Effects of geometric isomerism in dinuclear platinum antitumor complexes on aquation reactions in the presence of perchlorate, acetate and phosphate.
The aquation and subsequent reactions of the dinuclear Pt antitumor complexes [{trans-PtCl(NH(3))(2)}(2)(mu-NH(2)(CH(2))(6)NH(2))](2+) (1,1/t,t) and [{cis-PtCl(NH(3))(2)}(2)(mu-NH(2)(CH(2))(6)NH(2))](2+) (1,1/c,c) in 15 mM perchlorate, acetate or phosphate solutions were followed at 298 K by [(1)H,(15)N] HSQC 2D NMR spectroscopy. Rate and equilibrium constants for the initial reversible aquation and the subsequent reversible reaction with phosphate or acetate are reported. The rate constant for the first aquation step is two-fold lower for 1,1/c,c than 1,1/t,t but the anation rate constants are similar so that the equilibrium lies further towards the chloro form for the 1,1/c,c compound. A pK (a) value of 6.01+/-0.03 was determined for the diaquated species [{cis-Pt(NH(3))(2)(H(2)O)}(2)(mu-NH(2)(CH(2))(6)NH(2))](4+) (1,1/c,c-3) which is 0.4 units higher than that of the 1,1/t,t compound. The rate constants for the binding of acetate and phosphate to 1,1/t,t are similar, but the rate constant for the reverse reaction is close to ten-fold higher in the case of phosphate so that equilibrium conditions are attained more rapidly (12 h compared with 64 h). On the other hand, for 1,1/c,c the rate constants for the forward and reverse reactions with acetate and phosphate are quite similar so that equilibrium conditions are reached very slowly (80-100 h) and a greater proportion of phosphate-bound species are present. The reduced lability of the bound phosphate for 1,1/c,c is attributed to the formation of a macrochelate phosphate-bridged species which was characterized by (31)P NMR and ESI-MS. The speciation profiles of 1,1/t,t and 1,1/c,c under physiological conditions are explored.
Zhang
Junyong
J
School of Biomedical & Chemical Sciences, University of Western Australia, Crawley, WA, 6009, Australia.
Thomas
Donald S
DS
Davies
Murray S
MS
Berners-Price
Susan J
SJ
Farrell
Nicholas
N
D000085:Acetates / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D007536:Isomerism; D008958:Models, Molecular; D009944:Organoplatinum Compounds / Q000737:chemistry; D010472:Perchlorates / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry; D012996:Solutions; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
D000085:Acetates; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010472:Perchlorates; D010710:Phosphates; D012996:Solutions; D014867:Water