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Synthesis directed towards Agelasines, Agelasimines, Asmarines and Analogs; Bioactive Marine Natural Products. Lise-Lotte Gundersen Department of Chemistry, University of Oslo, Norway. 21:a Organikerdagarna, Åhus 2008. 23. Organisk-kjemiske vintermøte, Geilo 2008. Marine organisms
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Synthesis directed towards Agelasines, Agelasimines, Asmarines and Analogs; Bioactive Marine Natural Products Lise-Lotte Gundersen Department of Chemistry, University of Oslo, Norway
21:a Organikerdagarna, Åhus 2008 23. Organisk-kjemiske vintermøte, Geilo 2008
Marine organisms • Algaeand invertebrates (sponges, mollusks, tunicates etc) • Rich sources of bioactive compounds - Defence • Antimicrobial • Antineoplastic
Nature2004, 430, 242 Nature 2004, 431, 892: “Antibiotics are the worst sort of pharmaceuticals because they cure the disease”
Purine-Containing Natural Products from Marine Sponges Agelasines Agelasimines Asmarines • Total synthesis • Synthesis of analogs • Bioactivities
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
Synthesis of Trixagol and Agelasine E Isolated from Bellardia trixago TL, 1978, 3491 Isolated from Agelas sp. Tetrahedron Lett. 1984, 2989
Synthesis of Trixagol and ent-Trixagol Tetrahedron1997, 53, 3527 Bakkestuen et al., Tetrahedron 2003, 59, 115
Synthesis of Agelasine E and ent-Agelasine E Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025
Synthesis of Agelasine D Manool Agelasine D Sclareol Isolated from Agelas sp. Tetrahedron Lett. 1984, 2989 Salvia sclarea (Clary Sage)
Synthesis of Agelasine D - Initial Approach Drawbacks: Lack of selectivity Utenova et al., Tetrahedron Lett. 2004, 45, 4233
Improved Synthesis of Agelasine D Synthesis of geometrically pure allyl bromide Vik et al., J. Nat. Prod. 2006, 69, 381
Improved Synthesis of Agelasine D - Regioselective N-alkylation Vik et al., J. Nat. Prod. 2006, 69, 381
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
Synthesis of Agelasine F Isolated from pennyroyal (Mentha Pulegium) Isolated from Agelas sp.
X-ray; minor isomer sulfone Proszenyak et al., Manuscript
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
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
* Roggen et al. Manuscript
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
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
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
Bakkestuen et al., Org. Biomol. Chem. 2005, 3, 1025 Vik et al., Bioorg. Med. Chem. 2007, 15, 4016
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
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
Purine-Containing Marine Natural Products from Marine Sponges Agelasines Agelasimines Asmarines
Asmarines • Isolated from marine sponges (Raspailia sp.) • 11 comp. (Asmarine A - J) • No total syntheses • Bioctivities: Cytotox.
Previous strategies for construction of the 7-membered ring No ex. of formation of bond c or d
Formation of bond d - Initial attempts Vik et al. Tetrahedron. Lett. 2007, 48, 1931
Vik et al. Tetrahedron. Lett. 2007, 48, 1931
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