Stereospecific and Kinetic Control over the Hydrolysis of a Sterically Hindered Platinum Picoline Anticancer Complex

Abstract

cis-[PtCl 2 (NH 3 )(2-picoline)] (1) (AMD 473) is a recently reported active anticancer complex. Hydrolysis may be an important step in its intracellular activation and interaction with DNA. In this paper we employed [ 1 H, 15 N] 2 D NMR spectroscopy to determine the hydrolysis rates for each chloride ligand of this complex and its 3-picoline analogue 2. We also report the pK a values of the aqua and diaqua ligands as well as the X-ray crystal structures of 1 and 2. For the 3-picoline complex 2 the rate of hydrolysis of the Cl À trans to NH 3 (k 1b 1.0 Â 10 À4 s À1, I 0.1m, 310 K) is similar to that of cisplatin, but slower for the Cl À trans to 3-picoline (k 1a 4.5 Â 10 À5 s À1 ). Both of the first hydrolysis rates for the 2-picoline complex 1 are slower than those of 2, but in contrast to 2, the hydrolysis of the Cl À trans to NH 3 (cis to 2-picoline) is slower (k 1b 2.2 Â 10 À5 s À1) than for the Cl À trans to 2-picoline (k 1a 3.2 Â 10 À5 s À1). The crystal structure of 2 revealed that the pyridine ring is tilted by 498 with respect to the Pt square plane, whereas in 1 the ring is almost perpendicular (1038). This introduces steric hindrance by the CH 3 group towards an axial approach to Pt from above, leading to a destabilisation of the expected trigonal-bipyramidal transition state, an effect well-known in substitution reactions of Pt II complexes. The pK a values for the monoaqua adducts of 1 (6.13 and 6.49) and 2 (5.98 and 6.26 for H 2 O trans to picoline and NH 3 , respectively) and for the diaqua adducts (5.22, 7.16 for 1 and 5.07, 6.94 for 2) are b 0.3 units lower than for cisplatin. The slowness of the hydrolysis, combined with the dominance of (inert) hydroxo species, is expected to contribute to a greatly reduced reactivity of the sterically-hindered 2-picoline complex under intracellular conditions.

Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile

“…This principle has been adopted for the related platinum anticancer complex cis-[Pt(NH 3 )(2-picoline)Cl 2 ] (picoplatin), which is currently undergoing clinical trials (11). The reactions of picoplatin with water and other nucleophiles are much slower than those of cisplatin and related complexes lacking steric hindrance at the axial sites (12)(13)(14). The lesser reactivity of picoplatin, particularly with thiols, prevents undesired deactivation of the complex before it can reach DNA.…”

cis-[PtCl2(NH3){2-(2-hydroxyethyl)pyridine}] − an Analogue of the Anticancer Drug AMD473: Unusual Hydrolysis Rates and pKa Values for the Diaqua Adduct

“…These structural features are similar to those of the 2-picoline complex AMD473 (103°and H 3 C···Pt 3.22 Å ). [4] The PtϪN1 distance (2.028 Å ) is also similar to that of the 2-picoline complex (2.017 Å ). No intramolecular hydrogen bonding is observed between the hydroxyl group and the two Cl ligands.…”

“…[2,3] In reactions of cisplatin with DNA, hydrolysis is known to be the rate-limiting step. The steric influence of 2-picoline plays an important role in decreasing the rates of hydrolysis and substitution reactions of AMD473, [4,5] and also in promoting high stereoselectivity in the formation of a GG intrastrand adduct with a 14-mer DNA duplex. [6] In order to elucidate further the role of pyridine substituents in determining the reactivity of platinum(II) picoline complexes, we have studied the hydrolysis rates of the AMD473 analogue cis-[PtCl 2 (NH 3 ){2-(2-hydroxyethyl)pyridine}] (1) and determined the pK a values of its monoaqua and diaqua adducts by [ 1 H, 15 N] NMR studies of complex 1 labelled with 15 NH 3 .…”

The status of platinum anticancer drugs in the clinic and in clinical trials

“…204 This provides steric hindrance to the attack of the drug by nucleophiles, particularly thiols. In vitro studies demonstrated picoplatin's ability to overcome platinum drug resistance, showing anticancer activity in cisplatin, carboplatin and oxaliplatin resistant cell lines.…”