DNA cleavage and binding selectivity of a heterodinuclear Pt–Cu(3-Clip-Phen) complex

Abstract

The synthesis and nuclease activity of a new bifunctional heterodinuclear platinum–copper complex are reported. The design of this ditopic coordination compound is based on the specific mode of action of each component, namely, cisplatin and Cu(3-Clip-Phen), where 3-Clip-Phen is 1-(1,10-phenanthrolin-3-yloxy)-3-(1,10-phenanthrolin-8-yloxy)propan-2-amine. Cisplatin is not only able to direct the Cu(3-Clip-Phen) part to the GG or AG site, but also acts as a kinetically inert DNA anchor. The nuclease activity of this complex has been investigated on supercoiled DNA. The dinuclear compound is not only more active than Cu(3-Clip-Phen), but is also capable of inducing direct double-strand breaks. The sequence selectivity of the mononuclear platinum complex has been investigated by primer extension experiments, which reveal that its interaction with DNA occurs at the same sites as for cisplatin. The Taq polymerase recognizes the resulting DNA damage as different from that for unmodified cisplatin. The sequence-selective cleavage has been investigated by high-resolution gel electrophoresis on a 36-bp DNA fragment. Sequence-selective cleavages are observed in the close proximity of the platinum sites for the strand exhibiting the preferential platinum binding sites. The platinum moiety also coordinates to the other DNA strand, most likely leading only to mono guanine or adenine adducts.Electronic supplementary materialThe online version of this article (doi:10.1007/s00775-008-0346-y) contains supplementary material, which is available to authorized users.

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“…The three most common platinating agents (cisplatin, carboplatin, and oxaliplatin) are indeed the best examples of DNA-targeted antitumor agents. It is generally agreed that DNA is the primary cytotoxic target for these complexes [58,59].…”

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“…Heterobimetallic complexes are bifunctional agents with two or more active metal centres capable of showing interactions with biological targets [100,101]. Present scenario witnesses a growing interest in the design of heterometallic complexes as agents for the treatment of different diseases [102,103].…”

Pincer‐Based Heterobimetallic Pt(II)/Ru(II), Pt(II)/Ir(III), and Pt(II)/Cu(I) Complexes: Synthesis and Evaluation of Antiproliferative Properties

“…Within this frame, heterobimetallic complexes could be very promising. [3][4][5][6][7][8][9] In particular, Pt(II) complexes have been associated with various other metal ions such as Au(I), [5] Pd(II), [6] Cu(II), [7] Ru(II) [8] and Re(I). [9] Some examples are depicted in Figure 1.…”

“…plex (Figure 1), the authors observed copper-induced DNA cleavage in the surroundings of GG sequences due to the specific coordination of the Pt(II) moiety to these sequences. [7] Another interest of heterobimetallic complexes is the design of theranostic agents. [10] In this case, one metal will act as the active principle and the second one will be used for luminescence [11] or MRI [12] detection.…”