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Fighting Malaria: From Artemisinin to ACT’s.

Fighting Malaria: From Artemisinin to ACT’s. . Ana Francis Carballo- Arce. May 5 th , 2011. www.hopeforallministries.org .(accessed January, 2011) . Outline. Malaria facts. http://www.nature.com/news/specials/malaria/index.html (accessed January, 2011) . Global map for Malaria.

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Fighting Malaria: From Artemisinin to ACT’s.

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  1. Fighting Malaria:From Artemisinin to ACT’s. Ana Francis Carballo-Arce May 5th, 2011 www.hopeforallministries.org .(accessed January, 2011)

  2. Outline

  3. Malaria facts http://www.nature.com/news/specials/malaria/index.html (accessed January, 2011)

  4. Global map for Malaria www.rollbackmalaria.org/worldmalariaday (accessed, April 28th)

  5. Principal available antimalarial drugs http://www.viablehealth.com/library3/herbs/herbs_cinchona.htm (accessed February 2011)

  6. Malaria over the past 50 years Engineering micro- organisms Artemisinin analogues (ACT) First total synthesis Discovery and isolation of artemisinin Malaria resistance

  7. Malaria cyclein the body Wellems, Thomas E.; et Al. J Clin. Invest. 2009;119(9):2496–2505 http://www.youtube.com/watch?v=wbe4LTb8Dt4 .(accessed march 2011)

  8. 1960 – Malaria Resistance • DDT was removed from the market because of the environmental damage • Mosquito developed resistance to DDT • The parasite developed resistance to available drugs • e.g. chloroquine Brown, Geoffrey D. Molecules 2010, 15, 7603-7698 Shel, EllenRuppel l. Atlantic Magazine.1997. available at: http://www.theatlantic.com/magazine/archive/1997/08/malaria-resurgence-of-a-deadly-disease/5755/

  9. Search for a new treatment • Late 1960’s and 1970’s, Tu You-You, head of the antimalarial research group at the China Academy of Traditional Chinese Medicine, discovered the activity of the plant. • “Sweet Annie” • The activity of the plant was first reported during the Jin dynasty • 284-346AD Liao; Fulong. Molecules . 2009, 14, 5362-5366 http://www.chinavitae.com/biography/Tu_Youyou (picture)

  10. Isolation of active compound • 1972, a colourless crystalline substance is isolated. • The structure and stereochemistry were not determined until 1975 and published in 1977. Liao; Fulong. Molecules . 2009, 14, 5362-5366

  11. Artemisinin • Representing a new class of antimalarial agents, artemisinin is a sesquiterpenetrioxanelactone. Arsenault, Patric R. et Al. Current medicinal chemistry, 2008, 15, 2886-2896 Covello, Patric S. Phytochemistry. 2008, 69, 2881-2885

  12. Red blood stage in malaria cycle O’Neill, Paul M.; Barton, Victoria E.; Ward, Stephen A. Molecules 2010, 15, 1705-1721

  13. Mode of action of artemisinin Meshnick 1991: • the bioactivation of 1,2,4 trioxanes is triggered by iron (II) to generate reactive oxygen species. • the selectivity of artemisinin towards parasite-infected erythrocytes was then explained by the iron dependent bioactivation of the endoperoxide bridge. O’Neill, Paul M.; Barton, Victoria E.; Ward, Stephen A. Molecules. 2010, 15, 1705-1721 Meshnick, Steven R. et Al. Mol.Biochem. Parasitol. 1991. 49. 181-189

  14. Reductive Scission model By Posner And Jefford O’Neill, Paul M.; Barton, Victoria E.; Ward, Stephen A. Molecules 2010, 15, 1705-1721

  15. O’Neill, Paul M. et Al. Acc. Chem. Res. 2004, 37, 397-404

  16. O’Neill, Paul M. et Al. Acc. Chem. Res. 2004, 37, 397-404

  17. Molecular targets of artemisininI.Serca Sarco-Endoplasmic Reticulum Ca2+-ATPase pfATP6ase Jonathan Gershenzon & Natalia Dudareva. Nature Chemical Biology . 2007. 408 - 414 .

  18. Molecular targets of artemisininII. Alkylation of heme groups Artemisinin O’Neill, Paul M.; Posner, Gary H. Journal of Medicinal Chemistry, 2004, 47, 12, 2945- 2964

  19. Molecular targets of artemisininIII. ROS generation O’Neill, Paul M.; Posner, Gary H. Journal of Medicinal Chemistry, 2004, 47, 12, 2945- 2964

  20. Dosage of Artemisinin • Monotherapy: 20 mg/kg in a divided loading dose on the first day, followed by 10 mg/kg once a day for 6 days. • Combination therapy: 20 mg/kg in a divided loading dose on the first day, followed by 10 mg/kg once a day for two more days plus mefloquine http://www.rollbackmalaria.org/cmc_upload/0/000/014/923/am2_1-8.htm (accessed, may 2010)

  21. Sources of Artemisinin

  22. Plant Source • The content in the plant is low between 0.01-1.5%. • It is the commercial source. • It is found in the glandular trichomes.

  23. Biosynthesis Brown, Geoffrey. Molecules. 2010, 15, 7603-7698

  24. Carbon skeleton assembly Brown, Geoffrey. Molecules. 2010, 15, 7603-7698

  25. Oxidations CYP 71AV1 Brown, Geoffrey. Molecules. 2010, 15, 7603-7698

  26. Introduction of Oxygen Brown, Geoffrey. Molecules. 2010, 15, 7603-7698 Brown, Geoffrey .Tetrahedron. 2002, 58, 897-908

  27. Artemisinin ring closing L.-K. Sy, G. D. Brown .Tetrahedron.2002, 58 897-908

  28. Total syntheses • G. Schmid, W . Hofheinz in 13 steps, 1983 • Yadav in 9 steps, 2010

  29. Synthesis by G. Schmid, W . Hofheinz G. Schmid, W. Hofheinz, J. Am. Chem. Soc. 1983, 105 , 624

  30. Synthesis by G. Schmid, W . Hofheinz G. Schmid, W. Hofheinz, J. Am. Chem. Soc. 1983, 105 , 624

  31. Silicon induced chemistry G. Schmid, W. Hofheinz, J. Am. Chem. Soc. 1983, 105 , 624

  32. Synthesis by G. Schmid, W . Hofheinz Overall yield 2.1% G. Schmid, W. Hofheinz, J. Am. Chem. Soc. 1983, 105 , 624

  33. Yadav total synthesis J.S. Yadav , B. Thirupathaiah, P. Srihari, Tetrahedron. 2010.66 .2005–2009

  34. Yadav total synthesis Overall yield from citronellal to the photoxidation: 13% J.S. Yadav , B. Thirupathaiah, P. Srihari, Tetrahedron. 2010.66 .2005–2009

  35. Analogues: First generation SD90: required dose for 90% suppression of parasitemia. Dejan M.; Bogdan A. Šolaja. J. Serb. Chem. Soc. 2009. 74 (11) 1155–1193

  36. Second generation Dejan M.; Bogdan A. Šolaja. J. Serb. Chem. Soc. 2009. 74 (11) 1155–1193

  37. 1,2,4 trioxalanes Dong; Y. et Al. J. Med. Chem. 2005, 48, 4953-4961

  38. Spiroadamantane ring IC50 > 100 ng/mL IC50 : 44 ng/mL IC50 : 2.2 ng/mL Dong; Y. et Al. J. Med. Chem. 2005, 48, 4953-4961

  39. Key figures for analogs O’Neil, Paul. Nature. 2004. 430, 838-839

  40. OZ439 Roche-Medicines and Malaria Venture -Single dose -Low cost of goods -High oral bioavailability -phase III Charman, Susan A. et Al. PNAS. 2011.108, 11, 4400-4005

  41. Synthesis of trioxolanes The compounds are synthesized using the Griesbaum- co-ozonolysis Tan, Yuanqing. et Al. J. Org. Chem. 2004. 69. 6470-6473

  42. Cost of making artemisinin • Artemisia annuacycle between 12 -18 months • The yield from the plant extract is low; 17,000 ha of the plant are required to produce 100 million adult treatments per year. • In 2007, the demand of treatments was 400 million doses • Synthesis of artemisinin is not cost effective, in 2006 was estimated in a range between $900-$1600/kg Sambo L.G. Am. J. Trop. Med. Hyg., 2007, 77(Suppl 6), pp. 198–202

  43. Synthetic biology Artemisinin • Kiesling and his group, have engineered two organisms, to produce artimisinic acid, at levels up to 25 g/L. • Saccharomycescerivisiae • E. coli Sambo L.G. Am. J. Trop. Med. Hyg., 2007, 77(Suppl 6), pp. 198–202

  44. Kiesling and Ro; engineered yeast Sambo L.G. Am. J. Trop. Med. Hyg., 2007, 77(Suppl 6), pp. 198–202 Ro; Dae-Kyun et al .Nature . 2006, 440, 940-943 http://chemistry.umeche.maine.edu/CHY431/Synthetic2.html image (accessed February 2011)

  45. Making Artemisinin commercially available Sambo L.G. Am. J. Trop. Med. Hyg., 2007, 77(Suppl 6), pp. 198–202

  46. Patrick Covello Jay Keasling “This new development in the production of a malaria treatment represents a major development in the fight against the disease. It will strengthen Canada’s position as a world leader in health research and provide a reliable and affordable solution.” Saskatoon StarPhoenix • Canada’s federal government has spent $869,000 over eight years. • Sanofi-aventis will begin commercial-scale production in 2012. • The Bill & Melinda Gates Foundation, has contributed with $42.6 million. http://www.vancouversun.com/business/Canadians+make+malaria+breakthrough/4471342/story.html (accessed march 2011)

  47. Summary Shel, EllenRuppel l. Atlantic Magazine.1997. available at: http://www.theatlantic.com/magazine/archive/1997/08/malaria-resurgence-of-a-deadly-disease/5755

  48. Acknowledgements Dr. Arnason group Dr. Durst group

  49. Other uses for Artemisinin O’Neill; Paul M.; Barton, Victoria E. ; Ward, Stephen A. Molecules. 2010, 15(3), 1705-1721

  50. Potential non-malarial uses of artemisinin and derivatives DIBAL Artemisinin Dihydroartemisinin Ovarian Cancer, Oral Cancer Artesunate: Leukemia Melanoma, Prostate Cancer. Dimers have enhanced activity against cancer, but not good activity against malaria Patrick R. Arsenault, Kristin K. Wobbe and Pamela J. Weathers.CurrentMedicinal Chemistry, 2008, 15, 2886-2896

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