Hydrolysis products of cisplatin: pK a determinations via[1H, 15N] NMR spectroscopy

Abstract

The pK, values of ~i s -[ P t C l ( H ~o ) ( N H ~) ~l + (6.41) and C ~S -[ P ~( H ~O ) ~( N H ~) ~] ~+ (5.37 and 7.21) have been determined at 300 K via the use of I5N-edited 1H NMR spectroscopy and [IH, 15N] heteronuclear multiple quantum coherence spectroscopy; this allows rapid measurements at low (millimolar) concentrations, and so avoids some of the problems associated with other methods. Cisplatin, ~i s -[ P t C l ~( N H ~) ~l1, is a widely used anticancer drug. Its mechanism of action is thought to involve activation via hydrolysis inside cells where the C1-concentration is much lower (ca. 4 mmol dm-3) than outside cells (ca. 104 mmol dm-3) .273 Platinum(~~)-OH~ bonds are more reactive towards DNA (e.g. guanine N7) than either Pt-CI or Pt-OH b0nds~4.5 and it is important therefore to determine the pK, values of the coordinated water molecules in the cisplatin hydrolysis products cis-[ PtC1( H20)(NH3)2] + 2 and cis-[ Pt( H20)2-(NH3)2]2+ 3. This is difficult to do because reactions of these species with base are complicated by the further hydrolysis of 2, and by the slow formation of hydroxo-bridged polymers. These complicate the interpretation of potentiometric titration curves.5-7 The pK, values of species in mixtures can be determined by NMR spectroscopy provided they have suitable resonances which can be monitored as a function of pH. 2b r 2a /I @ \ \ Cis -[ P t C I (0 H 2 ) (N H3) 21' cis -[ P t (0 H2)2 (N H

Effects of (N7)-Coordinated Nickel(II), Copper(II), or Platinum(II) on the Acid-Base Properties of Guanine Derivatives and Other Related Purines[≠]

“…The properties of the latter can be qualitatively explained by applying the concept of the trans influence. [40] Thus, the pK a values for the aqua ligands (in the case of the diaqua species they refer to pK a1 ) of trans-[(NH 3 ) 2 Pt(H 2 O) 2 ] 2 (4.35), [41] trans-[(NH 3 ) 2 -Pt(Cl)(H 2 O)] (5.63), [41] cis-[(NH 3 ) 2 Pt(H 2 O) 2 ] 2 (5.93, [42] 5.37, [43] 5.24 [44] ), and cis-[(NH 3 ) 2 Pt(Cl)(H 2 O)] (6.85, [42] 6.41 [43] ) follow the expectation for the sequence of the trans influence, which is NH 3 b Cl À b OH 2 , despite differences in charge. In other words, the acidity of an aqua ligand is, to a first approximation, dependent on its binding strength to Pt 2 , which in turn is influenced by the nature of the donor atom trans to the aqua ligand.…”

Platination of A GG Site on Single‐Stranded and Double‐Stranded forms of A 14‐Base Oligonucleotide with Diaqua Cisplatin followed by NMR and HPLC

“…As the reactions with the dicationic, dihydrolyzed product of cisplatin, cis-[Pt(H,O),(NH,),1*+ 1, were expected to be much faster, the present study was carried out at the lower temperature of 288 K. To avoid the introduction of further equilibria which would have complicated the kinetic scheme, we chose a pH of 4.8. At this pH, the formation of the hydroxo forms of 1 (pK, values 5.37 and 7.21 [15]) can be neglected and the duplex structure is not destabilized by protonation of the G-N7 [IS].…”

Cisplatin Affects the Conformation of Apo Form, not Holo Form, of BRCA1 RING Finger Domain and Confers Thermal Stability

“…The result revealed a unique fragment ion ( þ 2) with a peak at m/z 656.29 obtained only from cisplatin -BRCA1 adduct digests (Fig. 10) [51]. This product potentially reacted with BRCA1 and yielded BRCA1-Pt(NH 3 ) 2 (OH) as described by the following reactions.…”