TY - CONF
T1 - THIOSEMICARBAZONES AS 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 - Van den Eynde, Benoît
AU - Wouters, Johan
AU - Masereel, Bernard
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 properties in general2 and to the inhibitory activity on ribonucleotide reductase in particular.3 Compounds of this class, such as marboran and triapine, are already used in medical practice.
Indoleamine 2,3-dioxygenase (IDO) is an extrahepatic heme dioxygenase catalysing tryptophan oxidation in the so-called kynurenine pathway of this amino acid catabolism. IDO is involved in tumoral immune resistance: various human tumours express the enzyme constitutively4 and the development and synthesis of IDO inhibitors has been an active area of research in the recent years.5 A structurally unrelated hepatic enzyme catalysing the same reaction, tryptophan 2,3-dioxygenase (TDO), has lately also been linked to cancer immunopathology.6 Our group very recently described a series of ethenyl indole-based TDO inhibitors yielding LM 10, a potent (IC50 = 2 uM in a cellular test), selective, orally bioavailable compound which, furthermore, shows anti-cancer activity in preclinical in vivo models in mice.7
In this work, the synthesis of a small library of aromatic thiosemicarbazones as well as their evaluation and SAR as TDO inhibitors is described. The best compound (ED 135) is roughly equipotent to LM 10 in the cellular test. A new pharmacological profile for aromatic thiosemicarbazones with a potential in an emerging way of cancer treatment is thus demonstrated.
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 properties in general2 and to the inhibitory activity on ribonucleotide reductase in particular.3 Compounds of this class, such as marboran and triapine, are already used in medical practice.
Indoleamine 2,3-dioxygenase (IDO) is an extrahepatic heme dioxygenase catalysing tryptophan oxidation in the so-called kynurenine pathway of this amino acid catabolism. IDO is involved in tumoral immune resistance: various human tumours express the enzyme constitutively4 and the development and synthesis of IDO inhibitors has been an active area of research in the recent years.5 A structurally unrelated hepatic enzyme catalysing the same reaction, tryptophan 2,3-dioxygenase (TDO), has lately also been linked to cancer immunopathology.6 Our group very recently described a series of ethenyl indole-based TDO inhibitors yielding LM 10, a potent (IC50 = 2 uM in a cellular test), selective, orally bioavailable compound which, furthermore, shows anti-cancer activity in preclinical in vivo models in mice.7
In this work, the synthesis of a small library of aromatic thiosemicarbazones as well as their evaluation and SAR as TDO inhibitors is described. The best compound (ED 135) is roughly equipotent to LM 10 in the cellular test. A new pharmacological profile for aromatic thiosemicarbazones with a potential in an emerging way of cancer treatment is thus demonstrated.
M3 - Poster
SP - Book of Abstracts, Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011), Ghent, 25 November 2011, p. 21
T2 - Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011)
Y2 - 25 November 2011
ER -