Aromatic Thiosemicarazones are inhibitors of tryptophan 2,3-Dioxygenase (TDO), an emerging target for cancer treatment

Thiosemicarbazones have received a great deal of attention due to their antineoplastic, antibacterial, antiviral, and antifungal activity.1 Their biological activity has been attributed to metal chelating properties2 and to the inhibitory activity on ribonucleotide reductase3 in particular. Compounds of this class, such as marboran and triapine, are already used in medical practice. It has recently been discovered that a hepatic enzyme involved in the tryptophan catabolism, tryptophan 2,3-dioxygenase (TDO), displays antimicrobial and immunoregulatory effects.4 It has also been shown to be a key modulator of neurogenesis and anxiety-related behavior in mice5 as well as a common mediator of genetic and environmental impacts in depression.6 TDO thus represents an emerging target for pharmacological intervention. We have synthesized a series of thiosemicarbazones (1) bearing a(n) (hetero)aromatic moiety, such as phenyl, indole, indazole, naphthalene, imidazole and quinoline, as well as optional substituents on the thiosemicarbazone chain. This class of compounds was evaluated in a cellular test against TDO and showed an inhibitory potency with the best compounds possessing IC50s in the micromolar range. A new pharmacological profile for aromatic thiosemicarbazones is thus demonstrated. This work was supported by FNRS-Télévie 7.4.543.07 and by the Walloon Region (grant 'CANTOL' n° 5678).