THIOSEMICARBAZONES AS INHIBITORS OF TRYPTOPHAN 2,3-DIOXYGENASE (TDO), AN EMERGING TARGET FOR CANCER TREATMENT

Eduard Dolusic, Sara Modaffari, Pierre Larrieu, Christelle Vancraeynest, Luc Pilotte, Didier Colau, Vincent Stroobant, Benoît Van den Eynde, Johan Wouters, Bernard Masereel, Raphaël Frédérick

Research output: Contribution to conferencePoster

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Abstract

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.
Original languageEnglish
PagesBook of Abstracts, Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011), Ghent, 25 November 2011, p. 21
Number of pages1
Publication statusPublished - 2011
EventAnnual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011) - Gand, Belgium
Duration: 25 Nov 2011 → …

Conference

ConferenceAnnual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011)
CountryBelgium
CityGand
Period25/11/11 → …

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Tryptophan Oxygenase
Indoleamine-Pyrrole 2,3,-Dioxygenase
Thiosemicarbazones
Oncology
Methisazone
Kynurenine
Ribonucleotide Reductases
Dioxygenases
Enzymes
Chelation
Bioactivity
Heme
Tryptophan
Antineoplastic Agents
Antiviral Agents
Tumors
Metals
Amino Acids
Oxidation

Cite this

Dolusic, E., Modaffari, S., Larrieu, P., Vancraeynest, C., Pilotte, L., Colau, D., ... Frédérick, R. (2011). THIOSEMICARBAZONES AS INHIBITORS OF TRYPTOPHAN 2,3-DIOXYGENASE (TDO), AN EMERGING TARGET FOR CANCER TREATMENT. Book of Abstracts, Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011), Ghent, 25 November 2011, p. 21. Poster session presented at Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011), Gand, Belgium.
Dolusic, Eduard ; Modaffari, Sara ; Larrieu, Pierre ; Vancraeynest, Christelle ; Pilotte, Luc ; Colau, Didier ; Stroobant, Vincent ; Van den Eynde, Benoît ; Wouters, Johan ; Masereel, Bernard ; Frédérick, Raphaël. / THIOSEMICARBAZONES AS INHIBITORS OF TRYPTOPHAN 2,3-DIOXYGENASE (TDO), AN EMERGING TARGET FOR CANCER TREATMENT. Poster session presented at Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011), Gand, Belgium.1 p.
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title = "THIOSEMICARBAZONES AS INHIBITORS OF TRYPTOPHAN 2,3-DIOXYGENASE (TDO), AN EMERGING TARGET FOR CANCER TREATMENT",
abstract = "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.",
author = "Eduard Dolusic and Sara Modaffari and Pierre Larrieu and Christelle Vancraeynest and Luc Pilotte and Didier Colau and Vincent Stroobant and {Van den Eynde}, Beno{\^i}t and Johan Wouters and Bernard Masereel and Rapha{\"e}l Fr{\'e}d{\'e}rick",
year = "2011",
language = "English",
pages = "Book of Abstracts, Annual One--Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011), Ghent, 25 November 2011, p. 21",
note = "Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011) ; Conference date: 25-11-2011",

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Dolusic, E, Modaffari, S, Larrieu, P, Vancraeynest, C, Pilotte, L, Colau, D, Stroobant, V, Van den Eynde, B, Wouters, J, Masereel, B & Frédérick, R 2011, 'THIOSEMICARBAZONES AS INHIBITORS OF TRYPTOPHAN 2,3-DIOXYGENASE (TDO), AN EMERGING TARGET FOR CANCER TREATMENT' Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011), Gand, Belgium, 25/11/11, pp. Book of Abstracts, Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011), Ghent, 25 November 2011, p. 21.

THIOSEMICARBAZONES AS INHIBITORS OF TRYPTOPHAN 2,3-DIOXYGENASE (TDO), AN EMERGING TARGET FOR CANCER TREATMENT. / Dolusic, Eduard; Modaffari, Sara; Larrieu, Pierre; Vancraeynest, Christelle; Pilotte, Luc; Colau, Didier; Stroobant, Vincent; Van den Eynde, Benoît; Wouters, Johan; Masereel, Bernard; Frédérick, Raphaël.

2011. Book of Abstracts, Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011), Ghent, 25 November 2011, p. 21 Poster session presented at Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011), Gand, Belgium.

Research output: Contribution to conferencePoster

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

ER -

Dolusic E, Modaffari S, Larrieu P, Vancraeynest C, Pilotte L, Colau D et al. THIOSEMICARBAZONES AS INHIBITORS OF TRYPTOPHAN 2,3-DIOXYGENASE (TDO), AN EMERGING TARGET FOR CANCER TREATMENT. 2011. Poster session presented at Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011), Gand, Belgium.