Colau, Didier

Dolusic, Eduard

Frédérick, Raphaël

Larrieu, Pierre

Masereel, Bernard

Modaffari, Sara

Pilotte, Luc

Stroobant, Vincent

Van den Eynde, Benoît

Vancraeynest, Christelle

Wouters, Johan

English

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

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RESEARCH OUTPUTS / RÉSULTATS DE RECHERCHEAuthor(s) - Auteur(s) :Publication date - Date de publication :Permanent link - Permalien :Rights / License - Licence de droit d’auteur :Bibliothèque Universitaire Moretus PlantinInstitutional Repository - Research PortalDépôt Institutionnel - Portail de la Rechercheresearchportal.unamur.beTHIOSEMICARBAZONES AS INHIBITORS OF TRYPTOPHAN2,3-DIOXYGENASE (TDO), AN EMERGING TARGET FOR CANCERTREATMENTDolusic, Eduard; Modaffari, Sara; Larrieu, Pierre; Vancraeynest, Christelle; Pilotte, Luc;Colau, Didier; Stroobant, Vincent; Van den Eynde, Benoît; Wouters, Johan; Masereel,Bernard; Frédérick, RaphaëlPublication date:2011Document VersionEarly version, also known as pre-printLink to publicationCitation for pulished version (HARVARD):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 TRYPTOPHAN2,3-DIOXYGENASE (TDO), AN EMERGING TARGET FOR CANCER TREATMENT', Annual One-Day Meetingon 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 November2011, p. 21.General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.            • Users may download and print one copy of any publication from the public portal for the purpose of private study or research.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying the publication in the public portal ?Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 23. Jun. 2020P029THIOSEMICARBAZONES AS INHIBITORS OF TRYPTOPHAN2,3-DIOXYGENASE (TDO), AN EMERGING TARGET FOR CANCERTREATMENTEduard Dolušić (a), Sara Modaffari (a), Pierre Larrieu (b), Christelle Vancraeynest (a), Luc Pilotte (b),Didier Colau (b), Vincent Stroobant (b), Benoît Van den Eynde (b), Johan Wouters (a), Bernard Masereel(a), Raphaël Frédérick (a)(a) Namur Drug Design and Discovery Center (ND3C), University of Namur (FUNDP), 61 Rue de Bruxelles, B-5000 Namur,Belgium; (b) Ludwig Institute for Cancer Research (LICR), Université Catholique de Louvain (UCL), 74 Avenue Hippocrate,B-1200 Brussels, Belgiumedolusic@fundp.ac.beThiosemicarbazones 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 andto the inhibitory activity on ribonucleotide reductase in particular.3 Compounds of this class, such as marboranand triapine, are already used in medical practice. Indoleamine 2,3-dioxygenase (IDO) is an extrahepatic heme dioxygenase catalysing tryptophan oxidation in theso-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 inhibitorshas been an active area of research in the recent years.5 A structurally unrelated hepatic enzyme catalysing thesame reaction, tryptophan 2,3-dioxygenase (TDO), has lately also been linked to cancer immunopathology.6 Ourgroup 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 activityin 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 SARas 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 cancertreatment is thus demonstrated.8 References1) Beraldo, H., Gambino, D., 2004, Mini-Rev. Med. Chem. 4, 31–39; Duffy, K.J., et al, 2002, J. Med. Chem. 45, 3573.2) Yu, Y., et al, 2009, J. Med. Chem. 52, 5271.3) Sartorelli, A.C., et al, 1967, Cancer Res. 27, 1614; Sartorelli, A.C., et al, 1971, Biochem. Pharmacol. 20, 3119 ; French,F.A., et al, 1970, J. Med. Chem. 13, 1117; Klayman, D.L., et al, 1983, J. Med. Chem., 26, 39; Demertzi, D.K., et al, 2001, J.Inorg. Biochem. 86, 555; Quiroga, A.G., et al, 1988, J. Med. Chem. 41, 1399.4) Uyttenhove, C., et al, 2003, Nat. Med. 9, 1269.5) Our contributions to the field: Röhrig, U. F., et al, 2010, J. Med. Chem. 53, 1172; Dolušić, E., et al, 2011, Bioorg. Med.Chem. 19, 1550; Dolušić, E., et al, 2011, Eur. J. Med. Chem. 46, 3058.6) Van den Eynde, B., et al, 2010; WO2010008427; Opitz, C. A., et al, 2011, Nature 478, 197.7) Dolušić, E., et al, 2011, J. Med. Chem. 54, 5320.8) This work was supported by FNRS-Télévie (7.4.543.07).

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

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

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