Archive for the ‘News’ Category

Upcoming event: The Discovery of Abiraterone

6 pm, 20th September 2012
Chemistry Centre, Burlington House, London

The nature of drug discovery is changing, but the UK remains a world leader in the development of new medicines. The discovery of Abiraterone is one recent success, developed at The Institute of Cancer Research (ICR) and The Royal Marsden Hospital (RMH). In 2011, it completed its journey from an idea to a life-extending treatment for men with advanced prostate cancer.

Keynote speaker: Professor Johann de Bono, Institute of Cancer Research  

Professor de Bono led on the drug’s development, taking it from Phase I first-in-man trials to the successful completion of Phase III trials. During his lecture he will highlight the Institute of Cancer Research’s unique partnership with the Royal Marsden hospital, with an emphasis on the bench-to-bedside approach that has already made a real impact on cancer patients’ lives. Professor de Bono’s talk will be followed by a chaired panel discussion which will address the question:

How can discovery programmes such as the successful work that led to the discovery of Abiraterone be repeated within the UK academic environment?

The evening will finish with a wine reception. This event is free to attend, but delegates must pre-register to guarantee admittance. Further details and online registration can be found at www.rsc.org/discovery-of-abiraterone

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Trojan horse tuberculosis treatment

During the Trojan war, Greeks built a huge wooden horse, hid men inside it and left it outside the city of Troy. The Trojans, claiming it as a victory trophy, brought it into their city. That night, the Greek force crept out of the horse, opened the gates for the rest of the Greek army and they destroyed the city of Troy

Marvin Miller at the University of Notre Dame and colleagues have synthesised analogues of iron scavenging compounds that contain a maleimide functional group for future drug conjugation. Miller explains that these compounds will be actively assimilated by the M. tuberculosis pathogen by the active iron transport system, but can also carry a lethal agent into the pathogen.

One of the challenges of synthesising drug conjugates is finding a suitable functional group to attach the drug to the conjugate. The maleimide functionalised mycobactin analogue synthesised by the team simplifies the synthetic route by reducing the need for protecting groups. Thiol-maleimide chemistry can then be used to attach the drug.

Derek Tan, an expert in rational drug design at the Memorial Sloan–Kettering Cancer Center, US, is enthusiastic about the work. He believes that the advantage of the maleimide functional group is that it can react with nucleophiles, which may already be present in a potential conjugate drug, as opposed to electrophiles, which generally need to be synthetically introduced into the conjugate drug. This maleimide–mycobactin analogue ‘will enable the future synthesis of a wider array of potential Trojan horse antibiotics’, says Tan.

Miller and co-workers found that the maleimide–mycobactin analogue displayed antibiotic activity against Mycobacterium tuberculosis, but it was inactive against a broad panel of Gram-positive and Gram-negative bacteria. ‘The use of siderophores [iron chelating compounds] to deliver antibiotics exclusively into a single type of bacteria (e.g., Mtb, P. aeruginosa, E. coli), could reduce the administration of broad-spectrum antibiotics, minimising exposure and therefore the development of drug resistance’ says Miller.

In the future, the team intends to use a rational approach for selecting drugs to attach to the maleimide–mycobactin analogue, starting with drugs that inhibit essential survival processes.

References
1. R E Juárez-Hernández, S G Franzblau and M J Miller, Org. Biomol. Chem., 2012, DOI: 10.1039/c2ob26077h

2. Chemistry World story by Alisa Becker

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Improved drugs to treat malarial liver infection

Antimalarial drugs with increased in vitro activity have been developed by scientists in Portugal and the US. These novel drugs, called primacins, are active against two stages of malarial infection and are more active against liver parasites than the current clinical use drug, primaquine.

Mosquito-borne malaria is a highly infectious and potentially fatal disease that affects millions of people every year. When humans are bitten by a malaria-infected mosquito, they undergo a clinically silent liver-stage infection when thousands of malaria parasites (merozoites) are released into the bloodstream. Drugs that are active against liver parasites are rare and currently, primaquine is the only drug in clinical use. However, its use is hampered by low oral bioavailability and high hemotoxicity, making it unsuitable for pregnant women, children and the elderly.

The new primacins, developed by Paula Gomes from the University of Porto, Portugal, and co-workers combine primaquine with cinnamic acids, which are also known for their antimalarial activity. ‘This ‘‘covalent bitherapy’’ involves linking two molecules with individual intrinsic activity into a single agent, thus packaging dual activity into a single hybrid molecule,’ explains Gomes. ‘So far, none of the antimalarials reported in the literature combine these two antimalarial pharmacophores. Moreover, the chemistry underlying their preparation is simple and cheap, which is our constant concern when dealing with development of antimalarials, as malaria is mainly endemic to low income countries.’

Larry Walker, a professor in pharmacology at the University of Mississippi, US, agrees that the work is promising, but says that further experiments and animal testing are necessary. ‘What is new here is the finding that, using this liver stage parasite culture model, which is fairly new and very useful, they can show improved potency of these derivatives. This is really the most important feature of this study,’ he says. ‘However, it is important to keep in perspective what still needs to be done to have a real advance for this drug class. What is needed is to show that it improves activity in animal models; and more importantly, shows reduced hematological toxicity compared to primaquine.’

Gomes agrees that in vivo tests are the way forward: ‘The next step consists of establishing how active our compounds are in vivo, how are they absorbed, distributed, metabolised and eliminated,’ she says. ‘If the compounds are confirmed to be highly active in vivo, we’ll then step forward into the so-called pre-clinical assays.’

REFERENCES

1. Chemistry World story by Emma Eley

2. B Pérez et al, MedChemComm, 2012, DOI: 10.1039/c2md20113e

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Delivering insulin in a skin cream

Insulin could be administered topically rather than by needles in the future

Scientists in Japan have developed a way to administer insulin to patients through the skin. Such a method avoids one of the problems associated with injections and oral administration in which a drug’s concentration is reduced as it passes through the digestive system. It would also be a more pleasant experience for patients.

Masahiro Goto from Kyushu University in Fukuoka and SO Pharmaceutical Corporation in Kobe, and colleagues, prepared a capsule loaded with insulin that is able to penetrate the skin with its cargo.

The team made their capsule by surrounding insulin molecules with proteins and coating the protein molecules with a hydrophobic surfactant to form protein–surfactant complexes. Then, they added oligo-arginine peptides as protein transduction domains and dispersed the complexes in oil – isopropyl myristate – which is known to have a permeation-enhancing effect. ‘The main function of this new system is to promote protein penetration through the hydrophobic stratum corneum [outermost layer of the skin],’ explains Goto.

The team tested their delivery vehicle on pig skin and found that the solid-in-oil dispersion delivered six times more insulin into the skin than an aqueous solution. The peptides further enhanced the concentration of insulin delivered through the skin.

‘Transcutaneous protein delivery is a difficult problem, the solution of which could enhance the quality of life for patients in need of protein therapeutics,’ says Paschalis Alexandridis from the chemical and biological engineering department at the University of Buffalo, US, whose work includes pharmaceutical formulations. He adds that Goto’s work demonstrates the versatility of solid-in-oil nanodispersions as a platform for enhanced transdermal delivery of protein therapeutics and vaccines.

Goto and his team say that in theory such dispersion could be used for any drug that is soluble in water and can form a water-in-oil emulsion. They hope to be able to produce a transdermal vaccine in the future.

Original story from Chemistry World, written by Jennifer Newton

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2011 Impact Factor for OBC, MedChemComm & NPR

The 2011 Journal Citation Reports ® (Thomson Reuters, 2012) have just been released, which showed:

Organic & Biomolecular Chemistry: 3.696

MedChemComm: 2.8         (Partial IF only, based on five issues)

Natural Product Reports: 9.79

The Cambridge Editorial Office would like to thank everyone involved for their hard work and dedication to all three journals over the years. In particular, we would like to thank all of our Associate Editors, Editorial and Advisory Board members, authors and referees, without whom none of this would have been possible.

With another successful year in the bag, we hope you will join us in making this year even better…

Read more about the 2011 Impact Factors from across RSC Publishing on the RSC Publishing Blog.

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RSC US Roadshow 2012 – Week 4: North East

MedChemComm Editor Richard Kelly will be visiting several North East universities next week as part of the RSC US Roadshows 2012.

Week 4 sees the Royal Society of Chemistry visiting four universities in Pennsylvania and New York:

May 7th – University of Pittsburgh

May 8th – Pennsylvania State University

May 10th – University of Pennsylvania

May 11th – Columbia University

Read more about the US roadshows 2012:

Starting in mid April 2012, RSC Publishing has been touring the United States of America to share more than 170 years experience of publishing in the chemical sciences. Sixteen universities across the country are hosting these one-day events, which are open to all members of the hosting institute.

Attendees have the opportunity to explore RSC’s apps on mobile devices and meet informally with RSC editors. Lunchtime discussion groups explore reading habits and opportunities in the 21st century and an afternoon seminar give an insight into the world of scholarly publishing, with tips on how to get published in high impact journals. A demonstration of ChemSpider, and a guest lecture from an RSC associate editor or board member are available at many of the roadshows.

Follow the RSC Roadshows on Twitter – just look for #RSC2012.

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Building a nation of scientists

Goverdhan Mehta talks to Sheena Elliott and Elinor Richards about the progress of science in India and the challenges scientists face

Goverdhan Mehta is a researcher, specialising in organic synthesis. He has helped to build institutions in India – the Indian Institute of Technology, Kanpur, the University of Hyderabad, and the Indian Institute of Science, Bangalore. He was director of the Indian Institute of Science (1998-2005) and vice chancellor of the University of Hyderabad (1994-1998).

Your research is focused on organic chemistry. What attracted you to that field?

There is something intrinsically fascinating about organic chemistry. In my early high school years, when I was exposed to interesting chemical structures, I was attracted to them. I had a sense of appreciation for art and organic molecules to me provided a wonderful expression of art at a molecular level.

What are your main achievements in the field?

I have worked in many areas of organic chemistry, but it’s synthesis that’s given me the greatest pleasure. As organic chemistry advanced, different contemporary challenges came to my attention. The main driver for me to pursue those challenges was the intricacy of the target structure synthesis. There was also an element of expectation that perhaps our research might become useful to society. We continue to need new drugs for a variety of disorders, so we synthesised a large number of natural products; many of them are biologically active and it is quite possible that some of them can provide leads for new drug discovery.

Over the last few years, I have become interested in how to address a problem that the ageing population is facing – neurodegeneration. It has been shown that some natural products can slow down neurodegeneration. In some cases, there is also an indication that they can help restore lost cognitive function. So I have been working on the synthesis of such lead molecules. As I’m getting older, I recognise the need for doing something in that area!

You’ve won numerous awards. Which achievements are you most proud of?

I don’t think that awards and recognition have necessarily brought me a great sense of joy. They do bring a sense of satisfaction because your peers have recognised your work. But I don’t think any serious researcher works for awards. It is the sheer joy of research that keeps people going. Recognition has come my way, but don’t think that I can equate that with the joy of doing research.

What are the challenges facing scientists in India and how could these be overcome?

Scientists all over the world are facing challenges on two fronts. The first problem is that scientists are not being supported by society as much as they should and some governments are not always forthcoming in terms of providing budgetary support. The second problem is that scientists, and science in general, have become isolated both in terms of discipline and, to some extent, in terms of geographical location. This is being redressed now with increasing international collaborations, so in the geographical sense, the isolation is being reduced. But I think disciplinary isolation vis a vis other knowledge streams and fragmentation of science is still a serious challenge.

It is a good time for scientists in India because the government is very supportive of science. Funding is no longer as serious a problem as it is in other parts of the world. Recently, our prime minister said that the budget for science will be almost doubled over the next few years. But I’m not too sure that we as a scientific community are steering science in India in the direction that it ought to be heading. I believe that the government and the scientific community must set a goal that in the next 10 years, India will be among the world’s leading scientific countries.

What is your opinion on the perception that Indian science and research is falling behind the rest of the world, following recent comments by Prime Minister Manmohan Singh?

Prime Minister Singh’s statement referred mainly to China. China has made more progress in science and technology than India. Scientific productivity in India has increased, but not as much as in China. Since we are behind, to simply say that we are walking and walking well is not enough. We should be galloping to catch up. My judgement is that our progress is not commensurate with the support that the government is providing, and not commensurate with the capacity, capability, enthusiasm and the vibrancy that our youth have. We can achieve much more.

How do the different industries compare (the pharmaceutical industry in particular or the more general chemical industry)?

It is only over the last 10 or 12 years, since the economic reforms, that industry in India has grown at such a rate so as to be in a position to invest in research and development. I expect that investment by industry is going to rise; however, the current level of investment is not in an acceptable range. There are certain sectors – pharma, for example – and some other chemical industries, where I think India’s potential is immense, but there are some challenges with the policies that are being pursued. We have to devise a well thought out strategy.

The prime minister’s Science Advisory Council reported that there in an absence of any Indian universities among the world’s best. What is your opinion on the quality of universities in India?

I’m not a great believer in the ranking systems being followed, but the fact is that no Indian university features among the top few hundred  universities. However, if we were to look at undergraduate teaching, India has institutions that produce graduates through excellent teaching and training. The graduates are probably as good as they are anywhere else in the world. If you were to grade an institution on the quality of undergraduates, I would say that the Indian Institutes of Technology rank among the top 10 institutions in the world. But, if you bring in research and other elements, they will not feature anywhere near the top. So the quality of research is a serious problem. I think it is high time that the scientific community and scientific leadership in our country sort out an effective, implementable strategy to make a major shift.

You experienced difficulty obtaining a visa to travel to the US in 2006, when you were invited to give a lecture at the University of Florida. At the time, a report from the National Academy of Sciences in the US said that at least 3000 scientists had faced a similar problem. Have things improved since then or do you believe that the visa problem is hampering scientific progress and career development for scientists?

It was ironic that I and a leading scientist from the US, Jane Lubchenco (who at that time was president of the International Council for Science before I succeeded her), wrote an editorial about the principle of universatility of science and the visa regime in Science a few months before this happened. We wrote that it was important for the international growth of science that scientists were able to travel. Little did I realise that soon I would be a victim of this! I think the situation has improved, but a lot more needs to be done. While the US National Academy of Sciences is playing a very positive role towards this end, the academies can only do the advocacy. Eventually, it is the government and the state department of security staff that makes the final judgement.

If you have any spare time, how do you fill it?

For most scientists, and I’m no exception, your research is a hobby. What other profession can give you that pleasure and privilege? In a previous interview, I was asked what I would wish for. I said we Indians believe in rebirth and so the only wish I have is that if I were to be born again, I would be a scientist. I would like to be a chemist, hopefully a better one.

Read some of Goverdhan Mehta’s recent research:

Towards a temperature-guided molecular switch: an unusual reversible low-temperature polymorphic phase transition in a conformationally locked environment
Goverdhan Mehta and Saikat Sen, Chem. Commun., 2009, 5981
DOI: 10.1039/b905651c

Understanding the self-assembling process in crystalline cyclooctitols: an insight into the conformational flexibility of medium-sized rings
Goverdhan Mehta, Saikat Sen and Kotapalli Pallavi, CrystEngComm, 2008, 10, 534
DOI: 10.1039/b712877k

Additive induced polymorphous behavior of a conformationally locked hexol
Goverdhan Mehta, Saikat Sen and Kailasam Venkatesan, CrystEngComm, 2007, 9, 144
DOI: 10.1039/b613949c

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Issue 2 now online including hot articles on epigenetics

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

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

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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