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The isoprostanes from bench to bedside:

How chemistry taught medicine a new trick. The isoprostanes from bench to bedside:. Chris Brown Kiessling group. October 23, 2008. Prostaglandins and isoprostanes. Prostaglandin. Isoprostane. Lipid tails are trans Isolated from human tissue in 1933

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The isoprostanes from bench to bedside:

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  1. How chemistry taught medicine a new trick The isoprostanes from bench to bedside: Chris Brown Kiessling group October 23, 2008

  2. Prostaglandins and isoprostanes Prostaglandin Isoprostane • Lipid tails are trans • Isolated from human tissue in 1933 • Natural product synthesis completed in 1969 • Produced from arachadonic acid via cyclooxygenase enzymes • Lipid tails are cis • Natural product synthesis completed in 1984 • Isolated from human tissue in 1990 • Produced from arachadonic acid via nonenzymatic oxidation Goldblatt, M; Chem. Ind.1933, 52, 1056 – 1057 Euler, U. S. v. Arch. Exp. Path. Pharm.1934, 175, 78 – 84 Corey, E.J. et. al. JACS1969, 91, 5675 Corey, E.J. et. al. Tet. Lett.1984, 25, 5013-5016

  3. Examples of isoprostanes

  4. Isoprostane biosynthetic pathway ArachadonicAcid 15-F2T-Isoprostane Proton abstraction Reduction O2 O2 Sequential 5-exo cyclizations Morrow, J. et. al.PNAS1990 87, 9383-9387

  5. Step 1: Proton abstraction from arachadonic acid Szori, M. et. al.Phys. Chem. Chem. Phys.2007, 9, 1931-1940

  6. Step 2: Oxygenation of pentadienyl radical • Regioselectivity • Ψ3 orbital predicts addition at 3 positions • β-fragmentation (reverse reaction) • Slow for terminal peroxy radicals • Fast for bisallylic radical • Stereoselectivity • Facial selectivity is not biased • Peroxy radicals are racemic Porter, N. et. al. JACS1981, 103, 6447-6455 Weenen, H and Porter, N. JACS1982, 104, 5216-5221

  7. Step 3: The two 5-exo cyclizations

  8. Regioselectivity of the 1st cyclization • Competing cyclizations • 5-exo is strongly favored • β-scission is competitive • Baldwin’s Rules predict 5-exo cyclization Porter, N. et. al. JACS1976, 98, 6000-6005 Baldwin, J. JCS Chem. Comm.1976, 734-736

  9. Stereochemistry of the 1st cyclization • 5-exo cyclization gives unstablized 2° radical • β-scission is competitive • Only cis geometry preorganizes for 2nd cyclization Porter, N. et. al. Tet. Lett.1984, 25, 807 – 810

  10. The 2nd cyclization: historical context “The ring closure primarily forms bicyclo endoperoxides with cis substituents. This last feature departs radically from enzyme-mediated endoperoxide formation in that the natural prostaglandin stereochemistry is disfavored.” O’Connor, D. et. al. JACS1981, 103, 223-224 O’Connor, D. et. al. JACS1984, 106, 3577-3584

  11. Corey rationalization for cis geometry • Proposed prostaglandin biosynthetic route via 5-exo cyclization • Stereochemistry of radical precursor did not influence outcome • Frustrating result at the time PGF2α Corey, E.J. et. al. JACS1984, 106, 6425-6427

  12. Corey rationalization for cis geometry • Factors stabilizing the 2° radical • Donation from endoperoxide oxygen • Donation from pi system • Minimize sterics by placing the R-groups away from each other • Disrotatory cyclization gives isoprostane geometry Corey, E.J. et. al. JACS1984, 106, 6425-6427 Curran, D. and Porter, N. from Stereochemistry of radical reactions, VCH, Weinheim, 1996, pp. 67-68

  13. Step 4: Oxygenation of allylic radical • Final allylic radical is trapped by a second molecule of O2 • Addition to either face of the occurs • Generates the C-15 OH epimers • Reduction of peroxides completes the synthesis Yin, H. et. al. JACS2002, 124, 7745-7754

  14. Discovery of isoprostanes in humans • Lipids from human blood and urine isolated • GC-MS data indicated “prostaglandin like” compounds • Synthetic material from O’Connor confirmed one peak to be 15-F2T-IsoP • What were the others? Morrow, J. et. al., PNAS1990, 87, 9383-9387 Morrow, J. et. al.Bioch. Biophys. Acta.1994, 244-248

  15. Isoprostanes discovered, synthesis required • Identification of • additional • isoprostanes • Investigation of • biological activity

  16. Stereodivergent syntheses: Taber 12-F2T-IsoP 12-F2C-IsoP (+) ent-12-F2C-IsoP ent-12-F2T-IsoP Taber, D. et. al. JACS2002, 124, 13121-13126

  17. Retrosynthesis Mislow rearrangement Cyclopropane Ring opening Rh-cat. cyclopropanation aldol Taber, D. et. al.JACS2002, 124, 13121-13126

  18. Access to alpha diazo ketone Taber, D. et. al. JACS2002, 124, 13121-13126

  19. Lewis Acid-catalyzed ring opening Taber, D. et. al.JACS2002, 124, 13121-13126

  20. Resolution via chemoenzymatic acetylation Taber, D. et. al.JACS2002, 124, 13121-13126

  21. Completion of synthesis Taber, D. et. al.JACS2002, 124, 13121-13126

  22. Mislow rearrangement and deprotection

  23. Taber synthesis, strengths and weaknesses • Strengths • Sets 4 stereocenters in sequential cyclopropanation-ring opening steps • High-yielding chemoenzymatic resolution of enantiomers • Weaknesses • Lengthy due to FGI • Low-yielding steps • Chromatographic separation of diastereomers

  24. Snapper stereodivergent synthesis Schrader, T. and Snapper, M. JACS2002, 124, 10998-11000

  25. Retrosynthesis Schrader, T. and Snapper, M. JACS2002, 124, 10998-11000

  26. [2+2] cycloaddition and ROM Schrader, T. and Snapper, M. JACS2002, 124, 10998-11000

  27. Resolution of the trans isoprostanes

  28. Resolution of the 15-F2T series Schrader, T. and Snapper, M. JACS, 2002 124, 10998-11000

  29. Resolution of the cis isoprostanes

  30. Resolution of F2C isomers Schrader, T. and Snapper, M. JACS2002, 124, 10998-11000

  31. Completion of F2T and F2C Isoprostanes Schrader, T. and Snapper, M. JACS2002, 124, 10998-11000 Angelin, M. et. al.Eur. J. Org. Chem.2006, 4323-4326

  32. Summary of Snapper route • Strengths • Rapid entry into isoprostane scaffold • Effective meso desymmetrization • Excellent %ee • Weaknesses • Early resolution of isomers • parallel reactions • Not very stereodivergent • Trans and cis isoprostane routes diverge

  33. Isoprostane synthesis complete, medical studies needed

  34. 15-F2T Isoprostanes are enhanced in atherosclerotic vessels 30-fold Pratico, D. et. al.J. Clin. Invest.1997, 100, 2028-2034

  35. Pathogenesis of Atherosclerosis Hansson, G. NEJM 2005, 352 (16), 1685-1695

  36. Consequences of atherosclerosis • A: Coronary artery with fatal atherothrombosis • Unstable plaque • Thin fibrous cap • Rupture-induced blood clot • B: Close up of ruptured fibrous cap Hansson, G. NEJM 2005, 352 (16), 1685-1695

  37. Case-control study 93 people with heart disease 93 healthy people Age and gender matched Risk factors for heart disease New risk factor: 15-F2T Isoprostane Risk FactorRisk BMI 2.8 High LDL 8.3 Diabetes 11.0 Smoker 15.0 High BP 19.1 High IsoP 27.3 Prevention: Urinary 15-F2T IsoP is a risk factor for heart disease Schwedhelm, E. Circulation2004, 109, 843-848

  38. Treatment: Terutroban advanced to clinical trials • 15-F2T-IsoP binds the thromboxane (TP) receptor • TP receptor is known to promote atherosclerosis and atherothrombosis • Terutroban binds, inhibits TP receptor • Manufactured by Servier (France) • Currently in Phase III clinical trials Cemitiere, B. Bioorg. Med. Chem.1998, 1375-1380

  39. Isoprostanes: past, present and future Future Directions 1) Explore synthetic routes to other isoprostanes 2) Use F2T to diagnose heart disease 3) Discover the role of 15-A2-IsoP in neurotoxicity

  40. Ulf von Euler on the discovery of prostaglandin “ To give a truthful catalogue of all the events preceding a discovery could very well be disastrous for the potential glamour of it.” – Ulf von Euler Euler, U.S.v. Progress in Lipid Research1981, 20, xxxi-xxxv http://nobelprize.org/nobel_prizes/medicine/laureates/1970/euler.jpg

  41. Thank You • Laura Kiessling • Kiessling Group • Practice talk attendees • Aim • Becca • Joel • Katie • Lingyin • Margaret • Shane • Raja • Kat Myhre

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