Comparison of metabolic pathways of different α-N-heterocyclic thiosemicarbazones

Abstract

Clinical failure of novel drugs is often related to their rapid metabolism and excretion. This highlights the importance of elucidation of their pharmacokinetic profile already at the preclinical stage of drug development. Triapine, the most prominent representative of α-N-heterocyclic thiosemicarbazones, was investigated in more than 30 clinical phase I/II trials, but the results against solid tumors were disappointing. Recent investigations from our group suggested that this is, at least partially, based on the fast metabolism and excretion. In order to establish more detailed structure/activity/metabolism relationships, herein a panel of 10 different Triapine derivatives was investigated for their metabolic pathways. From the biological point of view, the panel consists of terminally dimethylated thiosemicarbazones with nanomolar IC50 values, derivatives with micromolar cytotoxicities comparable to Triapine and a completely inactive representative. To study the oxidative metabolism, a purely instrumental approach based on electrochemistry/mass spectrometry was applied and the results were compared to the data obtained from microsomal incubations. Overall, the investigated thiosemicarbazones underwent the phase I metabolic reactions dehydrogenation, hydroxylation, oxidative desulfuration (to semicarbazone and amidrazone) and demethylation. Notably, dehydrogenation resulted in a ring-closure reaction with formation of thiadiazoles. Although strong differences between the metabolic pathways of the different thiosemicarbazones were observed, they could not be directly correlated to their cytotoxicities. Finally, the metabolic pathways for the most cytotoxic compound were elucidated also in tissues collected from drug-treated mice, confirming the data obtained by electrochemical oxidation and microsomes. In addition, the in vivo experiments revealed a very fast metabolism and excretion of the compound. Graphical abstractStructure/activity/metabolisation relationships for 10 anticancer thiosemicarbazones were established using electrochemical oxidation coupled to mass spectrometry (EC-MS) and human liver microsomes analyzed by LC-MS Electronic supplementary materialThe online version of this article (10.1007/s00216-018-0889-x) contains supplementary material, which is available to authorized users.

Benzothiazolyl and Benzoxazolyl Hydrazones Function as Zinc Metallochaperones to Reactivate Mutant p53

“…Aside from toxicity due to copper or iron chelation, it was thought that part of the toxicity of the TSCs is related to the release of H 2 S during metabolism. 24 In fact, structure−activity relationship (SAR) studies in which the thiocarbamoyl structure was replaced by a 2-pyridinyl moiety showed a drastic reduction in toxicity and retention of biological activity. 25 The general design principle behind this class of chelators is similar in that the thiocarbamoyl moiety is replaced by a benzothiazole or benzoxazolyl.…”

Synthesis, Characterization and Biological Activity of Novel Cu(II) Complexes of 6-Methyl-2-Oxo-1,2-Dihydroquinoline-3-Carbaldehyde-4n-Substituted Thiosemicarbazones

“…No anodic processes were detected for H 2 L1-H 2 L3 in the available potential window. 3 Redox processes detected only upon reversing the potential scan direction at a low cathodic potential limit, or after the formation of wave I red at sufficiently low scan rates. Wave L red was also detected in the derived Cu(II) complexes 1-3 at the same potential value (Figures 4 and S2), therefore suggesting that the redox process was located far off from the influence of the metal center.…”

“…Great interest has been reserved in the last decades to the chemistry of thiosemicarbazones (TSC) of the type X-C(Z)=N-NH-C(=S)Y, where different combinations of X, Y and Z moieties have been introduced in the framework. This allows for the modulation of the lipophilic properties, chelating abilities and steric hindrance, also by the presence of additional functional groups, in order to attain an overall synergistic effect for their desired biological activity as such or that of their metal complexes [1][2][3][4][5][6][7][8][9][10][11][12]. A wide range of medicinal effects of thiosemicarbazones are well known (Chart 1): 1-methylisatin 3-TSC (Marboran, no longer produced as a drug) as being antiviral [13], 4-acetylaminobenzaldehyde-TSC (amithiazone, [14,15]) for the treatment of tuberculosis, 4-isopropylbenzaldehyde-TSC (cutisone [16]), 1,4-benzoquinone-amidinohydrazone-TSC (ambazone, [17]), di-2-pyridylketone-4,4′-dimethyl-3-TSC [18] and 3-amino pyridine-2-carboxaldehyde-TSC (Triapine, it has undergone Phase I and Phase II clinical trials, [19,20]) as potential antitumor drugs.…”

Reversing oncogenic transformation with iron chelation

“…Another issue that manifested was a short-lived patient response, suggesting patients develop resistance [ 24 , 30 ]. Triapine is rapidly metabolised and its metabolite is inactive, rendering it ineffective against solid tumours [ 31 , 32 ].…”