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Nicholas P. Farrell

Department Chair Professor Inorganic chemistry (804) 828-6320 npfarrell@vcu.edu

Education

B.S., University College, Dublin
Ph.D., University of Sussex

Research interests

Our major emphasis is on the biological and medicinal properties of novel transition metal complexes and their mechanisms of action. 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, use of gold complexes in arthritis, and even nitroprusside as a vasodilator. All these uses and effects have their origin in the inorganic chemistry of these complexes and their interactions with biological molecules. I have placed this area of research into both a bioinorganic and medicinal chemistry context in the book titled “Transition Metal Complexes as Drugs and Chemotherapeutic Agents” (Reidel-Kluwer 1990).

In platinum antitumor chemistry our objective is to design and develop complexes acting by new mechanisms of action. Complexes acting by different mechanisms may display an altered spectrum of antitumor activity and especially activity in cisplatin-resistant lines. The clinical utility of complexes such as cis-[PtCl2(NH3)2)] (cisplatin, cis-DDP) and [Pt(CBDCA)(NH3)2)] (carboplatin, CBDCA = 1,1-cyclobutane-dicarboxylate) is by now well established. However, two disadvantages are that the complexes have limited activity against many common human cancers and that they are susceptible to the phenomenon of acquired drug resistance. Resistance arises for a number of reasons and enhanced repair of DNA lesions is an important factor. Our working hypothesis is that complexes capable of DNA interactions not accessible to cisplatin will produce a different spectrum of adducts (lesions) to cisplatin which may be reflected in an altered spectrum of antitumor activity. Thus, there may exist a molecular mechanism to overcoming resistance. Our work concentrates on synthesis and design of structurally novel complexes, examination of their chemistry and description of the new modes of DNA binding (mode of formation, sequence specificity, conformational changes and reactions with DNA fragments). These features are further correlated with the antitumor activity and compared with the relevant properties of cisplatin.

The two principal structural types we are investigating are dinuclear bis(platinum) complexes containing two cis-Pt(amine)2 units linked by a variable length diamine chain, [{cis-PtCl2(NH3)}2(H2N(CH2)nNH2)] and transplatinum complexes of formula trans-[PtCl2L(L')] (L' = fused planar ring such as quinoline, L = NH3; L = L' = pyridine). These series are of particular interest because they mu02/02/2007isplatin. Thus, at least two demonstrably different mechanisms to cisplatin must operate. These are the first new mechanisms shown to operate for platinum complexes. We are currently defining the similarities and differences between these series with respect to their chemistry and biological properties.

Publications

Reviews

1. Farrell, N.: Platinum Anti-cancer Drugs. From Laboratory to Clinic. ACS Symposium Series 903 “Medicinal Inorganic Chemistry,” Sessler, J.A., Doctorow, S.E., McMurry, T.J. and Lippard, S.J. Eds., 62-79 (2005).

2. Farrell, N. Pre-clinical perspectives on the use of platinum compounds in cancer chemotherapy. Seminars in Oncology. 31:1-9 (2004).

3. Farrell, N.: Polynuclear Platinum Drugs. Metal Ions in Biol. Sys. 41:252-296 (2004).

4. Farrell, N.: Inorganic Complexes as Drugs and Chemotherapeutic Agents in "Comprehensive Coordination Chemistry, II,” eds. J.A. McCleverty and T.J. Meyer, (2004) Elsevier Pergamon (Oxford, UK) vol. 9, pp. 809-840.

Papers

1. Liu, Q., Qu, Y., Van Antwerpen, R. and Farrell, N., Mechanism of the Membrane Interaction of Polynuclear Platinum Anticancer Agents. Implications for Cellular Uptake, Biochemistry, 45 (2006) 4248-4256.
2. Oehlsen, M.E., Hegmans, A., Qu, Y. and Farrell, N., Effects of Geometric Isomerism in Dinuclear Antitumor Platinum Complexes on their Interactions with N-acetyl-L-methionine, J. Biol. Inorg. Chem., 10 (2005) 433-442.
3. Quintal, S.M.O., Qu, Y., Quiroga, A.G., Moniodis, J., Nogueira, H.I.S. and Farrell, N., Pyridine-carboxylate Complexes of Platinum. Effect of N,O-Chelate Formation on Model Bifunctional DNA-DNA and DNA-Protein Interactions, Inorg. Chem., 44 (2005) 5247-5253.
4. Anzellotti, A., Stefan, S., Gibson, D. and Farrell, N., Donor Atom Preferences in Substitution Reactions of Trans-platinum Mononucleobase Compounds. Implications for DNA-protein Selectivity, Inorg. Chim. Acta, 359 (2006) 3014-3019.
5. Anzellotti, A., Sabat, M. and Farrell, N., Study of Covalent and Non-Covalent Interactions for [Metal(dien)nucleobase]2+complexes with l-tryptophan Derivatives: Formation of Metal-tryptophan Species by Nucleobase Substitution Under Biologically Relevant Conditions, Inorg. Chem., 45 (2006) 1638-1645.
6. Harris, A.L., Ryan, J.J. and Farrell, N., Biological Consequences of Trinuclear Platinum Complexes: Comparison of BBR 3464 to its Non-covalent Congeners, Mol. Pharmacol., 69 (2006) 666-672.
7. Quiroga, G.A., Pérez, J.M., Navarro-Ranninger, C. and Farrell, N., Novel Transplatinum(II) Complexes with [N2O2] Donor Sets. Cellular Pharmacology and Apoptosis Induction in Pam 212-ras Cells, J. Med. Chem., 49 (2006) 224-231. 
8. Harris, A.L., Yang, X., Hegmans, A., Povirk, L., Ryan, J., Kelland, L.R. and Farrell, N., Synthesis and Characterization of the DNA Binding and Cytotoxicity of a Novel Trinuclear Highly Charged Compound, Inorg. Chem., 44 (2005) 9598-9600.
9. Zhang, J., Thomas, D.S., Davies, M.S., Berners-Price, S.J. and Farrell, N.: Effects of geometric isomerism in dinuclear platinum antitumor complexes on aquation reactions in the presence of perchlorate, acetate and phosphate. Journal of Biological Inorganic Chemistry. 10:652-666 (2005).

10. Marini, V., Christofis, P., Novakova, O., Kasparkova, J., Farrell, N. and Brabec, V.: Conformation, protein recognition and repair of DNA interstrand and intrastrand cross-links of antitumor trans-[PtCl2(NH3)(thiazole)]. Nuc. Acids Res.33:5819-5828 (2005).
11. Ma, E.S., Bates, W.D., Edmunds, A., Kelland, L.R. and Farrell, N.: Enhancement of Aqueous Solubility and Stability Employing a Trans Acetate Axis in Transplanar Amine Platinum Compounds while Maintaining the Biological Profile. J. Med. Chem.48: 5651-5654 (2005).
12. Liu, Q., Golden, M., D02/02/2007dinuclear Platinum-Zinc chelates as models for ternary Platinum-DNA-Protein Complexes and zinc ejection from zinc fingers. Evidence from studies using ESI-Mass Spectrometry. Chem. Commun, 4360 – 4362 (2005).
13. Ourliac-Garnier. I., Elizondo-Riojas, M., Redon, S., Farrell, N.P. and Bombard, S.: Cross-linking of the quadruplex structures of the AG3(T2AG3)3 human telomere sequences in Na+ and K+ solutions by dinuclear platinum complexes. Biochemistry. 44;10620-10634 (2005).
14. Oehlsen, M.E., Hegmans, A., Qu, Y. and Farrell, N.: A Surprisingly Stable Macrochelate Formed from the Reaction of cis-dinuclear Platinum Antitumor Compounds with Reduced Glutathione. Identification by the Use of (1H-15N and 195Pt) NMR Spectroscopy and Electrospray Ionization Mass Spectrometry. Inorg. Chem. 44:3004-3006 (2005).
15. Harris, A., Qu, Y. and Farrell, N.: Unique cooperative binding interaction observed between a minor groove binding Pt anti-tumor agent and Hoeschst Dye 33258. Inorg. Chem. 44:1196-1198 (2005).
16. Anzellotti, A.I., Ma, E.S. and Farrell, N.: Platination of nucleobases to enhance non-covalent recognition in protein-DNA/RNA complexes. Inorg. Chem. 44:483-485 (2005). Fojo, T., Farrell, N., Ortuzar, W., Tanimura, H., Weinstein, J. and Myers, T.G.: Identification of non-cross-resistant platinum compounds with novel cytotoxicity profiles using the NCI anticancer drug screen and clustered image map visualizations. Crit. Revs. Oncol./Hematol. 53:25-34 (2005).
17. Fojo, T., Farrell, N., Ortuzar, W., Tanimura, H., Weinstein, J. and Myers, T.G., Identification of Non-cross-resistant Platinum Compounds with Novel Cytotoxicity Profiles Using the NCI Anticancer Drug Screen and Clustered Image Map Visualizations, Crit. Revs. Oncol./Hematol., 53 (2005) 25-34.

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