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Professor |
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 mu09/29/2010isplatin. 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.
Updated October 2010
Anzellotti, A.I.; Bayse, C.A.; Farrell, N.P., Effects of Nucleobase Metalation on Frontier Molecular Orbitals: Potential Implications for pi-Stacking Interactions with Tryptophan. Inorganic Chemistry 2008,47, 10425-10431.
Demicheli, C.; Frezard, F.; Mangrum, J.B.; Farrell, N.P., Interaction of trivalent antimony with a CCHC zinc finger domain: potential relevance to the mechanism of action of antimonial drugs. Chemical Communications 2008, 4828-4830.
Strukl, J.V.; de Paula, Q.A.; Yang, X.H.; Qu, Y.; Farrell, N.P., Comparison of cis and trans-platinum mononucleobase compounds with DNA and protein models. Australian Journal of Chemistry 2008, 61, 694-699.
Zhang, J.Y.; Thomas, D.S.; Berners-Price, S.J.; Farrell, N., Effects of geometric isomerism and anions on the kinetics and mechanism of the stepwise formation of long-range DNA interstrand cross-links by dinuclear platinum antitumor complexes. Chemistry-A European Journal 2008, 14, 6391-6405.
Anzellotti, A.I.; Farrell, N.P., Zinc metalloproteins as medicinal targets. Chemical Society Reviews 2008, 37, 1629-1651.
Almaraz, E.; de Paula, Q.A.; Liu, Q.; Reibenspies, J.H.; Darensbourg, M.Y.; Farrell, N.P., Thiolate bridging and metal exchange in adducts of a zinc finger model and Pt-II complexes: Biomimetic studies of protein/Pt/DNA interactions. Journal Of The American Chemical Society 2008, 130, 6272-6280.
Hegmans, A.; Kasparkova, J.; Vrana, O.; Kelland, L.R.; Brabec, V.; Farrell, N.P., Amide-based Prodrugs of spermidine-bridged dinuclear platinum. Synthesis, DNA binding, and biological activity. Journal Of Medicinal Chemistry 2008, 51, 2254-2260.
Montero, E.I.; Benedetti, B.T.; Mangrum, J.B.; Oehlsen, M.J.; Qu, Y.; Farrell, N.P., Pre-association of polynuclear platinum anticancer agents on a protein, human serum albumin. Implications for drug design. Dalton Transactions 2007, 4938-4942.
Mitchell, C.; Kabolizadeh, P.; Ryan, J.; Roberts, J.D.; Yacoub, A.; Curiel, D.T.; Fisher, P.B.; Hagan, M.P.; Farrell, N.P.; Grant, S.; Dent, P., Low-dose BBR3610 toxicity in colon cancer cells is p53-independent and enhanced by inhibition of epidermal growth factor receptor (ERBB1)-Phosphatidyl inositol 3 kinase signaling. Molecular Pharmacology 2007, 72, 704-714.
Aris, S.M.; Gewirtz, D.A.; Ryan, J.J.; Knott, K.M.; Farrell, N.P., Promotion of DNA strand breaks, interstrand cross-links and apoptotic cell death in A2780 human ovarian cancer cells by transplatinum planar amine complexes. Biochemical Pharmacology 2007, 73, 1749-1757.
Kabolizadeh, P.; Ryan, J.; Farrell, N., Differences in the cellular response and signaling pathways of cisplatin and BBR3464 (([{trans-PtCl(NH3)2)}2)mu-((trans-Pt(NH3)2)((H2N(CH2)6)-NH2)2))]4+) influenced by copper homeostasis. Biochemical Pharmacology 2007, 73, 1270-1279.
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. Journal of the American Chemical Society 2006, 128, 16092-16103.
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Updated: 03/19/2012 |
