title: In vitro and in vivo biological activity screening of Ru(III) complexes involving 6-benzylaminopurine derivatives with higher pro-apoptotic activity than NAMI-A.
abstract: A series of novel octahedral ruthenium(III) complexes involving 6-benzylaminopurine (L) derivatives as N-donor ligands has been prepared by the reaction of [(DMSO)(2)H][trans-RuCl(4)(DMSO)(2)] with the corresponding L derivative. The complexes 1-12 have the general compositions trans-[RuCl(4)(DMSO)(n-Cl-LH)]⋅xSol (1-3), trans-[RuCl(4)(DMSO)(n-Br-LH)]·xSol (4-6), trans-[RuCl(4)(DMSO)(n-OMe-LH)]·xSol (7-9) and trans-[RuCl(4)(DMSO)(n-OH-LH)]·xSol (10-12); n=2, 3, and 4, x=0-1.5; and Sol = H(2)O, DMSO, EtOH and/or (Me)(2)CO. The complexes have been thoroughly characterized by elemental analysis, UV-visible, FTIR, Raman, and EPR spectroscopy, ES+(positive ionization electrospray) mass spectrometry, thermal analysis, cyclic voltammetry, magnetic and conductivity measurements. The X-ray molecular structure of trans-[RuCl(4)(DMSO)(3-Br-LH)]⋅(Me)(2)CO (5) revealed the distorted octahedral coordination in the vicinity of the central atom, and also confirmed that the 3-Br-L ligand is present as the N3-protonated N7-H tautomer and is coordinated to Ru(III) through the N9 atom of the purine moiety. The tested complexes have been found to be in vitro non-cytotoxic against K562, G361, HOS and MCF7 human cancer cell lines with IC(50)>100μM in contrast to the moderate results regarding the antiradical activity with IC(50)≈10(-3)M. On the contrary, in vivo antitumor activity screening showed that the prepared Ru(III) complexes possess higher pro-apoptotic activity than NAMI-A. The reduction of Ru(III) to Ru(II) and Ru(II)-species formation in tumor tissues was confirmed by means of a simple method of detection and visualization of intracellular Ru(II) by fluorescence microscopy. The originality of this method is based on the preparation of a Ru(II)-bipyridine complex in situ.
authors.affiliation: Regional Centre of Advanced Technologies and Materials, Department of Inorganic Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, Olomouc, Czech Republic. zdenek.travnicek@upol.cz
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Trávníček
authors.forename: Miroslava
authors.initials: M
authors.lastname: Matiková-Mal'arová
authors.forename: Radka
authors.initials: R
authors.lastname: Novotná
authors.forename: Ján
authors.initials: J
authors.lastname: Vančo
authors.forename: Kamila
authors.initials: K
authors.lastname: Stěpánková
authors.forename: Pavel
authors.initials: P
authors.lastname: Suchý
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001593:Benzyl Compounds; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007701:Kinetin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D008938:Mitosis / Q000187:drug effects; D008968:Molecular Conformation; D009336:Necrosis; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000494:pharmacology*; D011687:Purines; D012428:Ruthenium; D017975:Ruthenium Compounds
chemical_list: D000970:Antineoplastic Agents; D001593:Benzyl Compounds; D056831:Coordination Complexes; D009942:Organometallic Compounds; D011687:Purines; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D012428:Ruthenium; C480551:benzylaminopurine; D007701:Kinetin; D004121:Dimethyl Sulfoxide