Author Archive

Reviews on DNA methyltransferases, amphotericin B and antimalarial peroxides in Issue 3

On  the cover of this month’s issue is an image from Nadine Martinet et al. accompanying their review on small molecule inhibitors of DNA methyltransferases.  This article forms part of our recent Epigenetics collection, which also includes articles from Manfred Jung, Wolfgang Sippl, Antonello Mai and Stephen Frye.

Small molecules DNA methyltransferases inhibitors
Nadine Martinet, Benoît Y. Michel, Philippe Bertrand and Rachid Benhida
DOI: 10.1039/C1MD00194A

The issue also contains reviews from Peter Kovacic and Andrew Cooksy discussing the mechanism of the antifungal drug amphotericin B and Gary H. Posner et al. on recent advances in the design of cyclic peroxides for the treatment of malaria.

Novel, unifying mechanism for amphotericin B and other polyene drugs: electron affinity, radicals, electron transfer, autoxidation, toxicity, and antifungal action
Peter Kovacic and Andrew Cooksy
DOI: 10.1039/C2MD00267A

Antimalarial peroxides: advances in drug discovery and design
Rachel D. Slack, Alexander M. Jacobine and Gary H. Posner
DOI: 10.1039/C2MD00277A

View these and many other interesting articles online here

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Review article on β-lactams and β-lactone probes for chemical biology

β-lactams and β-lactone probes for chemical biologyThomas Böttcher and Stephan A. Sieber here review the use of β-lactams and β-lactones for activity-based protein profiling.  ABPP uses small molecules to target the active site of specific enzymes and is useful for understanding protein targets of natural products, drugs or synthetic libraries.   β-Lactams and β-lactones are ideal probes for ABPP due to their so-called ‘privileged structures’, i.e. they have a core scaffold that can be recognised by a wide range of enzyme classes and can be ‘fine-tuned to obtain customized target selectivity’.

Take a look at this detailed review, which provides an update to of the field of activity-based β-lactam and β-lactone probes and their applications in chemical biology:

β-Lactams and β-lactones as activity-based probes in chemical biology
Thomas Böttcher and Stephan A. Sieber
Med. Chem. Commun., 2012, Advance Article
DOI: 10.1039/C2MD00275B

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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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Mini-review on aminoglycoside resistance caused by N-6′-acetyltransferase

Kenward Vong and Karine Auclair, McGill University, discuss the mechanism of AAC(6′)s – N-acetyltransferase enzymes that confer resistance to aminoglycoside resistance by catalysing the addition of an acetyl group from acetyl coenzyme A (AcCoA) to the 6′-N of aminoglycosides.  They also discuss aminoglycoside analogues designed to overcome AAC(6′)s and strategies for blocking AAC(6′)s.

Understanding and overcoming aminoglycoside resistance caused by N-6′-acetyltransferase
Kenward Vong and Karine Auclair
DOI: 10.1039/C2MD00253A

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Review: a unified mechanism for amphotericin B

Peter Kovacic and Andrew Cooksy examine the multiple modes of action and toxicity of this important antifungal antibiotic.

Areas covered:

Autoxidation and metabolism
Electron affinity
Pro-oxidant action
Drug activity and ROS-OS
Antifungal mechanism: ET-ROS-OS
Physiological action
Antioxidant activity
Toxicity
Conjugated dicarbonyls

Novel, unifying mechanism for amphotericin B and other polyene drugs: electron affinity, radicals, electron transfer, autoxidation, toxicity, and antifungal action.
Peter Kovacic and Andrew Cooksy
DOI: 10.1039/C2MD00267A

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Issue 1 2012 just published!

Happy New Year to all our readers and welcome to our first issue of 2012!

On the cover of this issue is work by John Spencer et al. on the synthesis of a small library of ferrocene-based HDAC inhibitors via click chemistry – click JAHAs.  This article is from our forthcoming web collection on Epigenetics, take a look at some of the other interesting articles published in this series.

Click JAHAs: conformationally restricted ferrocene-based histone deacetylase inhibitors
John Spencer, Jahangir Amin, Ramesh Boddiboyena, Graham Packham, Breeze E. Cavell, Sharifah S. Syed Alwi, Ronald M. Paranal, Tom D. Heightman, Minghua Wang, Brian Marsden, Peter Coxhead, Matthew Guille, Graham J. Tizzard, Simon J. Coles and James E. Bradner.
DOI: 10.1039/C1MD00203A

Also in this issue are reviews on polyamine-based epigenetic modulators, Stat5 signalling inhibitors, protein structure-based pharmacophore modeling and hot papers on the inhibition of E. coli DXP synthase and a glucuronide prodrug of doxorubicin.

View the rest of the issue here

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Reviewing the pros and cons of protein structure-based pharmacophore modelling

Pharmacophore modelling is a useful tool for medicinal chemists to identify novel ligands to bind to a receptor.  This review from Chris de Graaf and colleagues describes the advantages, and challenges, of using 3D protein structures to predict pharmacophores (rather than using a ligand-based approach, which involves searching for similarities based on previously known active ligands).

The review covers (i) protein structure preparation, (ii) binding site detection, (iii) pharmacophore feature definition, and (iv) pharmacophore feature selection, concluding that ‘SBPs are valuable tools for hit and lead optimization, compound library design and target hopping, especially in cases where ligand information is scarce‘.

Read more….

From the protein’s perspective: the benefits and challenges of protein structure-based pharmacophore modeling
Marijn P. A. Sanders, Ross McGuire, Luc Roumen, Iwan J. P. de Esch, Jacob de Vlieg, Jan P. G. Klomp and Chris de Graaf
DOI: 10.1039/C1MD00210D

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