title: Water-soluble Ru(II)- and Ru(III)-halide-PTA complexes (PTA=1,3,5-triaza-7-phosphaadamantane): Chemical and biological properties.
abstract: Four structurally related Ru(II)-halide-PTA complexes, of general formula trans- or cis-[Ru(PTA)4X2] (PTA=1,3,5-triaza-7-phosphaadamantane, X=Cl (1, 2), Br (3, 4), were prepared and characterized. Whereas compounds 1 and 2 are known, the corresponding bromo derivatives 3 and 4 are new. The Ru(III)-PTA compound trans-[RuCl4(PTAH)2]Cl (5, PTAH=PTA protonated at one N atom), structurally similar to the well-known Ru(III) anticancer drug candidates (Na)trans-[RuCl4(ind)2] (NKP-1339, ind=indazole) and (Him)trans-[RuCl4(dmso-S)(im)] (NAMI-A, im=imidazole), was also prepared and similarly investigated. Notably, the presence of PTA confers to all complexes an appreciable solubility in aqueous solutions at physiological pH. The chemical behavior of compounds 1-5 in water and in physiological buffer, their interactions with two model proteins - cytochrome c and ribonuclease A - as well as with a single strand oligonucleotide (5'-CGCGCG-3'), and their in vitro cytotoxicity against a human colon cancer cell line (HCT-116) and a myeloid leukemia (FLG 29.1) were investigated. Upon dissolution in the buffer, sequential halide replacement by water molecules was observed for complexes 1-4, with relatively slow kinetics, whereas the Ru(III) complex 5 is more inert. All tested compounds manifested moderate antiproliferative properties, the cis compounds 2 and 4 being slightly more active than the trans ones (1 and 3). Mass spectrometry experiments evidenced that all complexes exhibit a far higher reactivity towards the reference oligonucleotide than towards model proteins. The chemical and biological profiles of compounds 1-5 are compared to those of established ruthenium drug candidates in clinical development.
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via L. Giorgieri 1, 34127 Trieste, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Battistin
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Scaletti
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via L. Giorgieri 1, 34127 Trieste, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Balducci
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Viale G.B. Morgagni 50, 50134, Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pillozzi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Viale G.B. Morgagni 50, 50134, Florence, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Arcangeli
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: luigi.messori@unifi.it.
authors.forename: L
authors.initials: L
authors.lastname: Messori
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via L. Giorgieri 1, 34127 Trieste, Italy. Electronic address: alessi@units.it.
authors.forename: E
authors.initials: E
authors.lastname: Alessio
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001965:Bromides / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000737:chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D045304:Cytochromes c / Q000737:chemistry; D000091344:Filaggrin Proteins; D045325:HCT116 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000737:chemistry; D007191:Indazoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008024:Ligands; D009841:Oligonucleotides / Q000737:chemistry; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000737:chemistry*; D011522:Protons; D012259:Ribonuclease, Pancreatic / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: C501763:1,3,5-triaza-7-phosphaadamantane; D000970:Antineoplastic Agents; D001965:Bromides; D002712:Chlorides; D056831:Coordination Complexes; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007093:Imidazoles; D007191:Indazoles; D008024:Ligands; D009841:Oligonucleotides; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D011522:Protons; D014867:Water; D012428:Ruthenium; D045304:Cytochromes c; D012259:Ribonuclease, Pancreatic; D000218:Adamantane
keywords: In vitro antiproliferative activity; Oligonucleotide interaction; PTA; Protein interaction; Ruthenium complexes