Organic & Biomolecular Chemistry Blog

Carboxylate-isostere analogs of daptomycin: synthesizing the next generation of antibiotics

27 Jun 2013

This paper is HOT as recommended by the referees, and is free to access for 4 weeks.
Published on behalf of Steve Moore, Organic & Biomolecular Chemistry web science writer.

The emergence of multi-drug resistant bacterial infections has created a pressing need for the identification of new drugs. This HOT article describes the chemical modification of daptomycin, an antibiotic used to treat Gram-positive bacterial infections. Because of its anionic character daptomycin has a high affinity to pulmonary surfactants, but this limits its use in the treatment of pulmonary infections.

Scott Miller and co-workers hypothesized that reducing surfactant interactions may increase the antibiotic activity of daptomycin. Consequently, they set out to convert the daptomycin carboxylic acid moieties to carboxylate isosteres. This paper reports a direct and efficient procedure to produce isostere analogues of daptomycin, suppressing backbone-cyclization side reactions. The use of a high resolution UPLC-MS/MS technique to characterise the synthetic products by fragmentation analysis is also described.

An efficient chemical synthesis of carboxylate-isostere analogs of daptomycin
Sabesan Yoganathan, Ning Yin, Yong He, Michael F. Mesleh, Yu Gui Gu and Scott J. Miller
DOI: 10.1039/C3OB40924D

Free to access for 4 weeks

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Latest HOT articles in OBC

27 Jun 2013

By Alessia Millemaggi.

These articles are HOT as recommended by the referees. And we’ve made them free to access for 4 weeks!

Promiscuity of a modular polyketide synthase towards natural and non-natural extender units
Irina Koryakina, John B. McArthur, Matthew M. Draelos and Gavin J. Williams
DOI: 10.1039/c3ob40633d

Synthesis of bis-α,α′-amino acids through diastereoselective bis-alkylations of chiral Ni(II)-complexes of glycine
Jiang Wang, Hong Liu, José Luis Aceña, Daniel Houck, Ryosuke Takeda, Hiroki Moriwaki, Tatsunori Sato and Vadim A. Soloshonok
DOI: 10.1039/c3ob40594j

Aerobic C–H amination of tetrahydrocarbazole derivatives via photochemically generated hydroperoxides
Naeem Gulzar and Martin Klussmann
DOI: 10.1039/c3ob40919h

Nanomolar cholera toxin inhibitors based on symmetrical pentavalent ganglioside GM1os-sym corannulenes
Martin Mattarella, Jaime Garcia-Hartjes, Tom Wennekes, Han Zuilhof and Jay S. Siegel
DOI: 10.1039/c3ob40438b

Nanomolar cholera toxin inhibitors based on symmetrical pentavalent ganglioside GM1os-sym corannulenes

Chemical-genetic identification of the biochemical targets of polyalkyl guanidinium biocides
Drew Bowie, Paria Parvizi, Dustin Duncan, Christopher J. Nelson and Thomas M. Fyles
DOI: 10.1039/c3ob40593a

All free to access for 4 weeks!

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Meet the team at ESOC 2013

26 Jun 2013

By Marie Cote, Deputy Editor.

I will shortly be attending the 18th European Symposium on Organic Chemistry (ESOC 2013) held in Marseilles, France, 7-12 July, and if you too are in attendance, I’d love to meet you there!

Dr Marie Cote, Oganic & Biomolecular Chemistry Deputy Editor

Please let us know if you will also be in attendance and would like to arrange a meeting – simply email us at the OBC editorial office.

OBC is delighted to be a media partner of the conference, and there’s lots to look forward to again on this 18th edition of the symposium:

Prof. Ben Feringa (University of Groningen, The Netherlands) will be presented with the 2013 Lilly European Distinguished Award,
Prof. Nazario Martin (Universidad Complutense de Madrid, Spain) is the recipient of the 2012 EuCheMs Lecture Award, and
Dr Joel Turconi (Sanofi, France) will present the SANOFI Lecture

Plenary lectures at the symposium will be given by :

Prof. Alexandre Alexakis (University of Geneva, Swiss)
Prof. Fernando P. Cossio (University of the Basque Country, Spain)
Prof. Ben Davis (University of Oxford, UK)
Prof. Frank Glorius (University of Muenster, Germany)
Prof. David MacMillan (Princeton University, USA)
Prof. Eiichi Nakamura (University of Tokyo, Japan)
Prof. Michael Orfanopoulos (University of Crete, Greece)
Prof. Joost Reek (Van ‘t Hoff Institute for Molecular Sciences, The Netherlands)
Prof. Raffaele Riccio (Universita degli studi di Salerno, Italy)
Prof. Doug Stephan (University of Toronto, Canada)

Access the full scientific programme

I look forward to meeting many of you in Marseilles!

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Stirring microwave synthesis

19 Jun 2013

By Alessia Millemaggi.

Highlighting an OBC article being featured in Chemistry World

It is next to impossible to achieve good mixing with traditional magnetic stir bars in the cylindrical vessels used in microwave synthesis. So scientists in Austria have designed a new stir bar.

Microwave synthesis is becoming more popular thanks to the dramatically reduced reactions times and improved yields it offers. However, as the majority of these reactions involve a small narrow reaction vessel, traditional horizontal stir bars often result in inefficient mixing which can cause temperature gradients to develop and reduce product yields.

Magnetic stirring usually involves a polymer coated AlNiCo or ferrite magnet and relies on the establishment of a liquid flow induced by centrifugal forces. These flow patterns involve a downward liquid motion towards the centre and an upward motion at the vessel wall. However, the strength of the magnet decreases rapidly over a period of months when subjected to the high temperatures of microwave synthesis and the limited size of the vessel restricts the establishment of flow patterns.

‘We noticed that in some instances the agitation of the reaction mixture using a standard magnetic stir bar was very poor. Sometimes the stirrer was not moving at all,’ says Oliver Kappe whose team at the University of Graz used a camera to look at a microwave system before designing the new stir bar.

Choice of magnetic material and shape were thought to be key to the success of the new stir bar. Vertical blade extensions were added to a more robust Sm₂Co₁₇ rare earth magnet. This not only extends the life of the stir bar but also significantly enlarges the cross-sectional area of the stirrer. A gap in the centre of the bar guarantees backflow which enforces flow patterns and extended blades mean that even the upper part of the system receives efficient mixing with the incorporation of additional holes and cut-outs inducing additional turbulence.

Read the full story in Chemistry World

Design and evaluation of improved magnetic stir bars for single-mode microwave reactor
David Obermayer, Markus Damm and C. Oliver Kappe
Org. Biomol. Chem., 2013, Accepted Manuscript
DOI: 10.1039/C3OB40790J

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Switching chirality in amino acids

17 Jun 2013

By Alessia Millemaggi.

Highlighting an OBC article being featured in Chemistry World

An international team of scientists has developed a purely chemical approach to interconvert L- and D-amino acids. This method could rival enzymatic routes used in industry, and enable cheaper production of some pharmaceuticals. interconversion-of-amino-acids_c3ob40541a_300m

While L-amino acids are an inexpensive and renewable source of chiral molecules, used by all cells to synthesise proteins, D-amino acids are scarce in nature and consequently more expensive. Despite their rarity in biological systems, D-amino acids are widely used in the pharmaceutical industry, occurring in many drugs, including antibiotics such as penicillin and anticancer agents such as goserelin.

Currently, D-amino acids are prepared industrially by enzymatically resolving racemic mixtures of amino acids. A readily available source of D-amino acids would obviate the need for resolution, simplifying synthetic routes to many pharmaceuticals.

Vadim Soloshonok, Ikerbasque Research Professor at the University of the Basque Country, Spain, and his colleagues, used inexpensive nickel(II) acetate and a modularly designed chiral ligand derived from α-(phenyl)ethylamine to transform natural amino acids into their unnatural enantiomers. A Ni(II) amino acid Schiff base complex with three stereogenic centres, including a stereogenic nitrogen, was formed under mild and operationally simple reaction conditions. The complex enables the stereocontrolled deprotonation of the α-carbon of amino acids to invert their stereochemistry.

Soloshonok says that this methodology could have a potentially huge impact on the multi-billion dollar amino acid market. ‘D-amino acids are starting materials in the synthesis of pharmaceutical drugs and if we can reduce the price of the starting materials we can make the pharmaceuticals more affordable to people.’

Read the full story in Chemistry World

Chemical approach for interconversion of (S)- and (R)-α-amino acids
Alexander E. Sorochinsky, Hisanori Ueki, José Luis Aceña, Trevor K. Ellis, Hiroki Moriwaki, Tatsunori Sato and Vadim A. Soloshonok
DOI: 10.1039/c3ob40541a

Free to access for 4 weeks

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An end to chasing molecules that were never there?

12 Jun 2013

By Alessia Millemaggi.

Highlighting an OBC article being featured in Chemistry World

Imagine finally completing a 30 step total synthesis only to discover that the molecule you were aiming for was the wrong one. The consequences of structural misassignment of complex organic molecules can be costly and time consuming, not to mention frustrating. Now, a new NMR method aims to highlight errors in proposed structures at a much earlier stage, preventing such scenarios.

NMR spectroscopy is a standard tool for elucidating the structure of organic molecules. This may be a straightforward job when confirming the identity of small molecules. However, in the case of complex molecules, the task becomes much more difficult and errors can result in the wrong structure being proposed.

Ariel Sarotti from the Rosario National University, Argentina, has developed a new, computationally inexpensive method combining calculated and experimental ¹³C NMR data to flag up incorrect structures. This rapid and simple process can determine if a candidate structure is incorrect, using trained artificial neural networks (ANNs) to find patterns in both the calculated and experimental data to do the decision making. A set of 200 molecules with known correct and incorrect NMR assignments was used to create and train the system. The subsequent testing phase correctly identified the incorrect structures of a set of 26 natural products. While some knowledge of computational chemistry is required, Sarotti’s development of an Excel spreadsheet tool will allow chemists to use the method without being experts in ANNs, making it much more accessible.

Read the full story in Chemistry World

Successful combination of computationally inexpensive GIAO 13C NMR calculations and artificial neural network pattern recognition: a new strategy for simple and rapid detection of structural misassignments
DOI: 10.1039/C3OB40843D

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New neuraminidase inhibitors to combat bird flu

04 Jun 2013

By Alessia Millemaggi.

This paper is HOT as recommended by the referees, and is free to access for 4 weeks.
Published on behalf of Steve Moore, Organic & Biomolecular Chemistry web science writer.

Avian influenza is an RNA virus, with subtypes classified by hemagglutanin and neuraminidase (NA) viral surface membrane glycoproteins. There are 9 NA serotypes of influenza A circulating within the avian population (N1-N9). At present, there are two commercially available NA inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza) and the threat of drug-resistant viruses is driving the development of new NA inhibitors.

The X-ray crystal structure of zanamivir-bound N1 show the C-4 guanidino group of zanamivir located near the 150-loop adjacent to the active site of NA. In this HOT article, Tsu-An Hsu, Chun-Cheng Lin and co-workers report the synthesis and inhibitory activity of a series of zanamivir derivatives with modified C-4 guanidino groups. The new, structurally modified zanamivir analogues retained inhibitory activity against H1N1 and H3N3 avian influenza viruses.

Synthesis of acylguanidine zanamivir derivatives as neuraminidase inhibitors and the evaluation of their bio-activities
Chien-Hung Lin, Tsung-Che Chang, Anindya Das, Ming-Yu Fang, Hui-Chen Hung, Kai-Cheng Hsu, Jinn-Moon Yang, Mark von Itzstein, Kwok Kong T. Mong, Tsu-An Hsu and Chun-Cheng Lin
DOI: 10.1039/c3ob40624e

Free to access for 4 weeks

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HOT – Taxol analogues offer promising new anti-cancer leads

29 May 2013

By Annabella Newton, RSC Blogs Writer.

Annabella Newton is an organic chemist and trainee patent attorney with Phillips Ormonde Fitzpatrick based in Melbourne, Australia.

In this HOT paper, K. C. Nicolaou and co-workers have developed a series of taxol analogues which show potent activity against several cancerous cell lines.

The fight against cancer is one of the hottest areas of drug discovery. Despite this, there is still a shortfall in treatment options and the disease is on the rise. The development of safer and more selective drugs is therefore required.

Paclitaxel (taxol) and docetaxel are two of the most highly successful anti-cancer drugs and much research has been performed focused on their synthesis and structure. K C Nicolaou and his group at Scripps are well-versed in the construction of paclitaxel; the group published one of the first total syntheses of this complex molecule in 1994.

10-Deacetylbaccatin III is an advanced synthetic precursor to paclitaxel and shares many its core structural features. Thanks to the synthetic efforts of recent years, it’s also readily accessible and therefore it provides an interesting starting point for further structure-activity relationship studies. Nicolaou and Valiulin have found that, upon treatment with diethylaminosulfur trifluoride (DAST), 10-deacetylbaccatin III undergoes a nifty vinylogous pinacolpinacolone rearrangement leading to a new enone structure and its fluorinated analogue.

Nicolaou and Valiulin have capitalised on this discovery and have prepared an small library of structurally analogous taxoids using this reaction. The library of analogues was submitted to screening program run by the National Cancer Institute (NCI) where the compounds were evaluated against 60 different cancerous cells lines. Several of the taxoids showed significant potency against numerous tumour cell lines. This study has revealed important information regarding the structure-activity relationship of the taxoid family of molecules. It has also produced some promising potential leads for new anti-cancer drugs.

Synthesis and Biological Evaluation of New Paclitaxel Analogs and Discovery of Potent Antitumor Agents
Kyriacos C. Nicolaou and Roman A. Valiulin
DOI: 10.1039/C3OB40654G

Free to access for 4 weeks

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The power of multivalency against cholera

23 May 2013

By Marie Cote, Deputy Editor.

An international team of scientists has synthesised a cholera inhibitor that matches both the valency and target sugar of the cholera toxin. The molecule is 100,000 times better at trapping the cholera toxin than inhibitors based on the target sugar alone.

Cholera is an acute intestinal infection that can be fatal in severe cases. It is caused by the cholera toxin, a protein with a disease causing A subunit, surrounded by five B subunits. The B subunits bind to GM1, a pentasaccharide sugar, on the cell membrane of intestinal cells. Once attached, the cholera toxin can inject its toxic A subunit into the cell.

‘Optimally, one would bind all 5 B subunits to one inhibitor that uses this natural GM1 sugar,’ explains Han Zuilhof, from Wageningen University, the Netherlands, who led the work. ‘This should yield the strongest one-on-one complex. Previous work combined either pentavalent scaffolds with simpler sugars, or non-pentavalent scaffolds with the real deal sugar.’ Now, Zuilhof and colleagues have created the first inhibitor that is both pentavalent and uses GM1.

Read the full article in Chemistry World

And read the OBC paper here:
Picomolar inhibition of cholera toxin by a pentavalent ganglioside GM1os-calix[5]arene
Jaime Garcia-Hartjes, Silvia Bernardi, Carel A. G. M. Weijers, Tom Wennekes, Michel Gilbert, Francesco Sansone, Alessandro Casnati and Han Zuilhof

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The 21st Lakeland meeting on Heterocyclic Chemistry and Synthesis, 40 years since the first meeting, was not to be missed!

20 May 2013

By Marie Cote, Deputy Editor.

Read the organisers’ highlights of the 2013 edition…

Were you there? Or you might have been following the live tweets from @Grasmere2013, updated by @APDobbs & @AzaPrins?

For a round up of the meeting and some highlight pictures, why not read below for a summary by this year’s organisers!

Grasmere 2013

The Heterocyclic Group began in 1967 and first held a Heterocyclic Conference in the Lake District village of Grasmere in May 1973. This meeting has been repeated every two years since, and the latest in this series took place 9-13th May 2013 and organised by Professors Adrian Dobbs (University of Greenwich) and David Knight (Cardiff University).

This was a landmark for the meeting, marking 40 years since the first such meeting and the 21st meeting in the series – the ‘coming of age’ symposium! The original founder of the meeting, Professor Otto Meth-Cohn was in attendance and one member of the group, Professor Gurnos Jones has attended all 21 meetings. As ever, lectures were held in Grasmere Village Hall and the conference booked-out two local hotels, as well as numberous B&B’s. Excellent science and food were in abundance during the meeting, as was the Lakeland rain, but a good time was had by all.

Highlights of the meeting included the presentations of two RSC Medals and their associated lectures: to Professor Scott Rychnovsky (UC Irvine, Pedler Medal) and Professor Chris Moody (University of Nottingham, Charles Rees Medal and Lecture).

Group photo outside Grasmere village Hall

Dr Robin Attrill (GSK); Prof Adrian Dobbs (Uni of Greenwich & Sec/Treasurer Heterocycli & Synthesis Group); Prof Scott Rychnovsky (recipient of the RSC Pedler Medal Award); Dr David Rees (Org Div President); Dr Marie Cote (Deputy Editor, OBC)

Prof Keith Jones (ICR); Prof Chris Moody (Uni of Nottingham, recipient of the RSC Charles Rees Award); Dr David Rees (Astex Pharmaceuticals)

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Organic & Biomolecular Chemistry Blog

Carboxylate-isostere analogs of daptomycin: synthesizing the next generation of antibiotics

Latest HOT articles in OBC

Meet the team at ESOC 2013

Stirring microwave synthesis

Switching chirality in amino acids

An end to chasing molecules that were never there?

New neuraminidase inhibitors to combat bird flu

HOT – Taxol analogues offer promising new anti-cancer leads

The power of multivalency against cholera

The 21st Lakeland meeting on Heterocyclic Chemistry and Synthesis, 40 years since the first meeting, was not to be missed!

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