Synthesis, DNA interaction and cytotoxicity studies of cis-{[1, 2-bis(aminomethyl)cyclohexane]dihalo}platinum(II) complexes.
A series of platinum compounds with an analogue structure to cisplatin have been synthesized and their biological activity against HL-60 cancer cell line has been studied. The interaction with DNA was evaluated by circular dichroism (CD), electrophoresis and atomic force microscopy (AFM) techniques showing slight but significant structure-dependent differences among the evaluated complexes. The cytotoxicity assays afforded interesting relationships between the structure and the biological activity, thus, a better antiproliferative activity was observed for the complexes with higher hydrophobicity: the methoxylated complexes showed better activity than the hydroxylated ones (17versus20 and 19versus21). Especially compound 22 having a fatty acid subunit presented a promising cytotoxic activity. On the other hand, dichloro complexes 12 and 13 had better activities than the diiodo complexes, probably due to their better metabolic stability. Between both dichloro complexes the aromatic one showed much higher activity, which could be rationalized on the basis of the intercalating ability of the benzene ring. The flow cytometry assays indicated that most of the complexes induced the cell death by apoptosis except for aromatic compound 12 and the lipophilic compound 22 that induced preferably a mechanism of necrosis.
de Mier-Vinué
Jordi
J
Departamento de Química Orgánica, Facultad de Química, Universidad de Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Spain.
Lorenzo
Julia
J
Montaña
Angel M
AM
Moreno
Virtudes
V
Avilés
Francesc X
FX
D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry / Q000379:methods; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared
D009944:Organoplatinum Compounds; D004247:DNA