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Research Projects III |
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3. Luminescent DNA binding probes.
BACKGROUND Investigations into the interaction of small molecules with DNA has led to the discovery of many therapeutic agents including antibiotics and anticancer drugs. Luminescent and redox active metal complexes are used as probes of the structure and physical properties DNA.[1] Most of this work is on complexes that can intercalate between the base-pairs of DNA (metallo-intercalators).
The Thomas group are investigating the synthesis of novel luminescent and/or redox active metal, and entirely organic, intercalators. WHY? Long term, this work may lead to sensors for specific genetic sequences and DNA structures involved in diseases such as cancer.
3a MONONUCLEAR DNA LIGHT SWITCHES. The most internationally studied metallointercalator is [Ru(phen)2(dppz)]2+ This cation binds to duplex DNA with high affinities (ca. 106 M-1) and displays a “DNA light switch” in which binding to DNA produces an enhancement by several orders of magnitude in the MLCT-based luminescence of the complex.[1] However this complex is difficult to derivatize. Work in the Thomas group has concerned related systems based on easily derivatized achiral, coordinatively unsaturated [Ru(dppz)] moieties. This work has led to a range of novel and surprising results. For example, the light switch complex shown below binds preferentially to GC sequences of duplex DNA.[2] |
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X-Ray Crystal structure of [Ru(tpym)(MeCN)(dppz)]2+, an achiral DNA light switch complex |
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3b DNA SCISSORS -ORGANIC INTERCALATORS BASED ON DPPZ TYPE MOLECULES. Simple water-soluble cations based on dppz and related molecules have been synthesised.[3] These systems intercalate into duplex DNA with high affinities and selectivites,[3,4] furthermore their unusual intramolecular charge transfer photo-excited states are capable of cleaving DNA. Such systems are useful as tools for biological/medical research |
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Frontier Molecular Orbitals of organic DNA cleavage system [DFT calculations and image courtesy of Dr Antony Meijer] |
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3c DINUCLEAR DNA CLIPS. Using the mononuclear complexes described in section 3a as building blocks we have developed a modular method for the synthesis of homodinuclear bis-intercalating systems.[5,6] Using this method, the nature of the metal, linker AND intercalating unit can be varied, e.g., heterodinuclear systems can be synthesised[7] This means that we can potentially tailor the physical properties of our systems AND/OR bind to specific extended DNA sequences |
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Models of dinuclear ruthenium(II) (LEFT) and rhenium(I) (RIGHT) bis-intercalating light switches |
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COLLABORATIONS ON THIS PROJECT: Computational studies (DFT) on both organic and inorganic systems are being carried out by Dr Anthony Meijer (Chemistry, University of Sheffield). Biophysical studies such as isothermal Calorimetry and work on quadruplex DNA are being carried out in collaboration with Dr Sham Haq, while High-field NMR studies on the interaction of these intercalators with DNA is being carried out in collaboration with Prof Mike Williamson (Molecular Biology and Biotechnology, University of Sheffield). Photophysical studies involve collaborations with Drs Julia Weinstein and Linda Swanson (Chemistry, University of Sheffield). Time resolved IR and Raman studies on the dinuclear systems are being carried out in collaboration with Drs Tony Parker, Pavel Matousek and Mike Towrie (Lasers for Science Facility, Rutherford Appleton Lab). |
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3D STRUCTURALLY SPECIFIC DNA LIGHT SWITCHES. Using the systems and methods described above we are investigating complexes that can be used to detect specific DNA structures, such as four-stranded DNA quadruplexes.[8] These structures are intimately connected to cancer genesis and treatment. See HERE for an explanation of why. |
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REFERENCES 1. “Kinetically inert transition metal complexes that reversibly bind to DNA,” C. Metcalfe, J. A. Thomas, Chem. Soc. Rev., 2003, 32, 214 – 224. 2. “A ruthenium dipyridylpyrazine complex that binds preferentially to GC sequences.” C. Metcalfe, H. Adams, I. Haq, J. A. Thomas, Chem. Commun., 2003, 1152 – 1153. 3. “DNA binding of an organic dppz-based intercalator.” T. Phillips, I. Haq, A. J.H.M. Meijer, H. Adams, I. Soutar, L. Swanson, M. J. Sykes, J. A. Thomas, Biochemistry, 2004, 43, 13657 - 65. 4. “Tuning DNA binding affinities and photoredox properties of water-soluble organic dppz analogues,” T. Phillips, C. Rajput, L. Twyman, I. Haq, Chem Commun, 2005, 4327-29. 5. “A facile synthetic route to bimetallic ReI complexes containing two dppz DNA intercalating ligands,” C. Metcalfe, M. Webb. J. A. Thomas, Chem. Commun., 2002, 2026-2027. 6. “A facile route to bimetallic ruthenium dipyridophenazine complexes,” C. Metcalfe, I. Haq, J. A. Thomas, Inorg. Chem., 2004, 43, 317-323. 7. “A Multifuctional Light-Switch: DNA Binding and Cleavage Properties of a Heterobimetallic Ruthenium-Rhenium Dipyridophenazine Complex” – with Simon P. Foxon, Michael Towrie, Anthony W. Parker, Michelle Webb, Angew. Chem. Intl. Ed., 2007, 46, 3686-3688. 8. “Dinuclear RuII complexes that display high affinity binding to duplex and quadruplex DNA,” C. Rajput, L. Swanson, R. Rutkaite, I. Haq, J. A. Thomas, Chem. Eur. J., 2006, 12, 4611 - 4619. |
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Research Projects III |
