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

“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”

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

Marine Sponges?

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 Tetrahedron 1997, 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)

Drawbacks: Lack of selectivity 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., Synthesis 1990, 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

Intermediate in synthesis of other natural products ?

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

Proszenyak et al., Manuscript

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

* 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 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