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Synthesis directed towards antimicrobial purines

Synthesis directed towards antimicrobial purines. Lise-Lotte Gundersen Department of Chemistry, University of Oslo, Norway. >25% of all deaths worldwide direct result from infection. Nature 2004 , 430 , 242. History of antimicrobial drugs Quinine ( Cinchona pubescens ; malaria) ca. 1825

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Synthesis directed towards antimicrobial purines

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  1. Synthesis directed towards antimicrobial purines Lise-Lotte Gundersen Department of Chemistry, University of Oslo, Norway

  2. >25% of all deaths worldwide direct result from infection Nature2004, 430, 242

  3. History of antimicrobial drugs • Quinine (Cinchona pubescens; malaria) ca. 1825 • Salvarsan (syphilis) 1912 • Sulfa drugs (bacterial infections) ca. 1935

  4. Penicillin • 1928: Penicillumnotatum (= P. chrysogenum) inhib. Staph. aureus growth • (Flemming) • 1938: Isolation “penicillin” (Florey, Chain) • 1941: Penicillin on humans • 1943: Big-scale production penicillin • 1943: Structure penicillin G proposed (Chain) • 1945: Nobelprize in medicine; Fleming, Chain, Florey • 1945: X-ray structure penicillin G (Hodgkin) • 1957: Synthesis penicillin G (Sheehan)

  5. Other classes of antibacterial antibiotics 1947: Chloramphenikol 1944: Streptomycine (aminoglykoside) 1948: Chlorotetraycline (tetracyclines) 1945: Cefalosporine C (cefalosporines) 1950: Picromycine (makrolides) Bacitracine (peptides) 1959: Rifamycine (ansamycines) US Surgeon General, 1967: “The war against infectious diseases has been won”

  6. Emerging and re-emerging infections ca. 1980 (AIDS)-date. Nature2004, 430, 242

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

  8. Our Activities: • Purine-Containing Antimicrobial Natural Products • from Marine Sponges Agelasines Agelasimines Asmarines • Selective Antimycobacterial Purines

  9. Marine Sponges?

  10. 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 • Inhibition of Na,K-ATPase Brown Tube Sponge: Agelas sp. 2.5 feet long

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

  12. Synthesis of Trixagol and ent-Trixagol Trixagol Bakkestuen et al., Tetrahedron 2003, 59, 115

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

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

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

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

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

  18. Synthesis directed towards Agelasine F Isolated from pennyroyal (Mentha Pulegium) Isolated from Agelas sp. Tetrahedron Lett. 1984, 2989

  19. Proszenyak et al., Unpublished

  20. Proszenyak et al., Unpublished

  21. Intermediate in synthesis of other natural products ?

  22. Type A structure Type B structure Synthetic intermediate - simpler side chain, Even better activities than naturally occuring agelasines!! Structure - Activity Relationships • Type A more active than type B structure • ( otherwise same subst.) • R’ must be relatively long and preferably • contain unsaturation(s)

  23. Antimicrobial activities Also activity against several cancer cell lines Vik et al., Bioorg. Med. Chem. 2007, 15, 4016

  24. Tuberculosis (TB) • Bacterial infection (Mycobacterium tuberculosis) • Inhalation • Lung most commonly attacked • All organs, incl. CNS, may be attacked • Before 1950; 50% of all sick died • First effective drug: Streptomycin (1943) - Toxic • Several less toxic drugs developed ca 1950-1962 WHO (1993): TB a “global emergency” • AIDS • Resistant strains • Migration • Powerty • Ca 3 mill deaths / year Agelas dispar

  25. Vik et al., Bioorg. Med. Chem. 2007, 15, 4016 Planta Med.2007, 73, 1410

  26. Activity Patogenic Protozoa Tropical diseases chloroquine 0.04 g/mL miltefosine 0.24 g/mL benznidazole 0.25 g/mL melarsoprol 0.005 g/mL Vik et al., Unpublished

  27. Viceral Leichmaniasis / Kala azar / Black Fewer • Infection - Leichmania donovani s.l. (protozoa) • Transmitted by sandflies • Deathly if untreated; 59.000 deaths/year • Treatment: Long time with antimon-compounds • (miltefosine, amfotericin B) • > 90% i Bangladesh, Brasil, India, Sudan Chagas disease / American Sleeping Sickness • Infection - Trypanosoma cruzi (protozoa) • Transmitted by insects (Teger) • Deathly if not treated in time (Ofthen long period without symptoms); • 13.000 deaths/year • Treatment: Nifurtimox or benznidazol, in the early phase • South- & Central America

  28. Our Activities: Purine-Containing Marine Natural Products from Marine Sponges Compounds with Antimicrobial Activities Agelasines Agelasimines Asmarines

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

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

  31. Formation of bond d - Initial attempts Ring Closing Metathesis (RCM) Vik et al. Tetrahedron. Lett. 2007, 48, 1931

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

  33. Our Activities: • Purine-Containing Antimicrobial Natural Products • from Marine Sponges Agelasines Agelasimines Asmarines • Selective Antimycobacterial Purines

  34. MIC M. Tub. 0.78 mg/mL Rifampin: MIC M. Tub. 0.25 mg/mL Langli et al., Tetrahedron 1996, 52, 5625 Bakkestuen et al. Bioorg. Med. Chem. Lett. 2000, 10, 1207 Gundersen et al. J. Med. Chem. 2002, 45, 1381

  35. Antimycobacterial 6-(2-Furyl)purines: The N-9 Substituents Bakkestuen et al., Tetrahedron Lett., 2003, 44, 3359 Gundersen et al. J. Med. Chem. 2002, 45, 1381

  36. Summary SAR knowledge but also non-purine analogs... Gundersen et al. J. Med. Chem. 2002, 45, 1381 Bakkestuen et al. J. Med. Chem. 2005, 48, 2710 Brændvang et al. Bioorg. Med. Chem. 2005, 13, 6360 Brændvang et al. Bioorg. Med. Chem. 2007, 15, 7144

  37. Acknowledgements • Synthesis • Dr. Anne Kristin Bakkestuen • Dr. Morten Brændvang • Abhijit K. Datta • Veronika Ernst • Anthony James • Aisvareya Kulendern • Dr. Geir Langli • Dr. Pedro O. Miranda • Dr. Edyta Nagrodzka • Dr. Agnes Prozenyak • Matthew L. Read • Heidi Roggen • Linda W. Tangen • Dr. Bibigul T. Utenova • Dr. Anders Vik • Bioactivities • Prof. Lars Bohlin & co-workers • Dr. Colin Charnock • Tuberculosis Antimicrobial Acquisition • and Coordinating Facility (TAACF) • WHO - TDR • Financial Support • NFR (FRINAT & KOSK) • UiO

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