EXAFS and IR Structural Study of Platinum-Based Anticancer Drugs' Degradation by Diethyl Dithiocarbamate

Abstract

Platinum compounds constitute a discrete class of DNA-damaging anticancer drug agents, including cisplatin, carboplatin, and oxaliplatin. The toxicity of such drugs raises the problem of waste detoxification. Diethyl dithiocarbamate (DDTC) is recommended by the World Heath Organization (WHO) for the destruction of cisplatin, but the degradation product has not been structurally characterized. This paper deals with the extended X-ray absorption fine structure (EXAFS) and IR structural study of the reaction products of DDTC with cisplatin, carboplatin, and oxaliplatin. Cisplatin and carboplatin give the same reaction product: Pt(DDTC)2. In the case of oxaliplatin, we observed the formation of [(diaminocyclohexane)(DDTC)Pt(II)]. In all cases, the replacement of labile ligands by strong ligands should lead to inactive compounds. Our results suggest that the WHO inactivation protocol might be extended to carboplatin and oxaliplatin. Nevertheless, this should be validated by toxicity tests of the degradation products.

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

“…The present study contributes to this goal, by coupling three forms of vibrational spectroscopy (infrared (FTIR), Raman and inelastic neutron scattering (INS)) with computational simulations and extended X-ray absorption fine structure (EXAFS). The latter is a method of choice for obtaining detailed information on the local structure of bioinorganic non-crystalline materials, [14][15][16] since even the weakest chemical bonds are not affected by the measurement, and is expected to fully elucidate cisplatin's interplay with DNA -its binding mode to adenine and guanine, and the effect of GSH on the drug's bioavailability. Indeed, this technique has been used successfully by other authors 15,16 for the study of the degradation of antitumour Pt(II) complexes in the presence of sulfur nucleophiles.…”

Characterizing Pt‐Derived Anticancer Drugs from First Principles: The Case of Oxaliplatin in Aqueous Solution

“…Several studies have appeared on the substitution kinetics and chemical stability of oxaliplatin in water solution, [9,10] in NaCl solution, [9] and in the presence of different chemical species (such as chloride anions, [11,12] diethyl dithiocarbamate, [13] carbonate buffers, [14] different nucleophiles, [15,16] etc.). The only structural determination of oxaliplatin in aqueous solution comes from the contributions of Provost and collaborators who have characterized it by means of EXAFS spectroscopy.…”

Quantitative liquid chromatographic determination of intact cisplatin in blood with microwave-assisted post-column derivatization and UV detection

“…Pt-glutathione [3], Pt-methionine [4], and MHC [14]. The molecular structure of the Pt-DDTC complex formed in the present study is unknown, but it is well established that the reaction between cisplatin and DDTC can generate the complex Pt(DDTC) 2 [4,14,[21][22][23], which has a molar absorptivity of about 20,000-25,000 M −1 cm −1 at approximately 344 nm [20,21]. Pt(DDTC) 2 may also be the product of the reaction between DDTC and the cisplatin analogs oxaliplatin [13] and carboplatin [22].…”

“…The molecular structure of the Pt-DDTC complex formed in the present study is unknown, but it is well established that the reaction between cisplatin and DDTC can generate the complex Pt(DDTC) 2 [4,14,[21][22][23], which has a molar absorptivity of about 20,000-25,000 M −1 cm −1 at approximately 344 nm [20,21]. Pt(DDTC) 2 may also be the product of the reaction between DDTC and the cisplatin analogs oxaliplatin [13] and carboplatin [22]. However, significant amounts of the complex Pt(DDTC) 3 was found in a former cisplatin study [23], and experiments with the Pt species H 2 (PtCl 6 ) have shown that its reaction with DDTC can generate the complexes Pt(DDTC), Pt(DDTC) 2 , Pt(DDTC) 3 , Pt 2 (DDTC) 3 [24].…”