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Title: Photoactivatable Ru(II) polypyridyl complexes as antibacterial agents
Author: Smith, Nichola Ann
ISNI:       0000 0004 5370 6111
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2015
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Novel photoactive ruthenium(II) complexes were designed to incorporate existing anti-tuberculosis drugs, isoniazid and nicotinamide, that could be released from the ruthenium(II) cage by photoactivation with visible light. Two sets of complexes were synthesised based on cis-[Ru(N-N')2(L)2][PF6]2and cis-[Ru(N-N')2(L)X][PF6], where N-N' is 2,2'-bipyridine (bpy) or 1,10-phenanthroline (phen), L is isoniazid (INH) or nicotinamide (NA) and X is either Cl or I. Their dynamic behaviour in solution was explored using NMR to probe the presence of atropisomers. In the case of cis-[Ru(bpy)2(NA)Cl][PF6] (1) and cis-[Ru(bpy)2(NA)I][PF6] (2), the rotation of NA is hindered on the NMR timescale at room temperature, behaviour that was surprisingly not observed for cis-[Ru(bpy)2(NA)2][PF6]2 (5). The hindered rotation was explored by computational methods (DFT) and revealed that hydrogen bonding between the halide and protons of the NA ligand hindered the rotation. The photochemical properties of the Ru(II) complexes were explored by UV-visible spectroscopy and liquid chromatography. All cis-[Ru(N-N')2(L)2][PF6]2complexes in aqueous solution release one ligand, L, in under 1 min using a blue LED (λirr = 463 nm, 50 mW cm- 2 ) to form the photoproduct cis-[Ru(N-N')2(L)(H2O)] 2+ . Continued photoirradiation releases a second ligand, L, with the production of various Ru(II) and Ru(III) aqua photoproducts (with both cis and trans geometry). Interestingly their production was dependent on the power of the light source. Complementary computational studies (DFT/TD-DFT) were utilised to understand structure-activity relationships with respect to photoactivity. The results from the calculations suggest that the number of key electronic transitions (notably1 MLCT) and the favourable leaving properties of the ligand, L, influence the rate of photorelease. In the latter case, a stronger p-accepting leaving ligand shifts the dissociative 3 MC state to lower energy, thus promoting more efficient ligand release. The photobiological properties of the Ru(II) complexes were explored by investigating binding to biomolecules and screening their antibacterial activity in vitro. The complex cis-[Ru(bpy)2(INH)2][PF6]2 (4) binds to the nucleobase 9-ethylguanine (9-EtG) after photoirradiation with a blue LED to produce cis-[Ru(bpy)2(INH)(9-EtG)] 2+ , however reaction with the amino acid L-cysteine was not observed. A 96-array blue LED (λirr = 465 nm, 20 mW cm-2 ) and 32-array multi-coloured LED (λirr = 465 nm, 520 nm, 589 nm and 625 nm, 5 mW cm-2 ) were designed in-house to screen the activity of the complexes in vitro. Their design and construction is described in detail. When tested against Mycobacterium smegmatis (a model for Mycobacterium tuberculosis), complexes cis-[Ru(bpy)2(INH)2][PF6]2 (4) and cis-[Ru(phen)2(INH)2][PF6]2 (6) showed the greatest activity upon photoirradiation for 1 min with a blue LED, with at least a 3x increase in potency when compared to the ligand alone, INH. Most importantly the complexes are inactive in the dark, showing that the antibacterial ligand is selectively released in vitro after photoirradiation. The complex cis-[Ru(bpy)2(MOPEP)2][PF6]2 (9), where MOPEP is 4-[2-(4-methoxyphenyl)ethynyl]pyridine, was initially designed to study two-photon activation via a femtosecond-pulsed laser. Surprisingly the complex was one-photon active with 600 nm and 800 nm light, due to the MOPEP ligand extending and increasing the intensity of the one-photon absorption band shoulder in the 600-800 nm region.
Supervisor: Not available Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry