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Indoleamine 2,3-Dioxygenase Inhibitory Activity of Derivatives of Marine Alkaloid

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).

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Indoleamine 2,3-Dioxygenase Inhibitory Activity of Derivatives of Marine Alkaloid

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  1. 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

  2. Indoleamine 2,3-Dioxygenase (IDO) • other substrates: serotonin, melatonin, tryptamine… • protoheme IX prosthetic group • monomeric (~45 kDa) • extrahepatic R. Schwarcz, Curr. Opin. Pharmacol. 2004, 4, 12. Dr. Eduard Dolušić JFB 2011 Liège 2

  3. Interest in IDO as a drug target • IDO expression in placenta is required for immune tolerance of fetus by the mother • Munn, D. H. et al, • Science1998, 281, 1191. • 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. Oncogene2008, 27, 3889. • many human tumors • constitutively express IDO • Uyttenhove, C. et al, • Nat Med2003, 9, 1269. Katz, J. B. et al, Imm. Rev.2008, 222, 206. Dr. Eduard Dolušić JFB 2011 Liège 3

  4. IDO inhibitors - background • inhibitors (lit.): IC50 = 4.8-7.7 mM Kumar et al, JMC 2008, 51, 4968. Ki = 200 nM Carr et al, JMC 2008,51, 2634. Ki = 61–70 nM Kumar et al, JMC 2008,51, 1706. IC50~100 mM clinical trials Sugimoto, H. et al, PNAS2006, 103, 2611. IC50=59–86 nM Yue et al, JMC 2009,52, 7364. IC50 = 50 mM Röhrig et al, JMC 2010, 53, 1172. Dr. Eduard Dolušić JFB 2011 Liège 4

  5. IDO inhibitors discovered by virtual screening Dolušić, E. et al; Bioorg. Med. Chem. 2011, 19, 1550. Dolušić, E. et al; EJMC 2011, doi:10.1016/j.ejmech.2011.02.049. Dr. Eduard Dolušić JFB 2011 Liège 5

  6. IDO inhibitors discovered by virtual screening Dolušić, E. et al; Bioorg. Med. Chem. 2011, 19, 1550. Dolušić, E. et al; EJMC 2011, doi:10.1016/j.ejmech.2011.02.049. Work on another (HTS) series in progress. Dr. Eduard Dolušić JFB 2011 Liège 6

  7. Marine pyrroloquinoline alkaloids: wakayin and tsitsikammamines • 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 Legentil, L. et al; JMC2006, 49, 2979. Delfourne, E.; Anti Canc. Agents Med. Chem. 2008, 8, 910. • pyrazolic derivatives of general (a) and (b) structures also exhibit topoisomerase I/II inhibitory activity; some of them are cytotoxic Dr. Eduard Dolušić JFB 2011 Liège 7

  8. 2010: two novel regioisomeric series of tsitsikammamine A analogues - synthesis • synthesized on the basis of the Michael addition chemistry 1M NaOH, dioxane, rt, overnight; b) BBr3, CH2Cl2, N2, 4h abs. EtOH, rt, 2h; b) TFA, CH2Cl2, rt, 4h; c) MnO2, CH2Cl2, rt, overnight; d) abs. EtOH, 4Å MS, D, 3h Dr. Eduard Dolušić JFB 2011 Liège 8 Rives, A. et al; Eur. J. Med. Chem. 2010, 45, 343.

  9. 2010: two novel regioisomeric series of tsitsikammamine A analogues - synthesis 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 Dolušić JFB 2011 Liège 9 Rives, A. et al; Eur. J. Med. Chem. 2010, 45, 343.

  10. 2010: two novel regioisomeric series of tsitsikammamine A analogues – pharmacological evaluation • a cytotoxic synthetic intermediate 8b with an unknown mechanism of action was identified • products were evaluated in an MTT colorimetric antiproliferative assay against several cancer and normal (fibroblast) cell lines Dr. Eduard Dolušić JFB 2011 Liège 10 Rives, A. et al; Eur. J. Med. Chem. 2010, 45, 343.

  11. IDO inhibitory activity of tsitsikammamine derivatives Dr. Eduard Dolušić JFB 2011 Liège 11

  12. Conclusion • several tsitsikammamine A analogues display (sub)micromolar potencies in an IDO enzymatic test • 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 Dolušić JFB 2011 Liège 12

  13. Collaborators Ludwig Institute for Cancer Research Brussels Branch Didier Colau Pierre Larrieu Luc Pilotte Vincent Stroobant Benoît Van den Eynde D3C, FUNDP Namur Eduard Dolušić Raphaël Frédérick Bernard Masereel Sara Modaffari Laurence Moineaux Christelle Vancraeynest Johan Wouters Université Paul Sabatier Laboratoire SPMIB Toulouse, France Evelyne Delfourne Arnaud Rives Euroscreen SA Sébastien Blanc Delphine Colette Graeme Fraser ULB Brussels Lab. de Toxicologie Robert Kiss Benjamin Le Calvé €€€ FNRS (Belgium) Biowin (CANTOL: convention n5678) Thank you for your attention! Dr. Eduard Dolušić JFB 2011 Liège 13

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