Platinated copper(3-clip-phen) complexes as effective DNA-cleaving and cytotoxic agents.
The synthesis and biological activity of three heteronuclear platinum-copper complexes based on 3-Clip-Phen are reported. These rigid complexes have been designed to alter the intrinsic mechanism of action of both the platinum moiety and the Cu(3-Clip-Phen) unit. The platinum centers of two of these complexes are coordinated to a 3-Clip-Phen moiety, an ammine ligand and two chlorides, which are either cis or trans to each other. The third complex comprises two 3-Clip-Phen units and two chloride ligands bound in a trans fashion to the platinum ion. DNA-cleavage experiments show that the complexes are highly efficient nuclease agents. In addition, a markedly difference in their aptitude to perform direct double-strand cleavage is observed, which appears to be strongly related to the ability of the platinum unit to coordinate to DNA. Indeed, complex 6 is unable to coordinate to DNA, which is reflected by its incapability to carry out double-strand breaks. Nonetheless, this complex exhibits efficient DNA-cleavage activity, and its cytotoxicity is high for several cell lines. Complex 6 shows better antiproliferate activity than both cisplatin and Cu(3-Clip-Phen) toward most cancer cell lines. Furthermore, the cytotoxicity observed for 1 is for most cell lines close to that of cisplatin, or even better. Cu(3-Clip-Phen) induces very low cytotoxic effects, but a marked migratory activity. Complex 6 presents DNA-cleavage properties comparable to the one of Cu(3-Clip-Phen), but it does not show any migratory activity. Interestingly, both Cu(3-Clip-Phen) and 6 induces vacuolisation processes in the cell in contrast to complex 1 and cisplatin. Thus, the four complexes cisplatin tested, Cu(3-Clip-Phen), 1 and 6 stimulate different cellular responses.
Ozalp-Yaman
Seniz
S
Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands.
de Hoog
Paul
P
Amadei
Giulio
G
Pitié
Marguerite
M
Gamez
Patrick
P
Dewelle
Janique
J
Mijatovic
Tatjana
T
Meunier
Bernard
B
Kiss
Robert
R
Reedijk
Jan
J
D000970:Antineoplastic Agents / Q000737:chemistry*; D010584:Bacteriophage phi X 174 / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry*; D004279:DNA, Viral / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D010984:Platinum / Q000737:chemistry*
D000970:Antineoplastic Agents; D004279:DNA, Viral; D010984:Platinum; D003300:Copper