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Indoleamine 2,3-Dioxygenase Inhibitory Activity of Derivatives of Marine Alkaloid Tsitsikammamine A. Dr. Eduard Dolušić Drug Design and Discovery Center Department of Pharmacy University of Namur (FUNDP), Belgium. Indoleamine 2,3-Dioxygenase (IDO). - PowerPoint PPT Presentation
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Indoleamine 2,3-Dioxygenase Inhibitory Activityof Derivatives of Marine Alkaloid
Tsitsikammamine A
Dr. Eduard DolušićDrug Design and Discovery Center
Department of PharmacyUniversity of Namur (FUNDP), Belgium
Indoleamine 2,3-Dioxygenase (IDO)
Dr. Eduard DolušićJFB 2011 Liège 2
R. Schwarcz, Curr. Opin. Pharmacol.2004, 4, 12.
NH2
O
NH
O OH
O
O2
NH2
NH
O
OH
monomeric (~45 kDa)
protoheme IX prosthetic
group
extrahepatic
other substrates: serotonin, melatonin,
tryptamine…
Interest in IDO as a drug target
Dr. Eduard DolušićJFB 2011 Liège 3
many human tumorsconstitutively express
IDOUyttenhove, C. et al,
Nat Med 2003, 9, 1269.
IDO expression in placenta is required
for immune tolerance of fetus by
the motherMunn, D. H. et al,
Science 1998, 281, 1191.
Katz, J. B. et al, Imm. Rev. 2008, 222, 206.
cancer immunotherapy shows limited efficacy in vivo; IDO plays a crucial role
Munn, D. H.; Mellor, A. L. J. Clin. Invest. 2007, 117, 1147.Prendergast, G. C. Oncogene 2008, 27, 3889.
Sugimoto, H. et al,PNAS 2006, 103, 2611.
Dr. Eduard DolušićJFB 2011 Liège 4
IDO inhibitors - background
inhibitors (lit.):
IC50 = 4.8-7.7 MKumar et al, JMC 2008,
51, 4968.
Ki = 61–70 nM
Kumar et al, JMC 2008,51, 1706.
Ki = 200 nMCarr et al, JMC
2008,51, 2634.
IC50=59–86 nMYue et al, JMC
2009,52, 7364.
S
N
SH
IC50 = 50 MRöhrig et al, JMC 2010, 53, 1172.
H2NN
O
OH
IC50~100 Mclinical trials
Dr. Eduard DolušićJFB 2011 Liège 5
IDO inhibitors discovered byvirtual screening
Dolušić, E. et al; Bioorg.Med. Chem. 2011, 19, 1550.
Dolušić, E. et al; EJMC2011, doi:10.1016/j.ejmech.2011.02.049.
Dr. Eduard DolušićJFB 2011 Liège 6
Dolušić, E. et al; Bioorg.Med. Chem. 2011, 19, 1550.
Dolušić, E. et al; EJMC2011, doi:10.1016/j.ejmech.2011.02.049.
Work on another
(HTS) series in progress.
IDO inhibitors discovered byvirtual screening
Dr. Eduard DolušićJFB 2011 Liège 7
Marine pyrroloquinoline alkaloids:wakayin and tsitsikammamines
Legentil, L. et al;JMC 2006, 49, 2979.
Delfourne, E.; Anti Canc.Agents Med. Chem.
2008, 8, 910.
wakayin (1): isolated in 1991 from the ascidian Clavelina species
reported to have diverse bioactivities including cytotoxicity and topoisomerase I inhibition
tsitsikammamines A (2) and B (3): isolated in 1996 from a Latrunculiidae sponge
similar bioactivity profile to wakayin
pyrazolic derivatives of general (a) and (b) structures also exhibit topoisomerase I/II inhibitory activity; some of them are cytotoxic
Dr. Eduard DolušićJFB 2011 Liège 8
2010: two novel regioisomeric series of tsitsikammamine A analogues -
synthesis
Rives, A. et al; Eur. J. Med. Chem. 2010, 45, 343.
synthesized on the basis of the Michael addition chemistry
a) abs. EtOH, rt, 2h; b) TFA, CH2Cl2, rt, 4h;c) MnO2, CH2Cl2, rt, overnight; d) abs. EtOH, 4Å MS, , 3h
a) 1M NaOH, dioxane, rt, overnight; b) BBr3, CH2Cl2, N2,
4h
Dr. Eduard DolušićJFB 2011 Liège 9 Rives, A. et al; Eur. J. Med. Chem. 2010, 45, 343.
2010: two novel regioisomeric series of tsitsikammamine A analogues -
synthesis
a) abs. EtOH, rt, 2h; b) TFA, CH2Cl2, rt, 4h;c) MnO2, CH2Cl2, rt, overnight; d) 1M NaOH, dioxane, rt, overnight; e) BBr3, CH2Cl2,
N2, 4h
Dr. Eduard DolušićJFB 2011 Liège 10 Rives, A. et al; Eur. J. Med. Chem. 2010, 45, 343.
products were
evaluated in an MTT
colorimetric antiproliferati
ve assay against
several cancer and normal (fibroblast) cell lines
a cytotoxic synthetic
intermediate 8b with an unknown
mechanism of action was identified
2010: two novel regioisomeric series of tsitsikammamine A analogues –
pharmacological evaluation
O
O
N
Ts
NH
MeO
NH2
8b
Dr. EduardDolušićJFB 2011Liège 11
IDO inhibitory activity of tsitsikammamine derivatives
several tsitsikammamine A analogues display (sub)micromolar potencies in an
IDO enzymatic test
Conclusion
a number of derivatives are also reasonably active in an IDO cellular test without being toxic
this class of compounds is a potential source of leads for the development of new anticancer compounds with a novel pharmacological profile (manuscript in preparation)
Dr. Eduard DolušićJFB 2011 Liège 12
Dr. Eduard DolušićJFB 2011 Liège 13
D3C, FUNDP NamurEduard Dolušić
Raphaël FrédérickBernard Masereel
Sara ModaffariLaurence Moineaux
Christelle VancraeynestJohan Wouters
Ludwig Institutefor Cancer Research
Brussels BranchDidier ColauPierre Larrieu
Luc PilotteVincent Stroobant
Benoît Van den Eynde
Euroscreen SASébastien BlancDelphine ColetteGraeme Fraser
Université Paul Sabatier
Laboratoire SPMIBToulouse, FranceEvelyne Delfourne
Arnaud Rives
ULB BrusselsLab. de Toxicologie
Robert KissBenjamin Le Calvé
Collaborators
€€€FNRS (Belgium)Biowin (CANTOL: convention n5678) Thank you for your
attention!
