Lise-Lotte Gundersen Department of Chemistry, University of Oslo, Norway

1. Synthesis directed towards Agelasines, Agelasimines, Asmarines and Analogs; Bioactive Marine Natural Products Lise-Lotte Gundersen Department of Chemistry, University of Oslo, Norway

2. 21:a Organikerdagarna, Åhus 2008 23. Organisk-kjemiske vintermøte, Geilo 2008

3. Marine organisms • Algaeand invertebrates (sponges, mollusks, tunicates etc) • Rich sources of bioactive compounds - Defence • Antimicrobial • Antineoplastic

4. Nature2004, 430, 242 Nature 2004, 431, 892: “Antibiotics are the worst sort of pharmaceuticals because they cure the disease”

5. Purine-Containing Natural Products from Marine Sponges Agelasines Agelasimines Asmarines • Total synthesis • Synthesis of analogs • Bioactivities

6. Marine Sponges?

7. Agelasines • Isolated from marine sponges (Agelas sp.) • 11 comp. (Agelasine A - I, epiagelasine C and ageline B) known to date • Total syntheses other groups: Agelasine A, B and C, and (±) agelasine F • Bioactivities: • Cytotoxic • Antimicrobial • etc. Brown Tube Sponge: Agelas sp. 2.5 feet long

8. Synthesis of Trixagol and Agelasine E Isolated from Bellardia trixago TL, 1978, 3491 Isolated from Agelas sp. Tetrahedron Lett. 1984, 2989

9. Synthesis of Trixagol and ent-Trixagol Tetrahedron1997, 53, 3527 Bakkestuen et al., Tetrahedron 2003, 59, 115

10. Synthesis of Agelasine E and ent-Agelasine E Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025

11. Synthesis of Agelasine D Manool Agelasine D Sclareol Isolated from Agelas sp. Tetrahedron Lett. 1984, 2989 Salvia sclarea (Clary Sage)

12. Synthesis of Agelasine D - Initial Approach Drawbacks: Lack of selectivity Utenova et al., Tetrahedron Lett. 2004, 45, 4233

13. Improved Synthesis of Agelasine D Synthesis of geometrically pure allyl bromide Vik et al., J. Nat. Prod. 2006, 69, 381

14. Improved Synthesis of Agelasine D - Regioselective N-alkylation Vik et al., J. Nat. Prod. 2006, 69, 381

15. Synthesis of Agelasine F Isolated from Agelas sp. Tetrahedron Lett. 1984, 2989 J. Am. Chem. Soc. 1984, 106, 1819 2 steps Asao et al., Synthesis1990, 382 Asao et al., Tetrahedron Lett. 1989, 30, 6397 (±) Agelasine F Asao et al., Tetrahedron Lett. 1989, 30, 6401

16. Synthesis of Agelasine F Isolated from pennyroyal (Mentha Pulegium) Isolated from Agelas sp.

17. X-ray; minor isomer sulfone Proszenyak et al., Manuscript

18. Proszenyak et al., Manuscript

19. Intermediate in synthesis of other natural products ?

20. Proszenyak et al., Manuscript Asao et al., Synthesis1990, 382 Asao et al., Tetrahedron Lett. 1989, 30, 6397 Asao et al., Tetrahedron Lett. 1989, 30, 6401

21. Proszenyak et al., Manuscript

22. Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025 Vik et al., J. Nat. Prod. 2006, 69, 381 Vik et al., Bioorg. Med. Chem. 2007, 15, 4016 Proszenyak et al., Arch. Pharm. Chem. Life Sci. 2007, 340, 625 Hill et al. Nucl. Acids Res. 1998, 26, 1144

23. Roggen et al. Manuscript

24. * Roggen et al. Manuscript

25. Bioactivities • Antibacterial (incl. Mycobacterium tuberculosis) • Antifungal • Antiprotozoal (incl. several causing tropical diseases; • i.e. Chagas disease, Viceral Leichmaniasis) • Antifouling • Antineoplastic Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025 Vik et al., J. Nat. Prod. 2006, 69, 381 Vik et al., Bioorg. Med. Chem. 2007, 15, 4016 Proszenyak et al., Arch. Pharm. Chem. Life Sci. 2007, 340, 625 Sjögren et al., Biofouling. 2008, 24, 251

26. Structure - Activity Relationships • Generally broad spectrum activity • Type A more active than type B structure ( otherwise same subst.) • R’ must be relatively long and preferably contain unsaturation(s) • R, R’’ and X; some modifications of activity spectrum

27. WHO (1993): Tuberculosis -TB a “global emergency” • AIDS • Resistant strains • Migration • Powerty • Ca. 3 mill deaths / year Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025 Mangalindan et al. Planta Med. 2000, 66, 364; Agelasine F

28. Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025 Vik et al., Bioorg. Med. Chem. 2007, 15, 4016

29. Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025 Vik et al., Bioorg. Med. Chem. 2007, 15, 4016 Vik et al., Planta Med.2007, 73, 1410

30. Antifouling activity - Barnacles Agelasine D and analogs inhibit settlement of Balanus improvisus cypris larvae, low tox. to cyprids Sjögren et al., Biofouling. 2008, 24, 251

31. Purine-Containing Marine Natural Products from Marine Sponges Agelasines Agelasimines Asmarines

32. Asmarines • Isolated from marine sponges (Raspailia sp.) • 11 comp. (Asmarine A - J) • No total syntheses • Bioctivities: Cytotox.

33. Previous strategies for construction of the 7-membered ring No ex. of formation of bond c or d

34. Formation of bond d - Initial attempts Vik et al. Tetrahedron. Lett. 2007, 48, 1931

35. Vik et al. Tetrahedron. Lett. 2007, 48, 1931

36. Acknowledgements • Bioactivities • Prof. Lars Bohlin & co-workers • Dr. Colin Charnock • Tuberculosis Antimicrobial • Acquisition & Coordinating Facility • (TAACF) • WHO - TDR • Synthesis • Dr. Anne Kristin Bakkestuen • Anthony James • Dr. Agnes Prozenyak • Heidi Roggen • Linda W. Tangen • Dr. Bibigul T. Utenova • Dr. Anders Vik • Financial Support • NFR (FRINAT & KOSK) • UiO