A Third Mode of DNA Binding:  Phosphate Clamps by a Polynuclear Platinum Complex

Abstract

We describe a 1.2 A X-ray structure of a double-stranded B-DNA dodecamer (the Dickerson Dodecamer, DDD, [d(CGCGAATTCGCG)]2) associated with a cytotoxic platinum(II) complex, [{trans-Pt(NH3)2(NH2(CH2)6(NH3+)}2-mu-{trans-Pt(NH3)2(NH2(CH2)6NH2)2}] (TriplatinNC). TriplatinNC is a multifunctional DNA ligand, with three cationic Pt(II) centers, and directional hydrogen bonding functionalities, linked by flexible hydrophobic segments, but without the potential for covalent interaction. TriplatinNC does not intercalate nor does it bind in either groove. Instead, it binds to phosphate oxygen atoms and thus associates with the backbone. The three square-planar tetra-am(m)ine Pt(II) coordination units form bidentate N...O...N complexes with OP atoms, in a motif we call the Phosphate Clamp. The geometry is conserved among the 8 observed phosphate clamps in this structure. The interaction appears to prefer O2P over O1P atoms (frequency of interaction is O2P > O1P, base and sugar oxygens > N). The high repetition and geometric regularity of the motif suggests that this type of Pt(II) center can be developed as a modular nucleic acid binding device with general utility. TriplatinNC extends along the phosphate backbone, in a mode of binding we call "Backbone Tracking" and spans the minor groove in a mode of binding we call "Groove Spanning". Electrostatic forces appear to induce modest DNA bending into the major groove. This bending may be related to the direct coordination of a sodium cation by a DNA base, with unprecedented inner-shell (direct) coordination of penta-hydrated sodium at the O6 atom of a guanine.

New trends for metal complexes with anticancer activity

“…Farrell et al have described a discrete binding mode based on interactions that utilize exclusively backbone functional groups [30 ]. The new binding mode was observed in the crystal structure of a double-stranded B-DNA dodecamer with TriplatinNC (13) (Figure 2b).…”

The status of platinum anticancer drugs in the clinic and in clinical trials

“…175, 176 More recently it has been shown to be able to form phosphate clamps with the backbone of DNA 177 and have possible interactions with membrane phospholipids.…”

Combining aspects of the platinum anticancer drugs picoplatin and BBR3464 to synthesize a new family of sterically hindered dinuclear complexes; their synthesis, binding kinetics and cytotoxicity

“…For multinuclear platinum complexes it has been shown that hydrogen bonding and electrostatic binding between the bridging ligand and the DNA helix is important in stabilising and directing the type of DNA adducts formed. 19,[26][27][28] The ligands synthesised in this work are therefore capable of acting as both hydrogen bond acceptors/donors and when pre-associated in the DNA minor groove, can potentially form hydrogen bonds to the bases as well as ion-dipole interactions with the anionic DNA backbone.…”