Cucurbituril binding of trans-[{PtCl(NH3)2}2(micro-NH2(CH2)8NH2)]2+ and the effect on the reaction with cysteine.
The effect of encapsulation by cucurbiturils Q[7] and Q[8] on the rate of reaction of the anti-cancer dinuclear platinum complex trans-[{PtCl(NH3)2}2(micro-NH2(CH2)8NH2)]2+ with the model biological nucleophiles glutathione and cysteine has been examined by NMR spectroscopy. It was expected that the octamethylene linking chain would fold inside the cucurbituril host and hence position the reactive platinum centres close to the cucurbituril portals, and thereby, confer resistance to degradation by biological nucleophiles. The upfield shifts of the resonances from the methylene protons in the linking ligand observed in 1H NMR spectra of the platinum complex upon addition of either Q[7] or Q[8] indicate that the cucurbituril is positioned over the linking ligand, with the Pt(II) centres projecting out of the portal. Furthermore, the relative changes in chemical shift of the methylene resonances suggest that the octamethylene linking chain folds within the cucurbituril cavity, particularly in Q[8]. Simple molecular models, based on the observed relative changes in chemical shift, could be constructed that were consistent with the proposed folding of the linking ligand within the cucurbituril cavity. Encapsulation by Q[7] was found to reduce the rate of reaction of the platinum complex with glutathione. Encapsulation by Q[7] and Q[8] was also found to reduce the rate of reaction of the platinum complex with cysteine, with Q[8] slowing the reaction to a greater extent than Q[7], consistent with the inferred encapsulation geometries. Encapsulation of dinuclear platinum complexes within the cucurbituril cavity may provide a novel way of reducing the reactivity and degradation of these promising chemotherapeutic agents with blood plasma proteins.
Bali
Mark S
MS
School of Physical, Environmental and Mathematical Sciences, University College, University of New South Wales, Australian Defence Force Academy, Northcott Drive, Campbell, ACT 2600, Australia.
Buck
Damian P
DP
Coe
Andrew J
AJ
Day
Anthony I
AI
Collins
J Grant
JG
D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001665:Binding Sites; D002214:Capsules; D002945:Cisplatin; D003545:Cysteine / Q000737:chemistry*; D005978:Glutathione / Q000737:chemistry; D007700:Kinetics; D047028:Macrocyclic Compounds / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D000099246:Cucurbit(n)urils
D000970:Antineoplastic Agents; D002214:Capsules; D002945:Cisplatin; D003545:Cysteine; D005978:Glutathione; D047028:Macrocyclic Compounds; D009944:Organoplatinum Compounds; D000099246:Cucurbit(n)urils; C034697:transplatin