Ude, Ziga and Kavanagh, Kevin and Twamley, Brendan and Pour, Milan and Gathergood, Nicholas and Kellett, Andrew and Marmion, Celine J. (2019) A new class of prophylactic metallo-antibiotic possessing potent anti-cancer and anti-microbial properties. Dalton Transactions, 48 (24). pp. 8505-9006. ISSN 1477-9226

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Abstract

Immunocompromised cancer patients are often at high risk of developing infections. Standard infection control measures are required to prevent the onset of infection but, under some circumstances, antimicrobial prophylaxis is necessary. We have developed a family of innovative metallo-antibiotics of general formula [Cu(N,N)(CipA)Cl] where N,N represents a phenanthrene ligand and CipA stands for a derivative of the clinically used fluoroquinolone antibiotic ciprofloxacin. The X-ray crystal structure of one member from this family, [Cu(phen)(CipA)Cl] (where phen is 1,10-phenanthroline), is also reported. These complexes combine into one drug entity a Cu-N,N-framework with DNA binding and DNA oxidant properties and an antibiotic derivative with known anti-proliferative and anti-microbial activities. The complexes were all found to exhibit excellent DNA recognition with binding affinity of lead agents in the order of ∼107 M(bp)−1. Biophysical studies involving calf thymus DNA indicate the complexes intercalate or semi-intercalate DNA via the minor groove. All complexes exhibited excellent nuclease activity with DNA strand scission being mediated predominantly via superoxide and hydroxyl radicals. The complexes were found to have promising anti-proliferative effects against a human breast adenocarcinoma cell line (MCF-7) and a human prostate carcinoma cell line (DU145) with low micromolar and, in some cases, nanomolar cytotoxicities observed. Selective targeting of Gram positive bacteria was also identified by this complex class with one lead compound having an order of magnitude greater potency against Methicillin-resistant S. aureus (MRSA) as compared to the CipA ligand. Importantly, from a clinical stand point, these complexes were also found to be well tolerated in an in vivo Galleria mellonella larvae model, which has both functional and structural similarities to that of the innate immune system of mammals.

Item Type:	Article
Keywords:	new class; prophylactic; metallo-antibiotic; possessing; potent; anti-cancer; anti-microbial; properties;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	14994
Identification Number:	https://doi.org/10.1039/c9dt00250b
Depositing User:	Dr. Kevin Kavanagh
Date Deposited:	08 Nov 2021 15:34
Journal or Publication Title:	Dalton Transactions
Publisher:	Royal Society of Chemistry
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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