Antimetastatic properties and DNA interactions of the novel class of dimeric Ru(III) compounds Na2[[trans-RuCl4(Me2SO)]2(mu-L)] (L = ditopic, non-chelating aromatic N-ligand). A preliminary investigation.
A novel class of dianionic Ru(III) dimers of formula Na2[[trans-RuCl4(Me2SO)]2(mu-L)], with L = pyrazine (pyz, 1), pyrimidine (pym, 2), 4,4'-bipyridine (bipy, 3), and 1,2-bis(4-pyridine) ethane (etbipy, 4), was developed by us with the specific aim of assessing their antitumor properties. The dimers are in fact structurally related to the antimetastatic mononuclear compound (ImH) [trans-RuCl4(Me2SO)(Im)] (NAMI-A, Im = imidazole). Preliminary results concerning the antineoplastic activity of 1-4 against the murine MCa carcinoma model, a tumor which spontaneously metastasizes in the lungs, are reported. Similarly to what is normally observed with NAMI-A, the treatment with the dimeric complexes was scarcely effective against the growth of the primary tumor. However, dimers 1, 2, and 4 reduced very effectively the number and, in particular, the weight of lung metastases (to about 5% with respect to controls); in particular, Na2[[trans-RuCl4(Me2SO)]2(mu-etbipy)] (4) was as effective as NAMI-A in reducing the spontaneous metastases at a dosage which, in terms of moles of ruthenium, is about 3.5 times lower compared to that normally used for NAMI-A. Furthermore, in vitro tests showed that dimers 1-4 are capable of forming interstrand cross-links with linearized plasmidic DNA in a time-dependent manner. All the dimeric species are more active in inducing cross-links compared to NAMI-A, and the dimer bridged by the etbipy ligand (4) is the most effective among those tested.
Alessio
E
E
Dipartimento di Scienze Chimiche, Università di Trieste, Italy. alessi@univ.trieste.it
Iengo
E
E
Zorzet
S
S
Bergamo
A
A
Coluccia
M
M
Boccarelli
A
A
Sava
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D004247:DNA / Q000737:chemistry*; D019281:Dimerization; D005260:Female; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008808:Mice, Inbred CBA; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D012428:Ruthenium
D000970:Antineoplastic Agents; D008024:Ligands; D009942:Organometallic Compounds; D012428:Ruthenium; D004247:DNA