taken as a pill.

David Pryde and his team from Pfizer Global Research and Development, Sandwich, have made new compounds to activate a protein in the immune system called TLR7 – toll-like receptor 7 – which fights the infection. Toll-like receptors identify foreign DNA, such as a virus, and produce proteins that inhibit the virus’ replication.

300 million people suffer from hepatitis C worldwide. The virus that causes the disease resides in the liver and can lead to cirrhosis, with some sufferers requiring liver transplants. Current treatments only cure half of patients and are administered intravenously. Recent research has focused on increasing the effectiveness of the drugs and on developing oral treatments.

Pryde’s team made heterocyclic analogues based on the structure of purines, known activators of TLR7 and the basis of current oral drugs. ‘The most potent TLR7 agonists are purine-based,’ explains Pryde. ‘But we wanted to design potent non-purine based agonists to maximise the chances of avoiding any unwanted off-target pharmacology.’¬†


The compounds activate a protein in the immune system, which fights hepatitis¬

Read the full story in Chemistry World

The discovery of a novel prototype small molecule TLR7 agonist for the treatment of hepatitis C virus infection
David C. Pryde, Thien-Duc Tran, Peter Jones, Gemma C. Parsons, Gerwyn Bish, Fiona M. Adam, Mya C. Smith, Donald S. Middleton, Nick N. Smith, Frederick Calo, Duncan Hay, Michael Paradowski, Katie J. W. Proctor, Tanya Parkinson, Carl Laxton, David N. A. Fox, Nigel J. Horscroft, Giuseppe Ciaramella, Hannah M. Jones, Jonathan Duckworth, Neil Benson, Anthony Harrison and Rob Webster.
Med. Chem. Commun., 2011, DOI: 10.1039/c0md00197j
Link to journal article

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Fighting back against antibiotic resistant bacteria-MedChemComm in Chemistry World

Scientists in Japan have revealed how vancomycin dimers are effective against vancomycin-resistant bacteria.

Vancomycin, a glycopeptide antibiotic, is used to treat bacterial infections in cases when other antibiotics are ineffective. However, the development of vancomycin resistant enterococci (VRE) and Staphylococcus aureus means that researchers are turning to different forms of vancomycin to improve its efficacy.

Hirokazu Arimoto at Tohoku University, Sendai, and colleagues had previously shown that  vancomycin dimers displayed excellent antibacterial activity against vancomycin-resistant bacteria. Now, they have shown how the dimers interact with the bacteria.

Read the full story in Chemistry World.

The paper is free to access!

New insight into the mode of action of vancomycin dimers in bacterial cell wall synthesis
Osamu Yoshida, Jun Nakamura, Hidenori Yamashiro, Kenji Miura, Sayaka Hayashi, Kosei Umetsu, Shu Xu, Hideki Maki and Hirokazu Arimoto
Med. Chem. Commun., 2011
DOI: 10.1039/c0md00230e

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MedChemComm Issue 2 published on line- Free access!

Our second issue of MedChemComm 2011 is here already!

This new and exciting issue comes with two reviews.
The first one by Paul Leeson and collegues on the impact of ion class and the time on the properties of oral drugs and the second one by Peter Kovacic and Ratnasamy Somanathan on the mechanisms of aromatic primary amines and the influence on the physiological activity.

The issue also contains six vibrant concise articles that bring you the best medicinal chemistry research.
From 2D and 3D activity landscape representations to imaging contrast agents. For those of you who are more synthetic medchems you can find articles on the synthesis and biological activities of AA-Trp-Trp-OBzl and isoquinolones. We close the issue with a study of activation energies and their influence in the stability of drugs and a final article on HIV-integrase inhibitors.

What do you think? We would like to receive your feedback on the new RSC medicinal chemistry journal MedChemComm!

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HOT: Silencing the threat of HIV

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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Combating cold sores – MedChemComm in Chemistry World

This MedChemComm article by Giovanni Grassi and colleagues in Messina, Italy, has been highlighted in the RSC magazine Chemistry World.

New compounds to fight the herpes simplex virus (HSV-1), which causes cold sores, have been made by researchers from Italy. The compounds’ antiviral activity could be enhanced further by encapsulating them in a cyclodextrin nanocarrier that acts as a delivery system.

Giovanni Grassi and colleagues from the University of Messina made indole-3,4-diones that share structural features with inhibitors of kinase – an enzyme linked to many diseases. The inhibitors were recently reported to prevent viral replication in vitro. ‘The diones showed remarkable anti HSV-1 activity in vitro,’ says Grassi. They then encapsulated the most effective dione in an amphiphilic – both hydrophilic and lipophilic – cyclodextrin. These nanocarriers increased the ability of the antiviral agents to penetrate into target cells.

Read the full story here.

The article is now free to access and you can download it here.

Synthesis and anti HSV-1 evaluation of novel indole-3,4-diones
Angela Scala, Massimiliano Cordaro, Antonino Mazzaglia, Francesco Risitano, Assunta Venuti, Maria Teresa Sciortino and Giovanni Grassi, Med. Chem. Commun., 2011
DOI: 10.1039/c0md00190b

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