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Bryostatins: Selected Syntheses Biological Activity, and Analogue Design

Bryostatins: Selected Syntheses Biological Activity, and Analogue Design. Hao Peng. Beauchemin Research Group Department of Chemistry University of Ottawa. http://student.britannica.com/eb/art/print?id=86904&articleTypeId=0. Outline. Introduction Bryozoan and bryostatin

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Bryostatins: Selected Syntheses Biological Activity, and Analogue Design

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  1. Bryostatins: Selected Syntheses Biological Activity, and Analogue Design Hao Peng Beauchemin Research Group Department of Chemistry University of Ottawa http://student.britannica.com/eb/art/print?id=86904&articleTypeId=0

  2. Outline • Introduction Bryozoan and bryostatin Pharmaceutical applications Limited resources and possible solutions • History of bryostatins total syntheses • Trost’s Bryostatin-16 total synthesis (2008) • Biological activities study and Wender’s analogue design • Conclusion

  3. The Marine Bioactive Product Bryostatin was first discovered in Bugula neritina, a species of bryozoan, at the gulf of Mexico in 1968. It was produced by Endobugula sertula, a symbiont bacteria of the bryozoan. The compound was found to protect bryozoan larva frompredation orinfection. Bryostatin has biomedical potential and can be used as an anti-cancer agent as well as memory enhancement agent. Bugula neritina http://www.uq.edu.au/meeg/images/bugula_neritina.jpg

  4. Gulf of Mexico Gulf of Japan California

  5. Bryostatin Family B A B A B A C C C Bryostatin 3, 19, 20 (Bryostatin 3, 19 only have C20 substituent) 20 members of bryostatin have been isolated and characterized. Hale; Hummersone; Manaviazar; Frigerio Nat. Prod. Rep.2002, 19, 413 Schaufelberger et al J. Nat. Prod.1991, 54, 1265 Pettit; Gao; Blumberg; Herald; Coll; Kamano; Lewin; Schmidt; Chapuis J. Nat. Prod. 1996, 59, 286

  6. Bryo-1: Chemotherapeutic Object In 1982, structure of the most abundant member, Bryostatin 1, was determined after the challenging Isolation by Pettit, Clardy, and coworkers at the Arizona State Cancer Institute and Cornell University. Pettit; Herald; Doubek; Herald; Arnold; Clardy J. Am. Chem. Soc.1982, 104, 6846 Smith; Smith; Pettit Biochem. Biophys. Res. Comm. 1985, 132, 939

  7. Potent Chemotherapeutic Candidate In National Cancer Institute (NCI): 38 clinical trials of bryostatin 1 were done or being underway currently. 15 trials of bryostatin 1 combining with other chemotherapeutic agents are in Phase II as well. Doses required in vivo are extremely low. Sanjeev. B. et al. J. Nat. Prod. 2008, 71, 492 http://clinicaltrials.gov/.

  8. Memory Enhancement Agent Alzheimer’s disease was observed by Dr. Alois Alzheimer in 1901, and the main symptom was great memory loss. According to Alzheimer’s disease statistics (USA, 2004) The 7th leading cause of death, causing mortality in 65,829 people; The third most expensively treated disease; More than 5 million Americans are estimated to currently have it; Projected that by 2050, that number will exceed 14 million More recent research proved bryostatin is helpful to improve learning ability as well as memory retention. In NCI, the clinical trail of Bryostatin 1 to Alzheimer’s disease is underway. Jarin. H. and Daniel. L. A, PNAS, 2007, 104, 19571 http://www.metromusictherapy.com/alz_stroke_park.asp

  9. Isolation completed in 10 months Bugula neritina Bryostatin 1 18 grams Limited Supply and Possible Solutions 14 Tonnes The production is expensive, and will cause ecological issue. • Solutions: • Aquaculture: time-consuming • Biosynthesis: still underway • Total synthesis: can provide material on gram scale Schaufelberger et al.J.Nat.Prod. 1991, 54, 1265 Thakur; Jain; Natalio; Hamer; Thakur; Müller Biotech. Adv.2008,26, 233 Sudek,S. et al. J. Nat. Prod. 2007,70, 67 Kerr; Lawry; Gush Tetrahedron Lett. 1996,37, 8305

  10. Outline • Introduction Bryozoan and bryostatin Pharmaceutical applications Limited resources and possible solutions • History of bryostatins total syntheses • Trost’s Bryostatin-16 total synthesis (2008) • Biological activities study and Wender’s analogue design • Conclusion

  11. Bryostatin 7 Bryostatin 2 Bryostatin 3 The History of Total Synthesis After bryostatin was founded in 1968, only 3 total syntheses were reported in 32 years. n-Pr n-Pr 1999 Evans 2000 Nishiyama and Yamamura 1990 Masamune All the 3 total syntheses required more than70 steps and over 40-step longest linear sequences. Therefore, they are inefficient methods for material supply. Kageyama; Tamura; Nantz; Roberts; Somfai; Whritenour; Masamune J. Am. Chem. Soc.1990, 112, 7407 Evans; Carter; Carreira; Charette; Prunet; LautensJ. Am. Chem. Soc. 1999, 121,7540 Ohmori; Ogawa; Obitsu; Ishikawa; Nishiyama; Yamamura Angew. Chem. Int. Ed. 2000, 39, 2290

  12. Main Synthetic Challenges Main challenges in bryostatin synthesis: 1) Three heavilysubstituted tetrahydropyran rings 2) The congested E-alkene of C16-17 3) Two base/acid sensitiveexo-cyclic enoates 4) A numerous Oxygen-containing functionalities on the macro-lactone. B A 16 17 C n-Pr

  13. Strategies In Common Evans 1999 : B A 16 17 1 25 C Evans; Carter; Carreira; Charette; Prunet; Lautens J. Am. Chem. Soc. 1999, 121,7540

  14. Yamaguchi Macrolactonization • Main advantages: • 1) Operational simplicity • 2) High reacting rate • 3) Lack of by-products Laszlo K et Barbara Czako, in Strategic applications of named reactions in organic synthesis, p500 Evans; Carter; Carreira; Charette; Prunet; Lautens J. Am. Chem. Soc. 1999, 121,7540

  15. Julia Olefination • Main features: • 1) High(E)-stereoselectivity • 2) The (E)-selectivity is increased with • increasing chain branching of R1,R2 and R3. • 3) Strong basic reaction condition Laszlo K et Barbara Czako, in Strategic applications of named reactions in organic synthesis, p230

  16. Julia Olefination Mechanism: Acyloxy sulfone Laszlo K et Barbara Czako, in Strategic applications of named reactions in organic synthesis, p230

  17. Drawback of Julia-Olefination Bryostatin 2 synthesis (Evans et al, 1999) × Numerous protectinggroups for introduction of exo-cyclic enoate.

  18. Two Solutions Function-Oriented Synthesis (FOS): maintaining biological activities but simplifying structure (analogue design). Wender; Verma; Paxton; Pillow Acc. Chem. Res.2008, 41, 40

  19. Outline • Introduction Bryozoan and bryostatin Pharmaceutical applications Limited resources and possible solutions • History of bryostatins total syntheses • Trost’s Bryostatin-16 total synthesis (2008) • Biological activities study and Wender’s analogue design • Conclusion

  20. Barry M. Trost The Revolutionary Step in Bryostatin Total Synthesis In 2008, Barry M. Trost and Guangbin Dong reported a total synthesis of bryostatin 16. Ru- catalyzed coupling Main features: 1) Instead of Julia-olefination, E-alkene on C16-17 was stored in precursor in advance 2) Application of ruthenium-catalysed ene-yne coupling for Bring formation 3)Application of palladium-catalysed yne-yne coupling for Cring formation 4) Much shorter synthesis route (39 total, 26 linear) Pd-catalyzed coupling Trost and Dong Nature2008, 456, 485

  21. Metathesis Approach to Bryostatins In 2006, Thomas E. J. : ( E:Z=1:1) × When a geminal dimethyl group is on Carbon 18, the reaction did not work because of steric hinderance. Ball; Bradshaw; Dumeunier; Gregson; MacCormick; Omori; Thomas Tetra Lett2006 47 2223

  22. A Ring-Expanded Analogue Design Barry M. Trost (2007): Trost; Yang; Thiel; Frontier; Brindle J.Am.Chem.Soc2007129, 2206

  23. × No equilibrium TandemRu-Catalyzed Alkyne-Enone Coupling / Michael Addition Main features: 1) Mild reaction condition: alkyne ([0.5M]), catalyst (10 mol%), acetone, rt,40h; 2) Isolated yield: 39-80% (10 entries); 3) cis/trans ratios ranged from 5/1 to 8/1; 4) Completechemoselectivity. 5) Convergent further functionalization of TMS group. main product thermodynamic control Trost; Yang; Wuitschik, Org Lett2005, 7, 4761 Miller Angew. Chem. Int. Ed. 2009, 48, 2

  24. The reaction tolerated branching Nocross-couplingproduct The reaction showed complete chemoslectivity between different alkenes. Trost; Yang; Wuitschik Org Lett2005, 7, 4761 Trost; Machacek; Schnaderbeck Org Lett2000, 2, 1761 Trost et al Chem Rev 2001, 101, 2070

  25. Further Functionalization of Vinylsilane A good handle for functional group inter-conversion Trost; Yang; Wuitschik Org Lett2005, 7, 4761 Trost and Machacek Angew. Chem. Int. Ed. 2000, 41, 4693 Trost; Machacek; Schnaderbeck Org Lett2000, 2, 1761 Chou; Kuo; Wang; Tsai; Sun J. Org. Chem.1989, 54, 868 Qing and Yue Tetra. Lett.1997, 38, 8067

  26. Tandem Palladium-catalyzed terminal alkyne-ynoate coupling/cyclization 2 6-endo-dig cyclization Step 1 Step 2 5-exo-dig cyclization lactonization Main features: 1) Mild reaction conditions; 2) High regio- and chemo-selectivity 3) Moderate isolated yield for 2 steps (42~62%); 4) Pd(OAc)2 is the catalyst for both the 2 steps; 5) Geometry of exo-cyclic enoate is mechnism dependant Only favored when both inductive and steric effect on terminal alkyne (R1) Only favored at high T Trost and Frontier J.Am.Chem.Soc.2000, 122, 11727 Trost; Matsubara; Caringi J.Am.Chem.Soc.1989, 111, 8745 Trost and McIntosh J.Am.Chem.Soc.1995, 117, 7255

  27. Retrosynthesis of Bryostatin 16 A B E-alkene functionality was stored in precursor 8.

  28. Synthesis of A Ring Precursor ( S )- ( S )- Evans; Chapman; Carreira J. Am. Chem. Soc.1988, 110, 3560 Brown and Jadhav J. Am. Chem. Soc.1983, 105, 2092 Brownbridge; Chan; Brook; Kang Can. J. Chem. 1983, 61, 688 Evans; Carter; Carreira; Prunet; Charette; Lautens Angew. Chem. Int. Ed. 1988, 37, 2354

  29. Synthesis of A Ring Precursor Otera; Yano; Kawabata; NozakiTetrahedron Lett. 1986,27, 2383

  30. Synthesis of B and C Ring Precursors Lin; Loh J. Am. Chem. Soc.2003, 125, 13042 Dess; Martin J. Am. Chem. Soc.1991, 113 , 7277 Corey; Helal Angew. Chem. Int. Ed. 1998, 37, 1986 Trost; Yang; Thiel; Frontier; Brindle J.Am.Chem.Soc2007129, 2206

  31. Laszlo K et Barbara Czako, in Strategic applications of named reactions in organic synthesis, p402 Roth; Liepold; Müller; Bestmann Synthesis2004,1, 59 Nicolaou; Estrada; Zak; Lee; Safina Angew. Chem. Int. Ed. 2005, 44, 1378

  32. 1) AuCl(PPh3) (20 mol%), AgSbF6 (20 mol%), NaHCO3, DCM/MeCN, 0 °C to r.t. 73%; 2) Piv2O, DMAP, DCM, 50 °C, 62% Liu; Song; Song; Liu; Yan Org. Lett.2005, 7, 5409

  33. Comparison Bryostatin 2 Bryostatin 16

  34. Outline • Introduction Bryozoan and bryostatin Pharmaceutical applications Limited resources and possible solutions • History of bryostatins total syntheses • Trost’s Bryostatin-16 total synthesis (2008) • Biological activities study and Wender’s analogue design • Conclusion

  35. N: Nature product S: Totally synthetic drug with modification of an existing agent. Function Oriented Synthesis Strategy From 1981 to June 2006, in 1184New chemical entities (NCEs) ND: Nature product with semisynthetic modification S*: Made by total synthesis, but the pharmacophore Is/was from a natural product. The majority (57%:23% ND +30%S+4% S*) were derived from natural products, or were designed based on a natural product pharmacophore. only 5% introduced over this period were natural products themselves. Newman J. Nat. Prod., 2007, 70, 461

  36. Plasma membrane cytosol PKC and DAG Binding Activation Quaternary structure of PKC Protein kinase C (PKC) is a family of serine/ threonine kinases which affects growth factors, hormones, and neurotransmitters. PKC is the target of both tumour promoter and inhibitor Phospholipase C catalyzes PIP2 cleavage to IP3 and DAG PKC binds with DAG and translocates from the cytosol to plasma membrane PIP2: phosphatidyl inositol-bisphosphate IP3: inositol triphosphate DAG: diacylglycerol Castagna M et al, J. Bio. Chem, 1982,257, 7847 Caponigro F et al, Anti-Cancer Drugs,1997, 8, 26 Mackay and Twelves Endocrine-Pelated Cancer, 2003, 10, 389

  37. Tumour promoter / inhibitor PKC Phorbol esters bind to PKC and result in a tumour promotion. The tumour inhibiting activities of bryostatin- 1 is also related to its strong affinity toPKC. Competition: phorbol esters and bryostatin-1 bind to the same sites on PKC. Nishizuka.Y. Nature,1984,308, 693 Taylor and Andzelm Curr. Chem. Bio. 1997, 1, 219 Newton, Chem. Rev. 2001, 101, 2353

  38. Paul.A. Wender Pharmacophoric Model Wender started structure-activity studies of bryostatins in 1986 27 publicationson bryologue design, synthesis, biological evaluation. In 1988, the groups of Wender, Blumberg, and Pettit reported that a proposed pharmacophoric model to explain competitive binding between the three structure-different PKC activators to the same site on PKC. Wender et al, Proc. Natl. Acad. Sci. USA 1998, 95, 6624 Wender et al, Proc. Natl. Acad. Sci. USA 1988, 85, 7197

  39. Research findings: The binding of the bryostatins is only modestly affected by changes in the C4–C16 domain but diminished significantlyby alterations in the C19–C26 domain. Wender et al. Proc Natl Acad Sci USA,1988, 85, 7197 Pettit et al. Anti-Cancer Drug Design, 1992, 7,101.

  40. Space domain Recognition domain Pharmacophoric atoms Structure-Activity Studies The groups on C1, C19, and C26affect PKC binding greatly while A and B rings remotely control the orientation and mobility of the groups in recognition domain.

  41. nM = Selected Bryologues Design The region containing the putative pharmacophore was retained in an effort to begin simplifying the structure of these molecules without losing their activity completely. Wender et alJ. Am. Chem. Soc. 1998, 120, 4534 Wender et alJ. Am. Chem. Soc. 2002, 124, 13648 Wender; Koehler; Sendzik Org. Lett. 2003, 5, 4549 Stone et alJ. Med. Chem. 2004, 47, 6638

  42. Key Strategy of Macrolactonization in Wender’s Analogues 14

  43. Wender et alJ. Am. Chem. Soc. 1998, 120, 4534 Wender et alJ. Am. Chem. Soc. 2002, 124, 13648 Wender; Koehler; Sendzik Org. Lett. 2003, 5, 4549 Harada; Shintani; Oku J. Am. Chem. Soc1995, 117, 12346 Wender; Mayweg; Vandeusen Org. Lett. 2003, 5, 277

  44. Conclusion Bryostatin 16 Bryologue • Complementary approaches: • New methodologies provide more efficient routes • Simpler targets allow faster synthesis and retaining biological activities.

  45. Acknowledgement Prof. Andre Beauchemin Joseph Moran Isabelle Dion Jean-Gregoire Roveda Francis Loiseau Jennifer Pfeiffer Toni Rizk Ashley Hunt Peter Ng Christian Clavette Lei Zhang J-P Wan Fook Chen

  46. Comment P. A. Wender. 1998 B. M. Trost. 2006

  47. 30 9 7 A B 5 15 17 1 Bryostatins 1, 2, 4-9, 12, 14, 15 Bryostatins 10, 11, 13, 18 19 C Oxidation of C19-C20 alkene 20 Hydration of C19-C20 alkene 34 Bryostatin 16 Bryostatiin 17 (C21-C34 isomer) -------------------------------------------------------------------------------------------------------------------------------- Bryostatins 3, 19 Bryostatin 20 Possible synthetic-conversion from Bryostatin 16 Bryostatin 16 can be used in semi-syntheses of others bryostatins.

  48. The classes of PKC The PKC family comprises at least 12 isozymes and can be divided the three classes : (1) Conventional; (2) Novel; (3) Atypical pseudosubstrate occupied the substrate-binding cavity of protein kinase C, thus maintaining the enzyme in an inactive conformation (inhibitor) • References: • Nishizuka.Y. Nature 1984,308, 693 • Newton.A.C. Journal of Biological Chemistry 1995, 270,28495

  49. synthesis NMR analysis Biological test Analogue modeling and design Crystal structure research (X-ray) • Crystal structure research: • Using molecular mechanics calculations to find out lowest energy structures; • Then comparing their conformation with known solid state and solution structures of the bryostatins to find out most structurally similar structure. Blue: bryostatin 1 Yellow: designed analogue Reference: Paul. A.W. et al, Proc.Natl. Acad. Sci. USA, 1998, 95, 6624

  50. Biological evaluation = Significant activity was observed against all cell lines studied. Notably, preliminary experiments indicate that in several cell lines, designed bryostatin analogues have superior activity to bryostatin 1 itself. Reference: Tanaka Y et al. J Biochem1986;99:257

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