Abstract
Carboplatin, [Pt(NH3)2(CBDCA-O,O')], 1, where CBDCA is cyclobutane-1,1-dicarboxylate, is in wide clinical use for the treatment of ovarian, lung, and other types of cancer. Because carboplatin is relatively unreactive toward nucleophiles, an important question concerning the drug is the mechanism by which it is activated in vivo. Using [1H,15N] heteronuclear single quantum coherance spectroscopy (HSQC) NMR and 15N-labeled carboplatin, we show that carboplatin reacts with carbonate ion in carbonate buffer to produce ring-opened products, the nature of which depends on the pH of the medium. The assignment of HSQC NMR resonances was facilitated by studying the reaction of carboplatin in strong acid, which also produces a ring-opened product. The HSQC NMR spectra and UV-visible difference spectra show that reaction of carboplatin with carbonate at pH > 8.6 produces mainly cis-[Pt(NH3)2(CO3(-2))(CBDCA-O)]-2, 5, which contains the mono-dentate CBDCA ligand and mono-dentate carbonate. At pH 6.7, the primary product is the corresponding bicarbonato complex, which may be in equilibrium with its decarboxylated hydroxo analogue. The UV-visible absorption data indicate that the pKb for the protonation of 5 is approximately 8.6. Thus, the reaction of carboplatin with carbonate produces a mixture of ring-opened species that are anions at physiological pH. HSQC NMR studies on 15N-labeled carboplatin in RPMI culture media containing 10% fetal bovine serum with and without added carbonate suggest that carbonate is the attacking nucleophile in culture media. However, because the rate of reaction of carbonate with carboplatin at physiological pH is small, NMR peaks for ring-opened carboplatin were not detected with HSQC NMR. The rate of disappearance of carboplatin in culture medium containing 9 x 10(8) Jurkat cells is essentially the same as that in carbonate buffer, indicating that the ring-opening reaction is not affected by the presence of cells. This work shows that carbonate at concentrations found in culture media, blood, and the cytosol readily displaces one arm of the CBDCA ligand of carboplatin to give a ring-opened product, which at physiological pH is a mixture of anions. These ring-opened species may be important in the uptake, antitumor properties, and toxicity of carboplatin.
Highlights
Carboplatin, [Pt(NH3)2(CBDCA-O,O′)]1 (1 in Figure 1), where CBDCA is cyclobutane-1,1-dicarboxylate, is a secondgeneration Pt2+ anticancer drug, which is less oto- and nephrotoxic than cis-diamminedichloroplatinum(II), 2 [1, 2]
The peak at 4.50/-86.5, observed at later times, which has an 15N chemical shift similar to that of 3b, has been assigned to cis-[Pt(NH3)2(H2O)2]+2, 4 [23]. (Peak assignments are summarized in Table 1.) The presence of this complex was shown by earlier studies, which employed UV-visible spectroscopy to measure the kinetics of acid hydrolysis of carboplatin [24]
We show that carbonate ion at concentrations found in culture medium and blood readily displaces one arm of the CBDCA ligand of carboplatin to form a ring-opened product having bound carbonate
Summary
Carboplatin, [Pt(NH3)2(CBDCA-O,O′)]1 (1 in Figure 1), where CBDCA is cyclobutane-1,1-dicarboxylate, is a secondgeneration Pt2+ anticancer drug, which is less oto- and nephrotoxic than cis-diamminedichloroplatinum(II) (cisplatin), 2 [1, 2]. Both cisplatin and carboplatin have cis ammonia ligands, but in the latter, the two chloride ligands of cisplatin are replaced by a dicarboxylate chelate ring (Figure 1). While a thioether group can readily displace the bidentate chelate ring of carboplatin, the resulting Pt-methionine adduct is thermodynamically stable making transfer of the Pt to a target via breakage of the Pt-S bond difficult [3]. A cis-(NH3)2Pt(II) moiety, which is bound to the terminal Met of ubiquitin, cannot be transferred
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