1. Inventing New Synthetic Ring Enlargement Methods and Exploring the Use of Novel Trioxanes for the Treatment of Malaria William Maio The Johns Hopkins University Advisor: Professor Gary H. Posner
2. Outline: Part I: Inventing New Synthetic Methodology -Background -Tin-mediated n+3 reactions -Silicon-mediated n+3 reactions -Ring Enlargements -Ring Contractions Part II: Exploring the Use of Trioxanes for the Treatment of Malaria -Background -Fluoroartemisinin and derivatives -Biological Data
31. Part I: Conclusions Many new epoxide examples added synthetic value to the methodology Removal of HMPA allows for a more environmentally-friendly procedure Reduction/deprotection of the certain functionality on the side-chains of the lactones can lead to further ring enlarged systems Lactone to lactam ring contraction provides novel access to the sedum alkaloid family of natural products
32. Part II: Malaria Introduction One of the most deadly vector-born diseases known Complex lifecycle that involves two hosts: human and mosquito On average causes the deaths of about 2 million people each year Highest transmission is in tropical and subtropical areas Parasite resistance to current chemotherapies are emerging Mlambo, G. et. al. Am. J. Trop. Med. Hyg . 2008 , 78 , 114.
37. Competition Experiment 1 eq of DHA, 1 eq F-DHA, ½ eq MeOH, cat. TsOH After 30 min, all the MeOH was consumed and no F-Artemether had formed by NMR or by TLC Qualitatively speaking, the presence of the Fluorine atom Significantly retards the rate of acid-catalyzed etherification Relative to DHA Posner, G.H.; Maio, W.A.; Kalinda, A.S. Biorg. Med. Chem. 2008 , 16 , 5247 .
39. Synthesis of Fluoroartesunate and Biological Data Posner, G.H.; Maio, W.A.; Kalinda, A.S. Biorg. Med. Chem. 2008 , 16 , 5247 .
40. Part II. Conclusions The presence of a fluorine atom alpha to C10 significantly retards the acid- catalyzed hydrolysis of ether and ester derivatives The compounds were submitted for biological evaluation: unfortunately no new antimalarial was discovered This lack of antimalarial activity may be due to changes in lipophilicity, transport, and/or metabolism rather than to only the increased hydrolytic stability of these fluoro analogs
41. Acknowledgements Professors: Gary H. Posner Thomas Lectka John D. Tovar Lawrence Principe Tamara Hendrickson Craig Townsend Group Members: Dr. Mehmet Kharaman Dr. Mark A. Hatcher Dr. Sandra Sinishtaj Dr. Wonsuk Chang Dr. Jamie Singleton Alvin S. Kalinda Lectka Group Members: Dr. Ciby Abraham Data Analysis: Dr. Amy Sarjeant Dr. Phil Mortimer Dr. Charles Long Fordham Professors: Dr. James A. Ciaccio Dr. Moses Kalustian Family and Friends: Mom & Dad Grandma Rita Leah