Abstract
7-(4-(Decanoyl)piperazin-1-yl)-ciprofloxacin, CipA, (1) which is an analogue of the antibiotic ciprofloxacin, and its ruthenium(II) complex [Ru(η6-p-cymene)(CipA-H)Cl], (2) have been synthesised and the x-ray crystal structures of 1·1.3H2O·0.6CH3OH and 2·CH3OH·0.5H2O determined. The complex adopts a typical pseudo-octahedral ‘piano-stool’ geometry, with Ru(II) π-bonded to the p-cymene ring and σ-bonded to a chloride and two oxygen atoms of the chelated fluoroquinolone ligand. The complex is highly cytotoxic in the low μM range and is as potent as the clinical drug cisplatin against the human cancer cell lines A2780, A549, HCT116, and PC3. It is also highly cytotoxic against cisplatin- and oxaliplatin-resistant cell lines suggesting a different mechanism of action. The complex also retained low μM cytotoxicity against the human colon cancer cell line HCT116p53 in which the tumour suppressor p53 had been knocked out, suggesting that the potent anti-proliferative properties associated with this complex are independent of the status of p53 (in contrast to cisplatin). The complex also retained moderate anti-bacterial activity in two Escherichia coli, a laboratory strain and a clinical isolate resistant to first, second and third generation β-lactam antibiotics.
Highlights
The rational design and development of innovative anti-cancer platinum drug candidates to overcome dose-limiting toxic side effects and resistance associated with drugs in clinical use have produced a wide range of possible chemotherapeutics
In the 50 or so years since the discovery of the anti-cancer properties of cisplatin, it is surprising that none to date has been as successful as cisplatin and its analogues carboplatin or oxaliplatin
Bacteria used for testing were Escherichia coli (E. coli) strain ATCC25922, an antibiotic susceptible laboratory strain and E. coli clinical isolate CL2, isolated from a patient with a urinary tract infection
Summary
The rational design and development of innovative anti-cancer platinum drug candidates to overcome dose-limiting toxic side effects and resistance associated with drugs in clinical use have produced a wide range of possible chemotherapeutics. In the 50 or so years since the discovery of the anti-cancer properties of cisplatin, it is surprising that none to date has been as successful as cisplatin and its analogues carboplatin or oxaliplatin Recent advances in this field have included the exploitation of various Pt drug delivery vehicles [1] and the incorporation of metals other than Pt. Recent advances in this field have included the exploitation of various Pt drug delivery vehicles [1] and the incorporation of metals other than Pt In the latter regard, ruthenium compounds have demonstrated much promise with three Ru(III) complexes, NAMI-A (imidazolium trans[tetrachloro(dimethylsulfoxide)(1H-imidazole)ruthenate(III)]) [2,3], KP1019 (indazolium trans-[tetrachlorobis(1H-indazole)-ruthenate(III)]) [4,5,6] and NKP-1339, the sodium salt analogue of KP1019 [4], all (C.J. Marmion). Ruthenium(III) complexes may act as prodrugs, being reduced to and exerting their biological effect as Ru(II) in the more reducing environment of tumour cells
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