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New publication on the cytotoxic activity of organometallic di-iron complexes in cancer cell lines

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Recent collaborative work from NATURE-ETN and the University of Pisa has been published in Organometallics by ESR Maria Dalla Pozza from the group of Gilles Gasser at Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences (France), in collaboration with the team of Prof. Fabio Marchetti at the University of Pisa (Italy). The scientists investigated the anticancer activity of some di-iron compounds functionalised with sugar moieties to increase their cellular uptake and possibly their selectivity for cancer cells. The compounds, synthesised by Marchetti’s group, were tested against a panel of cancerous cells by ESR Maria Dalla Pozza.

Among the different categories of metal drug candidates, iron complexes based on the ferrocene scaffold have aroused notable interest. The antiproliferative activity of these compounds is ascribable to the redox chemistry of the ferrocenyl iron(II) center, which undergoes oxidation to Fe(III) in the tumour cells. This enhances the formation of toxic metabolites that lead to cell death. Di-iron compounds have been less investigated, however recent studies have disclosed a promising anticancer potential. In this study, the sugar functionalisation was performed on di-iron complexes to optimise the cytotoxic properties by exploiting the Warburg effect. Specifically, the anticancer activity of the compounds was evaluated using the resazurin assay and the scratch assay. Overall, this study pointed out that the antiproliferative activities of the new complexes correlate with their lipophilicity, ranging from moderate cytotoxicity to inactivity, and showing an absence of appreciable selectivity with respect to a non-cancerous cell line. On the other hand, analogous diiron complexes without the sugar moiety functionalisation, analysed as references, performed better in the same conditions. This confirms the potential of the present category of organometallics in the medicinal field.

Reference:
Schoch, S., Iacopini, D., Dalla Pozza, M., Di Pietro, S., Degano, I., Gasser, G., Di Bussolo, V., and Marchetti, F. Tethering Carbohydrates to the Vinyliminium Ligand of Antiproliferative Organometallic Diiron Complexes. 
Organometallics (2022). https://doi.org/10.1021/acs.organomet.1c00519

New publication examines the multi-modal activity of copper(II) and silver (I)-phendione complexes on DNA scission within P. aeruginosa

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Recent collaborative work from NATURE-ETN has been published in the Journal of Biological Inorganic Chemistry by researchers in the Kellett lab at DCU. Co-authors include NATURE-ETN coordinator Dr. Andrew Kellett, co-supervisor Dr. Georgia Menounou, and ESR Conor Bain. The paper investigated the multi-modal activity of copper(II) and silver(I) complexes with the N,N-coordinating ligand, 1,10-phenanthroline-5,6-dione, with particular focus on DNA damage within Pseudomonas aeruginosa.

The emergence of microbial drug-resistance in recent decades has given rise to the need for novel antimicrobial therapeutics. The metal-based complexes [Ag(1,10-phenanthroline-5,6- dione)2]ClO4 (Ag-phendione) and [Cu(1,10-phenanthroline-5,6-dione)3](ClO4)2.4H2O (Cu-phendione) have previously demonstrated efficient antimicrobial action against multidrug-resistant species. The focus of the study was to understand the binding potential of these complexes with double-stranded DNA using a combination of in silico and in vitro approaches. Promising results arising from this work revealed a potentially new class of antimicrobial drug candidate with a distinct therapeutic mechanism against the multidrug-resistant pathogen P. aeruginosa.

Molecular docking studies showed both complexes elicit a multi-mechanistic approach to DNA-binding via hydrogen bonding, hydrophobic and electrostatic interactions, with both complexes favouring minor groove binding. Of the two complexes, Cu-phendione achieved the highest binding affinity for both major and minor grooves with nearly 10x greater affinity to DNA than Ag-phendione and nearly 20x greater affinity than the phendione ligand alone. Cu-phendione achieved DNA scission through free radical oxidative damage, as well as DNA-nicking and relaxation of supercoiled plasmid DNA. It was concluded that both complexes elicit a dose-dependent effect, with successful DNA fragmentation within multi-drug resistant pathogen P. aeruginosa when treated with a single dose of Cu-phendione. This work proposes a novel dose-regulated class of metal-based antimicrobial therapeutics.

Reference:

Galdino, A.C.M., Viganor, L., Pereira, M.M., Devereux, M., McCann, M., Branquinha, M.H., Molphy, Z., O’Carroll, S., Bain, C., Menounou, G., Kellett, A., Dos Santos, A.L.S. Copper(II) and silver(I)-1,10-phenanthroline-5,6-dione complexes interact with double-stranded DNA: further evidence of their apparent multi-modal activity towards Pseudomonas aeruginosa. J Biol Inorg Chem (2022). https://doi.org/10.1007/s00775-021-01922-3

Global Tech Company Biotage acquires ATDBio

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On 20 October 2021, one of NATURE-ETN’s partners, ATDBio has announced that it has been acquired by Swedish multinational life sciences company Biotage for approximately £ 45 million. The acquisition will bring many years of experience and expertise in highly complex DNA and RNA production to Biotage. As a new part of the Biotage Group, the ATDBio founders will continue to work on these technologies with existing and new customers. While ATDBio is undergoing major changes, R&D projects such as the ones that are ongoing as part of NATURE-ETN – with early-stage researcher Diallo Traore on CRISPR-Cas 9 in live-cell imaging – will continue as planned.

“ATDBio is very proud to become part of the Biotage family, which shares our passion for innovation, customer focus and sustainability. With our deep understanding of nucleic acid chemistry, we can ensure superior quality oligonucleotide synthesis, and supply highly pure products. We make oligonucleotides for a broad range of academic and commercial customers, including some of the most significant biotech and pharma companies globally. We will now be able to scale up even further thanks to the global presence and world-leading separation science expertise of Biotage.  We will continue to innovate, helping our customers to bring the next generation of nucleic acid molecular diagnostics, vaccines and therapeutics to the market”, said Dr Tom Brown Jr, Director of ATDBio.

ATDBio was founded in 2004 by Professor Tom Brown (Snr), one of the world’s leading nucleic acids chemists, Dr Dorcas Brown, an expert in oligonucleotide synthesis, Dr Tom Brown (Jnr) and Dr Asha Brown. It has laboratories in Oxford and Southampton, UK. As a leader in complex oligonucleotide synthesis, ATDBio has been working on molecular diagnostics, nucleic acid-based therapeutics and vaccines in addition to a new generation of DNA and RNA sequencing technologies.

Press release (Biotage)

Press release (ATDBio)

Successful NATURE-ETN check meeting

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The NATURE-ETN check meeting with our European Commission Research Executive Agency (REA) Project Officer took place online on the 5th of October 2021. Our Coordinator reported on the progress of the project and the COVID-19- and Brexit-induced challenges encountered and successfully solved through effective mitigation measures and collaboration. On their side, our 15 ESRs introduced themselves, their project objectives and training ambitions. The discussions on the next steps and upcoming milestones with the REA Project Officer were both fruitful and informative.

This meeting was the occasion to highlight our appreciation for the REA’s flexibility and support in these uncertain times and our gratitude for being part of the Marie-Skłodowska-Curie Actions community. A community that now counts two Nobel Prize winners in Chemistry for the second year in a row.

Open position in Oxford, UK

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The research group of Prof. Tom Brown from the Oxford University Department of Chemistry is looking for an Early-Stage Researcher (ESR) for a period of three years. The ESR will work on a project entitled “chemically modified CRISPR systems for improved gene editing”, which aims to use cutting-edge nucleic acid chemistry to radically alter the mechanism by which the CRISPR-Cas9 system functions.

Deadline for application: 10 March 2021

Job description and application details

Picture: Bodleian Library, Oxford / Author: Zhushenje

First ESRs recruited

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Seven out of the 15 ESRs have started their position in Germany, United Kingdom, France and Czech Republic.

The NATURE- ETN intersectorial training programme will provide them  with unique multidisciplinary scientific training  in the fields of chemical synthesis, biochemistry and cell biology as well as transferable and business skills, thanks notably to the contribution of the industry partners.

You can read about their project and background in the “People” section.