1. Prof. Dr. Erick M. Carreira Laboratorium für Organische Chemie Eidgenössiche Technische Hochschule (ETH) Zürich, Switzerland Organic Chemistry in the Quest for Anticancer Therapeutics

2. Why we do, what we do ESTIMATED NUMBER OF “REALIAZABLE” MOLECULES 10 120 –10 200 ESTIMATED NUMBER OF KNOWN MOLECULES 0.0000000000000000000000000000 00000000000000000000000000000 00000000000000000000000000000 0000000000000000000001% 10 8

3. How do we find our way?

4. At a rate of 10 billion molecules/year, the synthesis project would take between 10 110 and 10 190 years !!! Continuing with the thought experiment... In the search for new pharmaceuticals, how do chemists deal with such odds?  High through-put screening (Combinatorial Chemistry)  Bio-informatics (Genomics)  Biostructural Chemistry  Synthetic Chemistry  Computational Chemistry Sets the limit to what is realizable or “makeable”

5. Top Twenty Drugs (Based on Sales) in 1990 Ranitidine Amoxicillin Amipicillin Captopril Enalapril Ibuprofen Nifedipine Cefaclor Cimetidine Atenolol Diclofenac Diltiazem Naproxen Cefalexin Lovastatin Famotidine Iohexol Cefatriaxone Proxicam Albuterol Antiulcer Antibiotic ACE-inhibitor NSAID Calcium antagonist Antibiotic Antiulcer Beta-Blocker NSAID Calcium antagonist NSAID Antibiotic Antihypercholesterolemic Antiulcer Contrast medium Antibiotic NSAID Bronchodilator 2400 2000 1800 1500 1400 1300 1000 900 750 600 (in Millions USD)Therapeutic ClassDrug Optically Pure * * * * Racemic mixture

6. When you look into a mirror it is not yourself you see, but a kind of apish error posed in fearful symmetry kool uoy nehW rorrim a otni ton si ti,ees uoy flesruoy dnik a tub rorre hsipa fo lufraef ni desop.yrtemmys Mirror by J. Updike

7. The Bioactivity of Mirror-image Molecules can be Starkly Different

8. Die Entwicklung des Arzneimittelmarktes seit 1980 (Geschätzter Jahresumsatz 2000: 100 Mia US$, davon 43% in Europa.) 1980 1990 1994 2000

9. Benefits to Optically Pure Pharmaceuticals Dose reduction Simplification of dose-response relationship Reduction in intersubject variability Minimization of toxicity from enantiomer

10. Cancer 1.Arises from the stepwise accumulation of genetic changes which lead a cell to undergo unlimited growth that is unresponsive to homeostatic regulatory mechanisms 2.Molecular and cell biology have identified cell phenotypes that are required for malignant transformations and the specific molecular pathways responsible for faulty programming of the cell

11. A Subway Map of Cancer Pathways Subway stops represent phenotypes required for malignant transformations Molecular pathways are represented by the subway lines

13. Natural Products with Anticancer Activities Antitumor:isolated from Vinca rosea Anticancer: isolated from mandrake Antineoplastic: Isolated from crocus Anticancer: isolated from Pacific Yew

14. Natural Products with Promising Anticancer Activities Breast Cancer Promotes assembly of microtubules and inhibits tubulin disassembly Sold as Paclitaxel

15. Ongoing investigations at Novartis, Roche, Brystol Myers Squibb, Schering Epothilones: Promising Anticancer Leads

16. Epothilone-producing myxobacterium (Sorangium cellulosum)

17. Epothilone -disrupts microtubulin dynamics (formation and growth) -inhibit cell proliferation at mitosis

18. Tubulin is a heterodimeric protein which constitutes the monomeric building blocks of microtubules. Microtubules are fundamental component of the cytoskeleton (the beams and conveyor belts of cells-the nanoweb of the cell). Microtubule dynamics is critical during cell division. A Cell Biology Primer

19. Cell Biology Primer:

21. Natural Products bind to microtubule assemblies and interfere with the dynamics-arresting cell growth

22. Medicinal Chemistry  Organic Synthesis -what are the structural features of the molecule that lead to activity? Chemical Genetics Small molecules as probes with which to understand cellular processes -can analogs be generated -improved activities -reduced side effects

23. How do we carve out the important structural features?

24. Total Synthesis of Epothilone Jeffrey Bode, E.M. Carreira J. Am. Chem. Soc. 2001, 123, 3611

26. A complementary approach to the synthesis problem involves bioengineering Biosynthesis is accomplished by the concatenation of synthetic enzymatic modules

27. Biosynthesis of Epothilones

29. Can an analogous modular chemical strategy be developed?

30. Construction of Aldol Fragments + + The Classic Aldol Approach The Dipolar Cycloaddition Approach

31. Retrosynthetic Analysis

32. Analogous Disconnections on Fragments The Synthesis of Polyketides is Reduced to Modular Nitrile Oxide Cycloadditions

33. A Parallel Analysis Can be Applied to Others-

34. Nitrile Oxide Cycloadditions: Aldol Equivalents Regio- and stereoselectivity can be difficult to control The Kanemasa Observation: S. Kanemasa J. Am. Chem. Soc. 1994, 116, 2324

35. Are such cycloadditions compatible with more highly functionalized edducts? If so…  Generalized, versatile strategy for polyketide synthesis  Convergent fragment coupling of polyketides

36. A General Strategy for the Construction of Polyketides:

37. Fragment Synthesis Epothilone A

38. Synthesis of Epothilone B

39. Epothilone B Chelation-Controlled Addittion

40. Key Methodology: Modular Synthesis of Polypropionates

41. General Protocol

42. A General Strategy for the Construction of Polyketides:

43. Yields: 90-95%

44. Stereochemical Correlations cis olefin syn aldol trans olefin anti aldol

45. Amphotericin: The Clinician's Drug of Choice for Fungal Infections II. Future Applications of the Catalytic Chemistry to Bio-organic Chemistry Serious Side effects; much interpatient variation Mechanism of action largely unknown

46. Amphotericin: The Clinician's Drug of Choice for Fungal Infections Polyene Amphotericin B Nystatin Formulation Liposomal Lipid Complex Colloidal Dispersion Liposomal Name Ambisome Abelcet Amphotec Amphocil Nyotran Company NeXstar The Liposome Co. Sequua in USA Zeneca in UK Aronex Status Marketed in UK Marketed in UK and USA Phase 4 Marketed Phase 2/3

47. The chemoselective synthetic manipulation of this natural product, as well as the construction of “smart” designed probes is non-trivial “…however, we are aware that selective modification of the hydroxyl groups involves very difficult chemical synthesis task…probably only through synthesis can derivatives be prepared…” Molecular Pharmacology 1997, 52, 560

48. Amphotericin B Channel Model Extrazellulär Cytoplasma AmB Cholesterin

49. Calculations suggest that it is critical in organizing channel Implicated in the formation of double channels Suggested to interact with sterol

50. Ongoing Applications in Polyketide Syntheses Dieter Muri Syn-Propionate aldols

51. Fragment Coupling

52. Diversity Oriented Synthesis

53. Start End

54. Arbeitsgruppe P. Aschwanden N. Becker D. Cereghetti C. Czeckelius L. Fader R. Faessler A. Fettes C. Fischer L. Scherer J. Waser T. Watanabe N. Wurtz J. Yasuoka P. Zarotti W. Zhao A. Zumbuehl S. Jonnson T. Knoepfel A. Lerchner N. Lohse C. Marti D. Muri S. Reber T. Ritter