Hydrolysis in Acidic Environment and Degradation of Satraplatin: A Joint Experimental and Theoretical Investigation

Abstract

For the synthesis and selection of active platinum-based anticancer drugs that perform better than cisplatin and its analogues, six-coordinate octahedral Pt(IV) complexes appear to be promising candidates as, being kinetically more inert and more resistant to ligand substitution than four-coordinate Pt(II) centers, they are able to minimize unwanted side reactions with biomolecules prior to DNA binding. Due to their kinetic inertness, Pt(IV) complexes have also been exploited to bypass inconvenient intravenous administration. The most prominent example is satraplatin (Sat.) which is the first platinum antineoplastic agent reported to have oral activity. The present paper deals with a theoretical DFT investigation of the influence that the acidity of the biological environment can have on the activity of satraplatin and analogous octahedral Pt(IV) complexes having two carboxylates as axial ligands. Moreover, here the outcomes of a joint electrospray ionization mass spectrometry and DFT investigation of the fragmentation pathways of the protonated satraplatin are reported. Calculations show that the simulated acidic environment has an important impact on the satraplatin reactivity causing a significant lowering of the barrier that is necessary to overcome for the hydrolysis of the first acetate ligand to occur. Data from electrospray ionization mass spectrometry, H NMR, and potentiometric experiments strongly suggest that the loss of CHCOOH from the protonated satraplatin ion [Sat. + H] takes place almost immediately upon dissolution of satraplatin in methanol-water, DO, and water solutions, respectively, at room temperature.

Host-Guest Complexation of Oxaliplatin and Para-Sulfonatocalix[n]Arenes for Potential Use in Cancer Therapy

“…Platinum drug-based chemotherapeutics (PBCs) are among the most potent broad-spectrum anticancer medicines which are used in chemotherapy of 50-70% of cancer patients [1,2]. The cytotoxic effects of cisplatin, the first generation PBC, were discovered coincidentally by Barnett Rosenberg in 1965 and found to possess potent broad-spectrum anticancer activity among different types of solid tumors [3,4].…”

“…Supplementary Materials: Figure S1: 1 HNMR spectra of (A) p-SC4 alone, (B) oxaliplatin alone, and (C) equilmolar ratio of amount of oxaliplatin and p-SC4. Structures of oxaliplatin and p-SC4 are shown with appropriate protons labeled, Figure S2: First derivative of ratio spectra of the mixtures containing successively increasing concentrations of oxaliplatin (ranging from 0.01-0.21 mM) and a fixed concentration of 0.2 mM p-SC4 all in distilled water using the spectrum of 0.2 mM of p-SC4 as a divisor, Table S1: ADMET study rsults of oxaliplatin, oxaliplatin/p-SC4, and oxaliplatin/p-SC6 complexes as performed by Discovery Studio 4.0.…”

PEGylated Chitosan Nanoparticles Encapsulating Ascorbic Acid and Oxaliplatin Exhibit Dramatic Apoptotic Effects against Breast Cancer Cells

“…To date, hundreds of PBDs have been synthesized and entered clinical trials to enhance the anticancer activities and minimize toxic effects (including nephrotoxicity, ematogenesis, and resistance) compared to cisplatin. From these developed PBDs, only carboplatin and oxaliplatin have been approved by FDA for cancer treatment [2][3][4][5].…”

Synthesis, Characterization and Host-Guest Complexation of Asplatin: Improved In Vitro Cytotoxicity and Biocompatibility as Compared to Cisplatin

“…Platinum-based anticancer drugs (PBDs) are powerful broad-spectrum antitumor treatments effective against many solid tumors, including breast cancer. Cisplatin (cisdiammine-(dichlorido)platinum(II)) is a first-generation platinum II-based complex that was granted US Food and Drug Administration (FDA) approval in the late 1970s [1][2][3][4]. To date, hundreds of PBDs have been synthesized and tested in clinical trials to enhance their anticancer activities, minimize toxic effects (including nephrotoxicity and emetogenicity), and overcome resistance as compared to cisplatin.…”

“…On the contrary, Pt(IV)-based drugs are promising substitutes that overcome the shortcomings of Pt(II) complexes. This is because they are kinetically more inert, and consequently, they could be administered via the oral route and demonstrate lower systemic toxicity than Pt(II) complexes [4]. Pt(IV) complexes act as prodrugs that, upon cellular entry, are activated by cellular reducing agents (such as ascorbic acid and glutathione), forming the corresponding Pt(II) active species.…”