Degradation and toxicity of mitoxantrone and chlorambucil in water

Abstract

The combination of liquid chromatography coupled to mass spectrometry (LC-MS) and acute toxicity studies with Daphnia magna was used to elucidate the water stability of the cytostatic compounds, mitoxantrone and chlorambucil, and their transformation products (TPs). Both compounds were rapidly degraded in water with the subsequent formation of bioactive TPs. Mitoxantrone suffered a rapid change in its conformation with the formation of four toxic TPs, which were unaltered and stable in water along the 2-day studied period. LC-MS analyses were allowed to identify the conformational changes of mitoxantrone that included the loss of the two amino alcohols (N-ethylethanolamina) [C 4 H 10 NO] ? , the loss of N-ethylethanolamina [C 4 H 10 NO] ? and N-methylethanolamina [C 3 H 8 NO] ? , the loss of CH 2 OH from the original molecule and the formation of mitoxantrone dicarboxilic acid. Chlorambucil was also rapidly degraded in water loosing a hydroxyl group and forming a bioactive TP that further degraded within the following 12 h. The degradation of chlorambucil was also related to an exponential loss of toxic activity towards D. magna survival. The present results indicate that LC-MS methods should target TPs since field concentrations of these compounds measured in water may not reflect their toxicity.

Anthracycline antibiotics derivate mitoxantrone—Destructive sorption and photocatalytic degradation

“…A third degradation product (DP3) of the molecule MTX at m/z 315 (t R = 4.51 min) min was identified at 90 min as 1,4-dihydroxy-5,8-diiminoanthracene-9,10(5H,8H)-dione and corresponded to the loss of N -ethylmethylamine (C 2 H 5 NHCH 3 ) and 2-(ethylamino)ethanol (C 2 H 5 NHCH 2 CH 2 OH) from the C-N bond breakage in the second degradation product (DP2). Neither derivative was identified in the solution [ 22 ]. DP3 is the same degradation product labelled MTX-TP2-OH in the MTX reaction with NaOH.…”

“…The use of TiO 2 also makes it possible to degrade mitoxantrone because the electrons can potentially oxidize it in the conduction band [ 23 ]. Mitoxantrone shows weak photolysis and spontaneous decomposition under UV light [ 1 ]. For the formal kinetic description of heterogeneous photocatalysis, the Langmuir–Hinshelwood equation [ 24 ] can be used, whereas mitoxantrone has a similar absorbance spectrum in the visible region, such as some azo-dyes, e.g., Reactive Black 5 [ 25 ].…”

“…Mitoxantrone is an anthraquinone that stops tumour growth by directly attacking DNA by cross-linking guanine bases in double helix chains of DNA. Mitoxantrone is excreted from the body in the urine at 6–11%, 25% in the faeces and the remainder in the metabolized form [ 1 ]. As with other medicinal products, parent products or metabolites are excreted and discharged into sewage through urban or hospital effluent and sewage treatment plants, where the effluents may be released into surface water.…”

Redox-Responsive Heparin–Chlorambucil Conjugate Polymeric Prodrug for Improved Anti-Tumor Activity

“…Chlorambucil's mechanism of action in cancer cells is binding its two reactive chloroethyl side chains with the nucleobases adenine and guanine at N3 and N7 that halt DNA replication and DNA damage through DNA strand linking [13][14][15]. Chlorambucil has a low water solubility, short half-life due to rapid degradation in the plasma, and serious toxicity to normal tissues, which are potential limitations in its clinical applications [16,17]. Therefore, strategies to improve the stability, solubility, and non-specific toxicity of Chl are highly required to improve its anti-cancer effect.…”

Possible Pathway for Ifosfamide Degradation via Fe-TiO2 Assisted Photo Catalysis

“…On the other hand their metabolites may prove to be more toxic compared with parent compound [1]. The main pollution sources with IF are represented by anti-cancer drugs synthesis wastewater and discharges from oncological clinics [2][3][4]. The total amount of IF and its metabolites eliminated by human body in a 24 h period represents 50% of administered IF dose [5] and ends up in the sewerage system [6].…”