Prof. Dr. Erick M. Carreira Laboratorium für Organische Chemie

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

2. Why we do, what we do 0.000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000001% ESTIMATED NUMBER OF “REALIAZABLE” MOLECULES 108 ESTIMATED NUMBER OF KNOWN MOLECULES 10120–10200

3. How do we find our way?

4. Continuing with the thought experiment... At a rate of 10 billion molecules/year, the synthesis project would take between 10110 and 10190years !!! In the search for new pharmaceuticals, how do chemists deal with such odds? High through-put screening (Combinatorial Chemistry)  Bio-informatics (Genomics)  Computational Chemistry  Biostructural Chemistry Sets the limit to what is realizable or “makeable”  Synthetic Chemistry

5. Top Twenty Drugs (Based on Sales) in 1990 Drug Therapeutic Class (in Millions USD) Ranitidine Amoxicillin Amipicillin Captopril Enalapril Ibuprofen Nifedipine Cefaclor Cimetidine Atenolol Diclofenac Diltiazem Naproxen Cefalexin Lovastatin Famotidine Iohexol Cefatriaxone Proxicam Albuterol Antiulcer Antibiotic Antibiotic ACE-inhibitor 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 1500 1400 1300 1000 1000 1000 1000 1000 1000 900 750 600 600 600 600 600 Optically Pure Racemic mixture * Optically Pure Racemic mixture * Optically Pure Racemic mixture * 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.) 1990 1980 2000 1994

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

10. Cancer • Arises from the stepwise accumulation of genetic changes which lead a cell to undergo unlimited growth that is unresponsive to homeostatic regulatory mechanisms • 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 Anticancer: isolated from Pacific Yew Antineoplastic: Isolated from crocus Antitumor:isolated from Vinca rosea Anticancer: isolated from mandrake

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

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

16. Epothilone-producing myxobacterium (Sorangium cellulosum)

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

18. A Cell Biology Primer 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.

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. II. Future Applications of the Catalytic Chemistry to Bio-organic Chemistry Amphotericin: The Clinician's Drug of Choice for Fungal Infections 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 Pharmacology1997, 52, 560

48. Amphotericin B Extrazellulär Cholesterin AmB Cytoplasma Channel Model

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

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