Farrell

Nicholas Farrell, Ph.D.

Professor
npfarrell@vcu.edu
(804) 828-6320
Temple 4413

Education

B. Sc. University College Dublin 1969

Ph.D. Sussex University 1973

Postdoctoral Fellowships. Simon Fraser University and The University of British Columbia.

Research

The broad impacts of our research are to expand the frontiers of the understanding of the role and utility of metal complexes in biology and medicine.  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 have 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). Research is by definition highly interdisciplinary combining chemical, computational

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. Research provides the scientific groundwork with long-term possibilities for new medicinal applications. Current projects also include the study of the “coordination chemistry” of zinc finger proteins, contributing to understanding of the design of antiviral (specifically HIV) coordination compounds from first principles. 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.

Books

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.

Selected publications

From over 200 refereed full papers and 30 reviews. Updated October 2013

Abbehausen, C, Peterson, EJ, de Paiva, RE., Corbi, PP, Formiga, ALB, Qu, Y, Farrell, N.P:

Gold(I)-phosphine-N-heterocycles. Biological activity and specific (ligand) interactions on the C-terminal HIVNCp7 zinc finger. Inorg. Chem. 2013 52, 11280–11287. doi: 10.1021/ic401535s.

Mangrum, JB, Zgani, I, Tsotsoros, SD, Qu, Y, Farrell, NP:  Zinc finger peptide cleavage by a dinuclear platinum compound. J. Chem. Soc. Chem. Comm. 2013 49, 6986–6988. doi: 10.1039/c3cc44219e.

Wedlock, LE, Kilburn, MR, Liu, R, Shaw, JA, Berners-Price, SJ, ,Farrell, NP: Nano-SIMS multi-element imaging reveals internalization and nucleolar targeting for a highly-charged polynuclear platinum compound. J. Chem. Soc. Chem. Comm. 2013 49, 6944–6946. doi: C3CC42098A.

Pinato, O, Musetti, C, Farrell, NP, Sissi, C: Platinum-based Drugs and Proteins: Reactivity and Relevance to DNA Adduct formation. J Inorg Biochem. 2013 122, 27-37. doi: 10.1016/j.jinorgbio.2013.01.007.

Quintal, SM,  Viegas, A, Erhardt, S, Cabrita, EJ, Farrell, NP: Platinated DNA affects zinc finger conformation. The interaction of a platinated single-stranded oligonucleotide and the C-terminal zinc finger of the HIVNCp7. Biochemistry. 2012 51, 1752-1761. doi: 10.1021/bi201834g

Ruhayel, R., Oke, M.-J., Langner, J.S., Zgani, I., Berners-Price, S.J. and Farrell, N.P.: Chimeric Platinum-Polyamines and DNA Binding. Kinetics of DNA Interstrand Crosslink Formation by Dinuclear Platinum Complexes with Polyamine Linkers. J. Amer. Chem. Soc. 2012 134, 7135-7146. http://www.ncbi.nlm.nih.gov/pubmed/22443454

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. http://www.ncbi.nlm.nih.gov/pubmed/22494465

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.

Anzellotti, A, Liu, Q, Bloemink, MJ, Scarsdale, JN, Farrell, N.P. Targeting the retroviral zinc finger-DNA iInteraction. A small molecule approach utilizing the electrophilic nature of trans-Platinum-nucleobase Compounds. Chemistry and Biology. 2006 13, 539-548. doi: 10.1016/j.chembiol.2006.04.004 (http://www.f1000biology.com/article/id/1032571/evaluation,Faculty of 1000 Biology).

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.

Selected Reviews

 Farrell, NP:  Progress in Platinum-Derived Drug Development.  Drugs of The Future. 37:795-806 (2012).

Quintal, SM, dePaula, QA, Farrell, NP: Zinc Finger Proteins as Templates for Metal Ion Exchange. Chemical and Biological Consequences. Metallomics. 3:121-139 (2011). doi: 10.1039/C0MT00070A

Farrell, NP: Platinum Formulations as Anticancer Drugs. Clinical and pre-clinical studies. Current Topics in Medicinal Chemistry. 11:2623-2631 (2011).  (Special Topic Issue).

Mangrum, JB, Farrell, NP:  Excursions in Polynuclear Platinum-DNA Binding. 2010. J. Chem. Soc. Chem. Comm. Feature 46, 6640-6650.

Aris, SM, Farrell, NP: Towards Antitumor Active trans-Platinum Compounds”. Eur. J. Inorg. Chem. 2009, 2009, 1293-1302.

Anzellotti, AI, Farrell, NP: Zinc Metalloproteins as Medicinal Targets. J. Chem. Soc. Chem. Soc. Reviews. 2008, 37, 1629-1651. {Reprinted for Chemical Biology (RSC) Volume 9, 2008}. doi: 10.1039/b617121b

Intellectual Property

From 20 primary patents, a total of over 70 patents includes selections, continuations-in-part and international filings. Experience in consulting on intellectual property issues and as an expert deposed witness in legal matters.

Awards and Honors

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 and currently President 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

Distinguished Scholar, College of Humanities and Sciences, Virginia Commonwealth University, 1997

Co-Chair Ninth International Symposium on Platinum Compounds in Cancer Chemotherapy, 2003a meeting which unites chemists, biochemists, pharmacologists and cancer clinicians.

Chair 1st Gordon Research Conference on Metals in Medicine, July 2002.