Chen, Feng (2018) Organometallic anticancer and antimicrobial complexes. PhD thesis, University of Warwick.

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Abstract

Platinum complexes, e.g. cisplatin, oxaliplatin, carboplatin, have been used for near 40 years in clinic as potent anticancer drugs. However, these drugs can cause severe side effects, and hence there is an urgent need to develop other metal based antiproliferative agents. For example, organometallic Ru II/III complexes possess potent anticancer activity but low cytotoxicity towards normal cells, which makes them promising alternatives to currently used anticancer drugs.

In this thesis, a series of neutral pseudo-octahedral Ru II-sulfonamidoethylenediamine complexes [(η⁶-arene)Ru(N,N’)X] where η⁶-arene is p-cym, biph and benzene, N,N’ is ethylenediamine chelating ligands with sulfonyl substituents (e.g. Ts or Nb) on one terminal N and various functional groups (e.g. Me, Me2, Et, benzyl, 4-fluorobenzyl or naphthalen-2-ylmethyl) on the other terminal N were synthesized and fully characterized, including X-ray crystal structures. These complexes catalyse the reduction of NAD⁺ regioselectively to 1, 4-NADH using sodium formate as hydride source under biologically relevant conditions. The catalytic efficiency depends markedly on the steric and electronic effects of the N-substituent, with turnover frequencies (TOFs) increasing with the enhancement of bulkiness and electron withdrawing of the substituents, achieving a highest TOF of 12.9 h⁻¹ for complex 10 [(η⁶-biph)Os(TsEnBz)Cl]. These complexes exhibited antiproliferative activity against A2780 human ovarian cancer cells. Co-administration with sodium formate (2 mM) increased their potency significantly towards A2780 cells. Substituted Ru II sulfonylethylenediamine complexes can also interact rapidly with glutathione (GSH) and N-acetyl-L-cysteine (NAC) to form S-bridged [(η⁶-arene)₂Ru₂(GS)₃]²⁺ or [(η⁶-arene)₂Ru₂(NAC)₃]⁺ dimers, and the presence of GSH can effectively hamper the catalytic reduction of NAD+ to NADH.

Next, a series of neutral organometallic tethered [Ru(η⁶-benzene-N-R-ethylenediamine)Cl] complexes was synthesized and characterized, where R = methylsulfonyl (Ms), toluenesulfonyl (Ts), trifluorobenzenesulfonyl (Tf) and 4-nitrobenzenesulfonyl (Nb), including their X-ray crystal structures. In general, these complexes also exhibited potent catalytic activity in the transfer hydrogenation of NAD⁺ to NADH with formate as hydride donor (310 K, pH 7), but with moderate antiproliferative activity towards human ovarian, lung, liver and breast cancer cell lines. Tethered Ru II complexes showed preferential binding to 9-ethylguanine (9-EG) over adenosine 5’-monophosphate (5’-AMP). However, DNA appears not to be the target, as little binding of complex 17 [Ru(η⁶-benzene-N-Ts-ethylenediamine)Cl] to ct-DNA or bacterial plasmid DNA was observed. Also, the tethered complexes bind rapidly to GSH, which might again hamper the transfer hydrogenation reactions in cells. Interestingly, these tethered Ru II complexes can induce a dose-dependent G1 cell cycle arrest and high level of reactive oxygen species (ROS) generation, which is likely to contribute to their antiproliferative activity. Diseases caused by bacterial infections, especially by multidrug-resistance bacteria, are the major cause of deaths worldwide. Traditional clinical drugs cannot cope with the rapid rise of drug resistance.

In this thesis, a new class of organometallic antimicrobial complexes of the type [(arene/Cpx)Ir(Big)Z]Z (where arene is para-cymene or biphenyl, Cpx = Cp* (tetramethylcyclopentadienyl), Cp*ph or Cp*biph, Big = biguanide ligands and functional sulfonyl substituted biguanide ligands, Z = Cl, Br and I) were synthesized and characterized by NMR, ESI-MS, elemental analysis and X-ray crystallography. These complexes not only have promising antibacterial activity against Gram-negative bacteria and excellent potency against Gram-positive bacteria, but also exhibit high antifungal potency towards C. albicans and C. neoformans. Most of the complexes have low cytotoxicity towards mammalian cells (HEK-293 human red blood cells and HaCaT keratinocyte cells), indicating a high selectivity. These Ir III complexes have a high stability in both medium even at high temperature (315 K). A mutant generation study suggests that S. aureus exhibits a low tendency to generate mutants in response to these complexes. Ir biguanide complexes 27 [(η5-CpXbiph)Ir(PhBig)]Cl, 30 [(η5-CpXbiph)Ir(TolBig)Cl]Cl and 33 [(η5-CpXbiph)Ir(TsTolBig)Cl] exhibited synergy with clinical drug vancomycin when co-administered in vancomycin-resistant Enterococci (VRE), with the MIC 256× lower at sub-MIC complex concentration. These complexes also exhibited potent anti-biofilm activity against biofilms generated by S. aureus. Potent antimicrobial activity against various microbes might provide an alternative pathway to treat drug resistant nosocomial pathogens.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Antineoplastic agents -- Development, Anti-infective agents -- Development, Organometallic compounds -- Therapeutic use, Organoruthenium compounds -- Therapeutic use
Official Date:	2018
Dates:	Date Event 2018 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Sadler, P. J.
Format of File:	pdf
Extent:	ix, 254 leaves : illustrations, charts
Language:	eng

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