TY - CONF
T1 - Aromatic Thiosemicarazones are inhibitors of tryptophan 2,3-Dioxygenase (TDO), an emerging target for cancer treatment
AU - Dolusic, Eduard
AU - Modaffari, Sara
AU - Larrieu, Pierre
AU - Vancraeynest, Christelle
AU - Pilotte, Luc
AU - Colau, Didier
AU - Stroobant, Vincent
AU - Wouters, Johan
AU - Masereel, Bernard
AU - Van den Eynde, Benoît
AU - Frédérick, Raphaël
PY - 2011
Y1 - 2011
N2 - 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).
AB - 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).
M3 - Poster
SP - Book of Abstracts, ASMC 11, St. Petersburg, Russia, August 21-25, 2011, P157
T2 - ASMC11 (4th International Symposium on Advances in Synthetic and Medicinal Chemistry).
Y2 - 21 August 2011
ER -