Effects of geometric isomerism in dinuclear antitumor platinum complexes on their interactions with N-acetyl-L-methionine

In this study, the reactions of N-acetyl-L-methionine (AcMet) with {trans-PtCl(NH₃)₂}₂-μ-H₂N(CH₂)₆NH₂](NO₃)₂ (BBR3005: 1,1/t,t 1) and its cis analog {cis-PtCl(NH₃)₂}₂-μ-{H₂N(CH₂)₆NH₂}]Cl₂ (1,1/c,c 2) were analyzed to determine the rate and reaction profile of chloride substitution by methionine sulfur. The reactions were studied in PBS buffer at 37°C by a combination of multinuclear (¹⁹⁵Pt, {¹H-¹⁵N} HSQC) magnetic resonance (NMR) spectroscopy and electrospray ionization time of flight mass spectrometry (ESITOFMS). The diamine linker of the 1,1/t,t trans complex was released as a result of the trans influence of the coordinated sulfur atom, producing trans-PtCl(AcMet)(NH₃)₂]⁺ (III) and trans-Pt(AcMet)₂(NH₃)₂]²⁺ (IV). In contrast the cis geometry of the dinuclear compound maintained the diamine bridge intact and a number of novel dinuclear platinum compounds obtained by stepwise substitution of sulfur on both platinum centers were identified. These include (charges omitted for clarity): {cis-PtCl(NH₃)₂}-μ-NH₂(CH₂)₆NH₂-{cis-Pt(AcMet)(NH₃)₂}] (V); {cis-Pt(AcMet)(NH₃)₂}₂-μ-NH₂(CH₂)₆NH₂] (VI); {cis-PtCl(NH₃)₂}-μ-NH₂(CH₂)₆NH₂-{PtCl(AcMet)NH₃] (VII); {PtCl(AcMet)(NH₃)}₂-μ-NH₂(CH₂)₆NH₂] (VIII); {trans-Pt(AcMet)₂(NH₃)}-μ-NH₂(CH₂)₆NH₂-{PtCl(AcMet)(NH₃)] (IX) and the fully substituted {trans-Pt(AcMet)₂(NH₃)}₂-μ-{NH₂(CH₂)₆NH₂] (X). For both compounds the reactions with methionine were slower than those with glutathione (Inorg Chem 2003, 42:5498–5506). Further, the 1,1/c,c geometry resulted in slower reaction than the trans isomer, because of steric hindrance of the bridge, as observed previously in reactions with DNA and model nucleotides.