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. 2015 May;2015(13):2295-2307.
doi: 10.1002/ejic.201500097. Epub 2015 Apr 9.

Hydrogen bonding and anticancer properties of water-soluble chiral p-cymene Ru(II) compounds with amino-oxime ligands

Yosra Benabdelouahab  1 , Laura Muñoz-Moreno  2 , Malgorzata Frik  3 , Isabel de la Cueva-Alique  1 , Mohammed Amin El Amrani  4 , María Contel  3 , Ana M Bajo  2 , Tomás Cuenca  1 , Eva Royo  1
Affiliations

Hydrogen bonding and anticancer properties of water-soluble chiral p-cymene Ru(II) compounds with amino-oxime ligands

Yosra Benabdelouahab et al. Eur J Inorg Chem. 2015 May.

Abstract

The investigation of the hydrogen-bonding effect on the aggregation tendency of ruthenium compounds [(η6-p-cymene)Ru(κNHR,κNOH)Cl]Cl (R = Ph (1a), Bn (1b)) and [(η6-p-cymene)Ru(κ2NH(2-pic),κNOH)][PF6]2 (1c), [(η6-p-cymene)Ru(κNHBn,κNO)Cl] (2b) and [(η6-p-cymene)Ru(κNBn,κ2NO)] (3b), has been performed by means of concentration dependence 1H NMR chemical shifts and DOSY experiments. The synthesis and full characterization of new compounds 1c, [(η6-p-cymene)Ru(κNPh,κ2NO)] (3a) and 3b are also reported. The effect of the water soluble ruthenium complexes 1a-1c on cytotoxicity, cell adhesion and cell migration of the androgen-independent prostate cancer PC3 cells have been assessed by MTT, adhesion to type-I-collagen and recovery of monolayer wounds assays, respectively. Interactions of 1a-1c with DNA and human serum albumin have also been studied. Altogether, the properties reported herein suggest that ruthenium compounds 1a-1c have considerable potential as anticancer agents against advanced prostate cancer.

Keywords: anticancer; arene ruthenium compounds; chiral syntheses; non-covalent interactions; oxime.

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Figures

Figure 1
Figure 1
Numbering of some of the different protons of amino-oxime ligands present in 1a, 1b
Figure 2
Figure 2
Concentration dependence of 1H NMR chemical shifts for one of the −CH26 protons of A) compound 1a in CDCl3, B) compound 1b in CDCl3.
Figure 3
Figure 3
Effect of derivative 1b on PC3 cells viability, compared to that of ammonium-oxime compound b·HCl and ruthenium dimer [(η6-p-cymene)RuCl2]2. Cells were treated with increasing doses of organic and ruthenium compounds for 3 hours. Cell viability was measured by means of MTT assay. The results are expressed as a percentage of live cells compared to control. Data are the mean ± S.E.M. of at least three experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.001 versus Control.
Figure 4
Figure 4
Effect of 1a-1c complexes on adhesion of PC3 cells to type-I collagen was studied after treatment with organic and organometallic compounds for 40 min. Data are the mean ± S.E.M. of at least three experiments. **, P < 0.01; ***, P < 0.001 versus Control.
Figure 5
Figure 5
The effect of organic and organometallic compounds on cell migration was studied in human prostate cancer PC3 cell line. Microscopic analysis of the cell-free area was carried out at the indicated time (24 h) after the addition of the neuropeptide and the width of the area invaded by prostate cells was estimated.
Figure 6
Figure 6
Electrophoresis mobility shift assays for cisplatin, [(η6-p-cymene)RuCl2]2, derivatives a·HCl-c·HCl and compounds 1a-1c (see Experimental for details). DNA refers to untreated plasmid pBR322. 1, 2, 3 and 4 correspond to metal/DNAbp ratios of 0.25, 0.5, 1.0 and 2.0 respectively.
Figure 7
Figure 7
(A) Fluorescence titration curve of HSA with compound 1a. Arrow indicates the increase of quencher concentration (10–100 µM). (B) Stern-Volmer plot for HSA fluorescence quenching observed with compounds 1a-1c, [(η6-p-cymene)RuCl2]2 and cisplatin.
Scheme 1
Scheme 1
Synthesis of chiral amino-oxime ruthenium compounds.
Scheme 2
Scheme 2
Synthesis of picolylamino-oxime ruthenium stereoisomers
Scheme 3
Scheme 3
Synthesis of amido-oximate ruthenium compounds 3a, 3b
See this image and copyright information in PMC

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