Nicholas Farrell, Ph.D.
B. Sc. University College Dublin 1969
Ph.D. Sussex University 1973
Postdoctoral Fellowships. Simon Fraser University and The University of British Columbia.
The broad impacts of our bioinorganic research are to expand the frontiers of the understanding of the role and utility of metal complexes in biology and medicine. Metal complex binding to biomolecules such as nucleic acids, proteins and their constituent components (purines, pyrimidines and amino acids) has been well documented. In more recent years we have recognized the importance polysaccharides, especially glycosaminoglycans, often called the “third” biomolecule. Our specific interests lie in understanding how the interactions of metal complexes can help understand biomolecular function and the long-term relevance for medicinal applications. This topic has been dominated in recent years by the use of platinum complexes in the clinical treatment of cancer but covers a broad field ranging from effects on viruses, bacteria, the historical use of gold complexes in arthritis, and even nitroprusside as a vasodilator. All these uses and effects have their origin in the coordination chemistry of these complexes and their interactions with biological molecules and biological approaches. I placed this area of research into both a bioinorganic and medicinal chemistry context in the earlier book “Transition Metal Complexes as Drugs and Chemotherapeutic Agents” (Reidel-Kluwer 1990).
Current projects include the study of the “coordination chemistry” of zinc finger proteins; Pt-DNA chemistry and development of the field of metalloglycomics. The reviews cited cover our work in these areas. In the study of zinc fingers as templates for metal ion replacement we were the first group to show a Au-catalyzed C-S aryl group transfer in Zinc Finger Proteins containing both ZnCys3His and ZnCys2His2 coordination sites (Cys= Cysteine, His = Histidine) . Diversity in gold finger structure has been elucidated by a novel use of Traveling-Wave Ion Mobility Mass Spectrometry and X-Ray Absorption Spectroscopy [2,3]. In DNA chemistry, the structure of the phosphate clamp, a third DNA-ligand binding mode discrete from intercalation and minor groove binding has been described in the solid state and solution [4-6]. Glycosaminoglycans, specifically Heparan Sulfate Proteoglycans have been identified as receptors for charged coordination complexes of Pt and Co, presenting a new discrete mechanism of cellular accumulation for these species [7,8,9]. Of especial interest from this work is the description of the biological activity of the iconic Co-based Werner’s Complex .
In platinum antitumor chemistry our objective is to design and develop complexes acting by new discrete mechanisms of action. Platinum-based drugs are an important part of the anticancer drug armamentarium. Polynuclear platinum complexes studied in our laboratory are a discrete structural class distinct from the clinically used mononuclear cisplatin, carboplatin and oxaliplatin. Structurally unique complexes acting by different mechanisms may display an altered spectrum of antitumor activity and especially activity in cisplatin-resistant lines. To achieve this goal it is necessary to design new chemotypes and delineate their biological action through systematic examination of the principal factors controlling platinum drug cytotoxicity and antitumor activity – cellular accumulation, target (DNA) interactions and the extent of metabolizing interactions. Proof of principle of the utility (and success) of this approach is afforded by the advance of BBR3464, a trinuclear, bifunctional DNA binding agent with an overall 4+ charge, to Phase II clinical trials, the first and only non-cisplatin analog to be introduced to humans. With this advance the paradigm of cisplatin-based antitumor agents was altered. The challenge for coordination chemists is to expand frontiers and to suggest new mechanisms of action and targets for biologically active inorganic compounds. Consideration of glycosaminoglycans as receptors has led to description of direct antimetastatic and antiviral effects of polynuclear platinum complexes [10-12].
Basic research provides the scientific groundwork for long-term possibilities of new medicinal applications. Science is multidisciplinary and international and we have benefitted from excellent collaborations especially from (in alphabetical order) Australia, Brazil, Czech Republic and Ireland. The potential application of our research results will demonstrate the linkage between discovery and societal benefit by expanding in a rational and innovative manner the knowledge gained in diverse scientific areas and placing both in new contexts and understanding.
Transition Metal Complexes as Drugs and Chemotherapeutic Agents, Farrell, N. in “Catalysis By Metal Complexes”, James, B.R. and Ugo, R., Eds., Kluwer Academic Press (1989). ISBN 9027728283.
Uses of Inorganic Chemistry in Medicine, Farrell, N., Ed., Royal Society of Chemistry (1999). ISBN 0 85404 444 2.
Platinum-Based Drugs in Cancer Therapy, Kelland, L.R. and Farrell, N. Eds., in “Cancer Drug Discovery and Development”, Teicher, B.A., Ed. Humana Press (2000). ISBN 0896035999.
Select reviews and papers
From over 270 refereed full papers and 40 reviews. Updated October 2021
- dePaiva, R.E.F., Du, Z., Nakahata, D.H., Lima, F.A., Cobi, P.P., Farrell, N.P.: Au-catalyzed C-S aryl group transfer in Zinc Finger Proteins. Angew. Chem. Intl. Ed. 2018, 57, 9305-9309 DOI: 10.1002/anie.201803082
- Du, Z., de Paiva, R.E.F., Nelson, K. and Farrell, N.P.: Diversity in Gold Finger Structure Elucidated byTraveling-Wave Ion Mobility Mass Spectrometry. Angew. Chem. 2017, 56, 4464-4467. PMID: 28319298. Designated Hot Paper (“chosen by the Editors for their importance in a rapidly evolving field of high current interest”).
- Abbehausen, C., de Paiva, R.E.F., Gomes,S.Q. Du, Z., Corbi, P.P,. Lima, F.A., Farrell, N.P.: X-Ray Absorption Spectroscopy combined with Time-Dependent Density Functional Theory elucidates differential substitution pathways of Au(I) and Au(III) with Zinc Fingers. Inorg. Chem. 2017, 57, 218-230. PMID:29227104
- Komeda, S., Moulaei, T., Woods, K.K., Chikuma, M., Farrell, N. and Williams, L.D.: Phosphate Clamps: A Novel Mode of DNA Interaction by a Polynuclear Platinum(II) Complex. J. Amer. Chem. Soc. 2006, 128, 16092-16103. PMID: 17165762
- Komeda, S, Moulaei, T, Chikuma, M, Odani, A, Kipping, R, Farrell, NP, Williams, LD: The Phosphate Clamp: A Small and Independent Motif for Nucleic Acid Backbone Recognition. Nuc. Acids Res. 2011, 39, 325-336. PMID: 20736180
- Qu, Y., Kipping, R.G. and Farrell, N.P.: Solution Studies on DNA Interactions of Substitution-inert Platinum Complexes mediated via The Phosphate Clamp. J. Chem. Soc. Dalton Trans. 2015, 44, 3563-3572. PMID 25524170.
- Silva, H., Frézard, F., Peterson, E.J., Kabolizadeh, P., Ryan, J.J. and Farrell, N.P.: Differential Cellular Accumulation Mechanisms for Platinum. Glycosoaminoglycan-mediated entry pathway for charged tri-platinum compounds. Mol. Pharm. 2012, 9, 1795-1802. PMID: 22494465
- de Paiva R.E.F., Peterson, E.J., Malina, J., Zoepfl, M., Hampton, J.D., Johnson, W.E., Graminha, A., Ourahmane, A., McVoy, M.A., Brabec, V., Berners-Price, S.J., Farrell, N.P.: On the Biology of Werner’s Complex Angew. Chem. Int. Ed. (2021) 60, 17123-17130 PMID 34105220.
- Gorle, A.K., Rajaratnam, P., Chih-Wei Chang, C.-W., von Itzstein, M., Berners-Price, S.J., Farrell, N.P.: Glycans as Ligands in Bioinorganic Chemistry. Probing the Interaction of a Trinuclear Platinum Anticancer Complex with defined Monosaccharide Fragments of Heparan Sulfate. Inorg. Chem. (2019) 58, 7416-7155. PMID:30632736.
- Gorle, A.K., Haselhorst, T., Katner, S.J., Everest-Dass, A.V., Hampton, J.D., Peterson, E.J., Koblinski, J.E., Katsuta, E., Takabe, K., von Itzstein, M., Berners-Price, S.J., Farrell, N.P.: Conformational Modulation of Iduronic Acid-Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound. Implications for Development of Antimetastatic Platinum Drugs. Angew. Chem. Intl. Edn. (2021) 60, 3283-3289. doi: 10.1002/anie.202013749 PMID: 33174390 (Designated Hot Paper). See also “Fighting Cancer from a Chair” Wiley Online Library Press Release:https://onlinelibrary.wiley.com/page/journal/15213773/homepage/press/202026press.html
- Shoup, M., Ourahmane, A., Ginsburg, E.P., Farrell, N.P., McVoy, M.A.: Substitution-inert platinum compounds inhibit human cytomegalovirus attachment and entry. Antiviral Research. (2020) 184, 104957. PMID: 33132195
- Bailly, B., Gorle, A.K., Dirr, L., Malde, A.K., Farrell, N.P., Berners-Price, S.J., von Itzstein, M.: Platinum complexes act as shielding agents against virus infection. J. Chem. Soc. Chem. Comm. (2021) 57, 4666-4669. DOI: 10.1039/D1CC01593A.
Farrell, N.P.: Medicinal Inorganic Chemistry. New Perspectives and Targets for the Periodic Table. Adv. Inorg. Chem. (AINC), Vol. 75. a thematic volume devoted to ‘Medicinal Chemistry’ Eds. R. van Eldik and P.J. Sadler.2020, Academic Press, pp57-86. https://doi.org/10.1016/bs.adioch.2019.10.003
Gorle, A.K., Berners-Price, S.J., Farrell, N.P.: Biological relevance of interaction of platinum drugs with O-donor ligands. Inorg. Chim. Acta 2019, 495, 118974. PMID: 31354168
Stelling, M.P., Motta, J.M., Mashid, M., Johnson, W.E., Pavão, M.S., Farrell, N.P.: Metal ions and The Extracellular Matrix in Tumor Migration. FEBS Review. 2019, 286, 2950-2964. PMID: 31379111.
Kellett, A., Molphy, Z., Slator, C., McKee, V., Farrell, N.P.: Molecular Methods for Probing Non-Covalent Metallodrug-DNA Interactions. Chemical Society Reviews, 2019, 48, 971-988. PMID: 30714595
Brabec, V., Kasparkova, J., Menon, V., Farrell, N.P.: in "Metallo-Drugs: Development and Action of Anticancer Agents", Vol. 18 of Metal Ions in Life Sciences, Eds A. Sigel, H. Sigel, E. Freisinger, R. K. O. Sigel, Walter de Gruyter, GmbH, Berlin, Germany, 2018, 43-86. PMID: 29394021
Farrell, N.P., Gorle, A.K., Peterson, Berners-Price, S.J.: Metalloglycomics in "Metallo-Drugs: Development and Action of Anticancer Agents", Vol. 18 of Metal Ions in Life Sciences, Eds A. Sigel, H. Sigel, E. Freisinger, R. K. O. Sigel, Walter de Gruyter, GmbH, Berlin, Germany, 2018, 109-140. PMID: 29394023
Komeda, S., Qu, Y., Mangrum, J.B., Hegmans, A., Williams, L.D. Farrell, N.P.: The Phosphate Clamp as Recognition Motif in Platinum-DNA Interactions. Inorg. Chim. Acta (In “Metal-Nucleic Acid Interactions – State of the Art“). 2016, 452, 25-33. DOI: 10.1016/j.ica.2016.04.052
From 20 primary patents, a total of over 70 patents includes selections, continuations-in-part and international filings. Extensive experience in consulting on intellectual property issues and as an expert deposed witness in legal matters.
Honors and awards
Institute of Chemistry of Ireland David Brown Award 2021. Award lecture given at Inorganic Ireland Symposium May 2021
University Award of Excellence, Virginia Commonwealth University, 2020
Inducted, Virginia Commonwealth University Chapter of The National Academy of Inventors, 2018.
Designated University Professor, Virginia Commonwealth University, 2017: “The University Professorship recognizes faculty members who “teach or conduct research that crosses discipline boundaries and have an established prominence in multiple fields of study, with national or international recognition in at least one field of study”.
Distinguished Research Award. Virginia Section American Chemical Society. 2015.
Corresponding Member of The Brazilian Academy of Sciences, 2013 (http://www.abc.org.br/). The Corresponding Members “shall be foreign researchers with recognized scientific merit, who have provided relevant collaboration to the development of science in Brazil”.
Jefferson Science Fellow through the US Department of State and The National Academy of Sciences from 2010-2015 (http://sites.nationalacademies.org/PGA/Jefferson/). In this capacity I currently serve as a US Member of The US-Ireland R&D Partnership Steering Committee.
Co-founder of The Wild Geese Network of Irish Scientists, devoted to fostering collaborations between scientists in Ireland and the rest of the world and highlighting the success of Irish scientists abroad (http://www.wildgeesenetwork.org)
Distinguished Research Scholarship Award, Virginia Commonwealth University, 2003
Co-Chair Ninth International Symposium on Platinum Compounds in Cancer Chemotherapy, 2003 a meeting which unites chemists, biochemists, pharmacologists and cancer clinicians.
Chair 1st Gordon Research Conference on Metals in Medicine, July 2002.