RSC Medicinal Chemistry Blog

Taking inspiration from honey bees, scientists in South Korea have incorporated a compound used in beehives into a new strong biomaterial with sustained antimicrobial properties.

CAPE-loaded PMMA (left) was found to be stronger than gentamycin-loaded (right) PMMA

Bone cements have been used in surgery since the 1940s and work like a grout to fill the gaps between orthopaedic implants and bones. The most commonly used bone cements are made from a synthetic resin called poly (methyl methacrylate), or PMMA, and have recently been loaded with antibiotics, such as gentamycin, in an attempt to reduce healthcare related infections. However, the addition of antibiotics has raised concerns over antibiotic resistance, potential carcinogenic effects and the reduced mechanical strength of PMMA.

To overcome these potentially harmful limitations, a team led by Jeong Ho Chang at the Korea Institute of Ceramic Engineering and Technology, have developed PMMA bone cement loaded with caffeic acid phenethyl ester (CAPE). CAPE is an active component of bee propolis, a resin-like mixture collected by honey bees from various trees and buds and used to fill small gaps in the beehive. CAPE is thought to have antimicrobial, anti-inflammatory, antioxidant and anti-cancer effects and has already been approved for use in foods, drinks and cosmetics by the Food and Drug Administration.

The researchers were not only able to demonstrate that CAPE-loaded PMMA is an effective antimicrobial against Staphylococcus aureus, but it also has much better compressive strength than antibiotic-loaded PMMA. This impressive strength is thought to be due to a higher packing density caused by reinforced chemical bonding between the PMMA and CAPE through homogeneous loading. In contrast, conventional antibiotic-loaded bone cements are not uniformly mixed and have low loading efficiencies, so the compressive strength is similar to native PMMA. This also explains why CAPE–PMMA exhibits more controlled and sustained antimicrobial release compared to bone cement loaded with gentamycin.

Antoni Tomsia, a biomaterials expert specialising in treatments for bone defects and diseases at the Lawrence Berkeley National Laboratory, University of California, US, thinks that the incorporation of natural antimicrobials is a good idea. However, he emphasises that antimicrobial implants must go hand-in-hand with ‘provider hand hygiene, patient decolonisation efforts, or environmental decontamination, plus sterilisation, to prevent infections.’

Initial studies were carried out in rabbits and Chang believes that CAPE-loaded PMMA bone cement could be used for human clinical applications after therapeutic efficacy evaluation. ‘We are trying to discuss and work with a medical orthopaedics doctor and I think we can report the new clinical data in the near future,’ reveals Chang.

Story first appeared in Chemistry World November 2014, written by Thadchajini Retneswaran.

Hye Sun Lee and Jeong Ho Chang’s article entitled ‘Antimicrobial spine-bone cement with caffeic acid phenethyl ester for controlled release formulation and in vivo biological assessments‘ featured on the cover of issue 2 of MedChemComm

The flow-based route required minimal manual intervention and was achieved despite poor solubility of many reaction components

UK chemists have used a combination of flow chemistry methods with solid-supported scavengers and reagents to synthesise the active pharmaceutical ingredient, imatinib, of the anticancer drug Gleevec. The method avoids the need for any manual handling of intermediates and allows the drug to be synthesised in high purity in less than a day.

Gleevec, developed by Novartis, is a tyrosine kinase inhibitor used for the treatment of chronic myeloid leukaemia and gastrointestinal stromal tumours. The drug molecule represents a particularly challenging target for flow chemistry because of the low solubility of many of the reaction components required for its synthesis. The team devised a new synthesis route that prevents the equipment blockages from product precipitation and avoids many of the labour and time intensive practices of traditional batch-based preparation.

The work proved to be a challenge. Steve Ley, at the University of Cambridge, who led the team, says that along the way, they ‘met some considerable obstacles and dead ends’. He remarks that ‘in order to overcome the need to change solvents between some of the reaction stages, we had to invent a new in-line evaporator, which served us well in this and in later synthesis studies’.

Unlike the conventional industrial synthesis of Gleevec, this newly developed route couples molecular fragments in a modular approach. Thomas Wirth, who works on microreactor technology at Cardiff University, UK, remarks that ‘although not designed to compete with the industrial synthesis, the modular approach allows an easy variation of building blocks for the efficient and rapid generation of Gleevec analogues for screening purposes’.

A total of nine analogues were synthesised using the final equipment set-up, which were then screened for anticancer activity. The findings revealed that the piperazine group in the drug molecule plays a role in receptor binding, rather than simply acting as a solubilising group as previously thought.

Ley’s team is now working to combine the synthesis and screening to provide information on products rapidly, as well as extending their approach to new functional materials.

Read the Organic & Biomolecular Chemistry paper, for free for 4 weeks here:

An expeditious synthesis of imatinib and analogues utilising flow chemistry methods
Mark D. Hopkin, Ian R. Baxendale and Steven V. Ley
Org. Biomol. Chem.
DOI: 10.1039/C2OB27002A

Story first published in Chemistry World.

With up to five million cases of the acute respiratory illness influenza leading to half a million deaths each year worldwide, the search for better treatments is important. Scientists from Australia and the US have developed a synthesis for a drug that gives higher yields and antiviral activity than currently used commercial drugs, such as Relenza (zanamivir) and Tamiflu (oseltamivir), they claim.

Although existing dimeric zanamivir compounds show significant therapeutic potential, the currently used synthesis method only produces the compounds in moderate yields. Benjamin Fraser and co-workers at the Australian Nuclear Science and Technology Organisation have designed a higher-yielding synthesis route, which can also prepare the dimers with new linker functionality.

The group prepared the new class of zanamivir dimers by using a known cycloaddition reaction that improved the coupling yields and allowed rapid optimisation of the antiviral activity as a function of the linker length. The dimers synthesised are among the most effective inhibitors of influenza to date, being up to 3000 times more potent than zanamivir. This potency may be because the dimers work by a dual mechanism: they inhibit neuraminidase (an enzyme on the virus’ surface and a target in influenza treatments) and their aggregation is enhanced.

Although vaccination programs reduce the risk of an epidemic influenza outbreak, there is still a need for antiviral drugs © Shutterstock

Fraser comments that the dimers are still at the research stage, so a significant amount of further testing is required before the drugs can be ready for human use. The group hopes to radiolabel the compounds in the future so the bio-distribution, metabolism and retention time in the lungs can be measured. Fraser also mentions that it may also be possible to obtain even greater antiviral activity by developing high order multimers, including trimers and tetramers of zanamivir, as each neuraminidase receptor on the virus has four active sites.

Although neither approach used by the group is new, comments Hans Streicher at the University of Sussex, UK, the study adds ‘valuable information regarding the optimal distance’ between the inhibitor moieties, and will thus aid the development of a new generation of anti-influenza drugs.

Story first published in Chemistry World

And read the full MedChemComm paper for free for 4 weeks here:

Synthesis of 1,4-triazole linked zanamivir dimers as highly potent inhibitors of influenza A and B
Benjamin H. Fraser, Stephanie Hamilton, Anwen M. Krause-Heuer, Philip J. Wright, Ivan Greguric, Simon P. Tucker, Alistair G. Draffan, Valery V. Fokin and K. Barry Sharpless

Despite being the focus of much recent research, it is estimated that over 400 million people are currently infected with malaria, schistosomiasis or hookworm. As an attempt to help remedy this, scientists in the US have developed a hybrid drug that is active against all three of these parasitic diseases.

Over 400 million people are infected with malaria, schistosomiasis or hookworm (shown)

Although a variety of approaches have been developed for the treatment of these diseases, there are often toxic side effects associated with the drugs and widespread resistance to frequently used molecules has developed. To help improve the drugs on offer for those infected, Bryan Mott at the National Institutes of Health, and co-workers, have been investigating combined therapeutics, which can be especially useful for multiple parasites endemic in the same region.

The group developed a hybrid drug containing two heterocycles: furoxan and quinoline. The researchers had previously seen that furoxan had demonstrated significant anti-parasitic activity and quinoline has also shown promise in the chemotherapy of a variety of other diseases. It is likely that quninoline works by a different, perhaps complimentary, mechanism to furoxan, therefore the group’s rationale was that the combination of the two molecules could be beneficial.

Read the full story in Chemistry World

And read the full MedChemComm paper here:
A furoxan–amodiaquine hybrid as a potential therapeutic for three parasitic diseases
Bryan T. Mott et al.
DOI: 10.1039/C2MD20238G

Broccoli and Brussels sprouts contain compounds that can inhibit the growth of bacteria that cause disease

Chemists from Israel say that the isothiocyanates sulforaphane and erucin, found in brassicaceae vegetables such as broccoli, Brussels sprouts, cabbage and cauliflower, inhibit growth of the disease-causing bacteria Pseudomonas aeruginosa.

Bacterial quorum sensing (QS) is the method by which bacteria communicate. Instead of language, they release signalling molecules into the environment and a single cell can sense the number of other local bacteria. By using QS, bacteria can coordinate their behaviour through gene expression and adapt to changing environmental conditions. With bacteria such as MRSA and Pseudomonas aeruginosa developing antibiotic resistance, alternative strategies to inhibit bacterial growth are necessary and QS inhibition has been suggested as a new strategy to prevent bacterial growth.

The team, led by Michael Meijler from Ben-Gurion University of the Negev, Be’er-Sheva, found that isothiocyanates from broccoli inhibit quorum sensing. ‘This might signal to the bacteria that conditions for colonisation are not optimal,’ he explains. ‘The benefits of eating vegetables to human health in general have been known for quite some time now. At the molecular level, not a great deal is known yet, providing a fertile ground for fundamental research.’

Read the entire Chemistry World story

And then read the full MedChemComm paper:
Sulforaphane and erucin, natural isothiocyanates from broccoli, inhibit bacterial quorum sensing
Hadas Ganin, Josep Rayo, Neri Amara, Niva Levy, Pnina Krief and Michael M. Meijler
DOI: 10.1039/C2MD20196H

A collagen-binding peptide with applications in wound healing has been developed by scientists in the US. The peptide is able to invade the strands of collagen, forming a strong and stable non-covalent bond at room temperature. Pendant drug molecules could be attached to the peptide and anchored at the wound site to aid wound healing…

Read the full article at Chemistry World, or read the Organic & Biomolecular Chemistry paper:

Peptides that anneal to natural collagen in vitro and ex vivo
Sayani Chattopadhyay, Christopher J. Murphy, Jonathan F. McAnulty and Ronald T Raines
DOI: 10.1039/C2OB25190F

Scientists in India are targeting enzymes responsible for catalysing the formation of bonds to repair nicks in the phosphodiester backbone of DNA – called DNA ligases – to tackle the ever-growing health concern of multi-drug resistant bacteria, in particular against tuberculosis.

Unlike current drugs, the new compound targets just the bacterial enzymes instead of both bacterial and human enzymes

DNA ligases use either adenosine triphosphate (ATP) or nicotinamide adenine dinucleotide (NAD⁺) as cofactors (small molecules that help promote biological reactions) in cellular processes, such as DNA repair and replication. Humans only have the DNA ligases that utilise ATP, but bacteria use both. Studies have shown that NAD⁺-dependent ligase is indispensable in several bacterial, including Mycobacterium tuberculosis and Escherichia coli, making them attractive drug targets.

The team from the Central Drug Research Institute in Lucknow synthesised and screened drugs from aryl hydroxamates to show that they were active against bacterial, but not human, versions of DNA ligase, as well as concluding that they did not have any general DNA interactions.

‘Hydroxamates offer a better chance to develop new economical anti-tuberculosis drugs. The ease of synthesis makes them attractive,’ says Rama Pati Tripathi, part of the team in Lucknow.

‘Developing new small molecule compounds that are able to distinguish between ATP- and NAD⁺-dependent ligases, such as the compounds presented here, is important for engineering molecules with increased levels of specificity,’ says Rommie Amaro, an expert on enzymological and drug discovery studies at the University of California, Irvine, US. ‘Such specificity is critical for these compounds to be useful from a clinical perspective.’ He adds that the work could help develop compounds that are active against RNA editing ligases. These are potential antiparasitic targets for several of the world’s most devastating diseases, such as Chagas disease and African sleeping sickness.

Synthesis and bioevaluation of aryl hydroxamates distinguishing between NAD⁺ and ATP-dependent DNA ligases
Vandna Kukshal, Mridul Mishra, Arya Ajay, Taran Khanam, Rahul Sharma, Divya Dube, Deepti Chopra, Rama Pati Tripathi and Ravishankar Ramachandran
DOI: 10.1039/C2MD00168C

Read the original article at Chemistry World

As we anticipated, Michael Hann’s review on molecular obesity has attracted loads of interest.

Chemistry World publishes a comment on this paper in the April Issue.

You can read the full story here and download the paper which is free to access here.

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

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

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