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)...

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Published in:Chemistry : a European journal 2018-03, Vol.24 (18), p.4643-4652
Main Authors: Gorle, Anil Kumar, Zhang, Junyong, Liu, Qin, Berners‐Price, Susan J., Farrell, Nicholas P.
Format: Article
Language:English
Subjects:
Ammonia
anticancer
Anticancer properties
Antitumor agents
Binding
Cancer
Chemistry
density functional theory
Equilibrium conditions
L-Serine
Magnetic resonance spectroscopy
NMR
NMR spectroscopy
Nuclear magnetic resonance
Phosphates
Phospholipids
Phosphoserine
Platinum
Rate constants
Sodium
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Summary: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. Amphipathic complementarity. A holistic approach to the molecular mechanism of platinum anti‐cancer agents extends DNA interactions to membrane heparan sulfate proteoglycans and phospholipids relevant to cellular accumulation and delivery. The amphipathic nature of polynuclear platinum compounds is remarkably complementary for strong interaction with the amphiphilic phospholipids leading to higher‐order structures.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201705822