Structural Factors Affecting Binding of Platinum Anticancer Agents with Phospholipids: Influence of Charge and Phosphate Clamp Formation

We report a detailed NMR and DFT study of the interaction of polynuclear platinum anticancer agents (PPCs) with negatively charged phospholipids as a mechanism for their cellular uptake. The reactions of fully 15N‐labelled [{trans‐PtCl(NH3)2}2(μ‐trans‐Pt(NH3)2{NH2(CH2)6NH2}2)]4+ (15N‐1, 1,0,1/t,t,t) and the dinuclear [{trans‐PtCl(NH3)2}2{μ‐H2N(CH2)6NH2}]2+ (15N‐2, 1,1/t,t) with the sodium salt of 1,2‐dihexanoyl‐sn‐glycero‐3‐phosphate (DHPA) were studied at 298 K, pH ≈5.4, by [1H,15N] HSQC 2D NMR spectroscopy. Both 15N‐1 and 15N‐2 form an initial mono‐adduct in which the DHPA is coordinated via the phosphate O atom. For the dinuclear 15N‐2, coordination of a second DHPA, in two different orientations, leads to two conformers of the bifunctional adduct. For 15N‐1, coordination of the second DHPA allows the central {PtN4} coordination unit to bind electrostatically to two additional DHPA molecules via phosphate clamp interactions, in an extended network. For both 1,0,1/t,t,t (1) and 1,1/t,t (2), equilibrium conditions are obtained more slowly (>35 h) than in the presence of phosphate (12 h) and in each case the rate constant for the first step of DHPA binding (kL) is about 8 times higher than that for phosphate, whereas the rate constants for the reverse reactions are quite similar. Reaction of 15N‐1 with the sodium salt of 1,2‐dihexanoyl‐sn‐glycero‐3‐[phosphatidyl‐l‐serine] (DHPS) showed only minor adduct formation via coordination to the N‐donor atom of the phosphoserine group.