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

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Presentation on theme: "Synthesis directed towards Agelasines, Agelasimines, Asmarines and Analogs; Bioactive Marine Natural Products Lise-Lotte Gundersen Department of Chemistry,"— Presentation transcript:

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 Rich sources of bioactive compounds - Defence
Algae and invertebrates (sponges, mollusks, tunicates etc) Rich sources of bioactive compounds - Defence Antimicrobial Antineoplastic

4 “Antibiotics are the worst sort of pharmaceuticals
Nature 2004, 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
Tetrahedron 1997, 53, 3527 Bakkestuen et al., Tetrahedron 2003, 59, 115

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

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

12 Drawbacks: Lack of selectivity
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., Synthesis 1990, 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., Synthesis 1990, 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 , 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 , 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 , 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 , 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 Synthesis Financial Support
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

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