Archive for May, 2011

HOT: drugs that go beyond the rule of five – or do they?

Lipinski’s rule of five is probably one of the first principles taught to a medicinal chemist, as it defines the chemical space likely to yield a successful oral drug. However, in recent years some drugs have moved beyond traditional rule of five space in order to access alternative or challenging targets.

In this HOT paper David S. Millan and colleagues at Pfizer R&D explore the influence of intramolecular hydrogen bonding on the membrane permeability and bioavailability of some of these drugs.  By determining the propensity of molecules to form intramolecular  hydrogen bonds they are able to revise previous assumptions about where certain molecules sit in chemical space.  They find that when hydrogen bonding is taken into account these drugs sit much closer to rule of five space – thereby explaining the successful absorption of drugs that otherwise violate rule of five principles.

To read more on this interesting new tool for predicting intramolecular hydrogen bonding, download the article which is currently free to access:

Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space
Alexander Alex, David S. Millan, Manuel Perez, Florian Wakenhut and Gavin A. Whitlock
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00093D

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Top ten most accessed articles in April

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

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

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  

Identification of target family directed bioisosteric replacements
Anne Mai Wassermann and Jürgen Bajorath 
Med. Chem. Commun., 2011, Advance Article, DOI: 10.1039/C1MD00066G  

The p53-MDM2/MDMX axis – A chemotype perspective 
Kareem Khoury, Grzegorz M. Popowicz, Tad A. Holak and Alexander Dömling 
Med. Chem. Commun., 2011, 2, 246-260, DOI: 10.1039/C0MD00248H, Review 

Platinum-oxazoline complexes as anti-cancer agents: syntheses, characterisation and initial biological studies 
Paras N. Yadav, Ramsay E. Beveridge, Jonathan Blay, Alaina R. Boyd, Maja W. Chojnacka, Andreas Decken, Ankur A. Deshpande, Michael G. Gardiner, Trevor W. Hambley, Michael J. Hughes, Leslie Jolly, Jacquelyn A. Lavangie, Timothy D. MacInnis, Sherri A. McFarland, Elizabeth J. New and Robert A. Gossage 
Med. Chem. Commun., 2011, 2, 274-277, DOI: 10.1039/C0MD00211A  

Natural products targeting telomere maintenance 
Jack Li-Yang Chen, Jonathan Sperry, Nancy Y. Ip and Margaret A. Brimble 
Med. Chem. Commun., 2011, 2, 229-245, DOI: 10.1039/C0MD00241K  

(Carboxydiamine)Pt(ii) complexes of a combretastatin A-4 analogous chalcone: the influence of the diamine ligand on DNA binding and anticancer effects 
Miroslava Zoldakova, Bernhard Biersack, Hana Kostrhunova, Aamir Ahmad, Subhash Padhye, Fazlul H. Sarkar, Rainer Schobert and Viktor Brabec 
Med. Chem. Commun., 2011, Advance Article, DOI: 10.1039/C1MD00042J  

Synthesis and biological evaluation of tetrazole containing compounds as possible anticancer agents 
Chebolu Naga Sesha Sai Pavan Kumar, Dusmant Kumar Parida, Amlipur Santhoshi, Anil Kumar Kota, Balasubramanian Sridhar and Vaidya Jayathirtha Rao 
Med. Chem. Commun., 2011, Advance Article, DOI: 10.1039/C0MD00263A 

Synthesis and efficient siRNA delivery of polyamine-conjugated cationic nucleoside lipids 
Sachin Prakash Patil, Jeong Wu Yi, Eun-Kyoung Bang, Eun Mi Jeon and Byeang Hyean Kim 
Med. Chem. Commun., 2011, Advance Article, DOI: 10.1039/C1MD00014D  

N-(5-substituted thiazol-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl) propanamides as glucokinase activators 
Zhiqing Liu, Qingzhang Zhu, Fuying Li, Lina Zhang, Ying Leng and Ao Zhang 
Med. Chem. Commun., 2011, Advance Article, DOI: 10.1039/C1MD00002K  

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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HOT: first example of an organometallic osmium complex with significant anti-cancer activity

The majority of therapeutics clinically available for cancer treatment are platinum-based and work via a DNA alkylation mechanism that leads to cell apoptosis.  But a number of cancers are resistant to apoptosis and not treatable with platinum-based drugs.

In this paper Peter Sadler (University of Warwick), Steve Shnyder (University of Bradford) and teams have developed an organometallic half-sandwich osmium complex that displays significant anti-cancer activity with negligible toxicity in vivo. Osmium is also a platinum group metal but has a completely different mode of action and appears to operate via redox mechanisms – making these complexes candidates for further investigation and potentially clinical trials.

Read more about this exciting find here – the article is currently free to access:

Anti-colorectal cancer activity of an organometallic osmium arene azopyridine complex
Steve D. Shnyder, Ying Fu, Abraha Habtemariam, Sabine H. van Rijt, Patricia A. Cooper, Paul M. Loadman and Peter J. Sadler
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00075F

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HOT: something old, something new – combining traditional Chinese medicine and computational chemical biology

There are a vast number biologically active natural products out there with the potential to cure any number of rather nasty diseases.  But searching for them and identifying their therapeutic targets can seem like a bewilderingly large task.  In this interesting paper Weidong Zhang and colleagues from several institutes in Shanghai have combined knowledge from traditional Chinese medicine with computational chemical biology to rapidly identify novel targets for natural products derived from plants.

The authors selected Bacopa monnieri (L.) Wettst (BMW) and Daphne odora Thunb. var. marginata (DOT) – which are used in traditional medicine for the treatment of diabetes and inflammation – and screened 19 compounds isolated from the plants against a potential drug target database using a reverse docking approach.  Based on these results and the clinical indication of the plants the DPP-IV protein (a therapeutic target for type II diabetes) was chosen for experimental validation.  When tested in vitro, 5 of the 19 compounds showed moderate inhibition of DPP-IV.  Then, from these five compounds analogues from an in-house library were screened, almost half of which again showed the ability to moderately inhibit the protein.

The authors emphasise that further work must be done to identify the synergistic pathways that result in the overall efficacy of traditional Chinese medicinal treatments, but this paper does demonstrate how it is possible to use natural products derived from clinically effective, but poorly understood, traditional treatments as a starting point for rapidly and successfully identifying new therapeutic targets.

Fast and effective identification of the bioactive compounds and their targets from medicinal plants via computational chemical biology approach
Shoude Zhang, Weiqiang Lu, Xiaofeng Liu, Yanyan Diao, Fang Bai, Liyan Wang, Lei Shan, Jin Huang, Honglin Li and Weidong Zhang
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C0MD00245C

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MedChemComm’s Most Cited

Take a look at MedChemComm‘s most cited articles so far. As with all of our articles, you can enjoy free access to these for the remainder of 2011:

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
GA

Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists
Julia M. Adam, Jim Cairns, Wilson Caulfield, Phillip Cowley, Iain Cumming, Morag Easson, Darren Edwards, Morag Ferguson, Richard Goodwin, Fiona Jeremiah, Takao Kiyoi, Ashvin Mistry, Elizabeth Moir, Richard Morphy, Jason Tierney, Mark York, James Baker, Jean E. Cottney, Andrea K. Houghton, Paul J. Westwood and Glenn Walker
Med. Chem. Commun., 2010, 1, 54-60
GA

Silver nanoparticles—the real “silver bullet” in clinical medicine?
Kenneth K. Y. Wong and Xuelai Liu
Med. Chem. Commun., 2010, 1, 125-131
GA

Cytotoxic sugar analogues of an optimized novobiocin scaffold
Alison C. Donnelly, Huiping Zhao, Bhaskar Reddy Kusuma and Brian S. J. Blagg
Med. Chem. Commun., 2010, 1, 165-170
GA

Photografted poly(methyl methacrylate)-based high performance protein microarray for hepatitis B virus biomarker detection in human serum
Yingshuai Liu, Weihua Hu, Zhisong Lu and Chang Ming Li
Med. Chem. Commun., 2010, 1, 132-135
GA

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
GA

Effect of particle shape on phagocytosis of CdTe quantum dot–cystine composites
Zhisong Lu, Yan Qiao, Xin Ting Zheng, Mary B. Chan-Park and Chang Ming Li
Med. Chem. Commun., 2010, 1, 84-86
GA

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HOT: Imaging Alzheimer’s disease brains

Senile plaques (SPs) and neurofibrillary tangles (NFTs) are two pathological hallmarks for Alzheimer’s disease. Unfortunately, there is no an effective and simple diagnostic method to detect them.

In this paper, Masahiro Ono, Hideo Saji and colleagues at Kyoto University, have developed a series of radioiodinated phenyldiazenyl benzothiazole (PBD) derivatives as probes for the imaging of NFTs in the brain. Imaging agents need to be able to both penetrate the blood-brain barrier after an intravenous injections and be rapidly washed out from the normal brain. Unfortunately, even though these radioiodinated PDB derivatives displayed high affinity for tau aggregates and good brain uptake, the persistent radioactivity in the brain made them unsuitable for imaging NFTs in vivo.

If you want to find out more about these ‘inspiring’  imaging agents, you can download the article for free.

Phenyldiazenyl benzothiazole derivatives as probes for in vivo imaging of neurofibrillary tangles in Alzheimer’s disease brains
Kenji Matsumura, Masahiro Ono, Shun Hayashi, Hiroyuki Kimura, Yoko Okamoto, Masafumi Ihara, Ryosuke Takahashi, Hiroshi Mori and Hideo Saji
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00034A

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HOT article: fragment screening for nicotinic acetylcholine receptors

Finding ligands to selectively bind to nicotinic acetylcholine receptor family of ligand gated ion channels is challenging due to the diversity of receptor subtypes, but ligands for the α7 subtype in particular could lead to new therapies for brain disorders such as schizophrenia and Alzheimer’s disease.

To screen for potential ligands Jeroen Kool (Leiden/Amsterdam Center for Drug Research) and colleagues recently developed an online fluorescence enhancement assay for the water-soluble acetylcholine binding protein (AChBP) – a model protein for the binding domain of α7 nicotinic acetylcholine receptors.  Using the related proteins Ls and Ac-AChBP  they sifted through in-house fragment libraries, discovering that Ls-AChBP is a better template for fragment screening and accurate, rapid hit exploration is possible using single point injections in the 96-well format.  They also produced an optimised hit with mM affinity for the α7 nicotinic acetylcholine receptor.

The authors hope that this technology will find applicability elsewhere – as it only requires a water-soluble protein and a good fluorescence enhancement tracer ligand.

Why not download the article and see for yourself – it’s currently free to access:

Online parallel fragment screening and rapid hit exploration for nicotinic acetylcholine receptors
Gerdien E. de Kloe, Jeroen Kool, Rene van Elk, Jacqueline E. van Muijlwijk-Koezen, August B. Smit, Henk Lingeman, Hubertus Irth, Wilfried M. A. Niessen and Iwan J. P. de Esch
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00031D

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