Mechanisms of reaction of L-methionine with carboplatin and oxaliplatin indifferent media: a comparison with cisplatin

The activity of platinum compounds is dependent on nucleophile substitution reactions. In this payer, we study the reactivity of L-met with carboplati n, oxaliplatin and cisplatin by following with HPLC-UV the concentration of L-met and by characterizing the resulting adducts with LC-MS. In the absen ce of NaCl, in water, the initial rate at which L-met concentration decreas es with cisplatin, oxaliplatin and carboplatin is 0.25 +/- 0.007, 0.057 +/- 0.01 and 0.17 +/- 0.02 mM h(-1), respectively. In phosphate buffer this ra te is 0.056 +/- 0.009 for cisplatin, 0.019 +/- 0.001 and 0.13 +/- 0.02 for carboplatin and oxaliplatin, respectively. Reactions of L-met with cisplati n occurred via its conversion into monoaqua species in water and into phosp hato-derivatives (AP) in phosphate buffer but finally the same methionine-p latinum adducts M2 [(NH3)(2)(met)]Pt, M4 and M5 [(met)(2)]Pt were character ized. Reaction of carboplatin with L-met occurred via the formation of M0 [ (NH3)(2)(met)(CBDCA)]Pt whose structure is consistent with the direct inter action of L-met with carboplatin. However, the same final products as those found with cisplatin were characterized. The reaction of oxaliplatin with L-met proceeded through a mechanism similar to that of carboplatin to give- M7 [(met)(DACH)]Pt. In the presence of NaCl, cisplatin directly reacted wit h L-met to yield at least five methionine-platinum adducts. The reaction of carboplatin gave the same adducts suggesting its transformation into cispl atin. The reaction of oxaliplatin with L-met occurred via the formation of aquated species A [(OH)(Cl)(DACH)]Pt which readily underwent reaction with L-met to form M6 [(met)(Cl)(DACH)]Pt and M7. This study shows that the reac tivity of cisplatin, carboplatin and oxaliplatin is dependent on the media in which they occur. The discrepancy between their reactions with L-met cou ld partly explain their therapeutic differences. Copyright (C) 1999 John Wi ley & Sons, Ltd.