Reduction mechanism of the Pt(IV) Satraplatin derivates by guanosine monophosphate; quantum mechanical study

Filip Šebesta, Jaroslav V. Burda

Faculty of Mathematics and Physics, Charles University, Ke Karlovu 3, 121 16 Prague 2, Czech Republic

The platinum IV compound Satraplatin (JM216) was selected for clinical development because of: a) high cytotoxic activity in vitro against several solid tumor cell lines, including cisplatin resistant ones; b) in vivo oral antitumor activity against a variety tumor models; c) a relatively mild toxicity profile and oral bioavailability. In Phase 2 clinical trials, satraplatin showed activity against several different cancers, including prostate, ovarian, and small cell lung cancers [1].

When PtIV(dach)Cl₄ reacts with dGMP or GMP the pH drops form 8.3 to 3.4, and yellow crystals are formed. The crystals were identified as PtII(dach)Cl₂ by IR analysis (3267, 3190, 3066, 2936, 2863, and 1564 cm-1). This indicates that both dGMP and GMP can reduced Pt(IV) to Pt(II) [2].

Quantum chemical tool was used to confirm the suggested reactions and explore the detailed reduction mechanism. Both thermodynamic and kinetic characteristics were determined at several computational levels. The AIM, NBO and frequency analyses were used for examination of all the individual complexes.

(1) Choi, S.; Filotto, C.; Bisanzo, M.; Delaney, S.; Lagasee, D.; Whitworth, J. L.; Jusko, A.; Li, C.; Wood, N. A.; Willingham, J.; Schwenker, A.; Spaulding, K. Inorg. Chem. 1998, 37, 2500-2504.

(2) Angelov, D.; Spassky, A.; Berger, M.; Cadet, J. J. Am. Chem. Soc. 1997, 119, 11373-11380.