New drugs are urgently needed for effective and non-toxic chemotherapy of widespread human diseases like malaria and cancer. We are blending chemical insights and synthesis skills with biological testing in vitro and then, for the most promising new chemical entities, in vivo to establish efficacy nnd safety. This interdisciplinary research characterizes our program at Hopkins for practical preclincial development of new drug candidates for chemotherapy of malaria andcancer. Based on our good mechanistic and synthetic progresswith anti-infective and anticancerperoxides like the natural trioxane artemisinin and some of its dinners, we propose the following five research goals for the next fiveyears: (1) to design, prepare, and evaluate new, structurally simple, easily prepared, inexpensive, potent and safe (a) monomeric synthetic endoperoxides; (b) dimeric synthetic endoperoxides (2) to design, prepare, and evaluate new, potent, and safe semi-synthetic dimers jrepared (a) from dihydroartemisinin acetate; (b) from artemisinin-9-en-10-aldehyde (3) to determine the molecular mechanism of action of our most promising dimeric endoperoxides and trioxanes. As synthetic and medicinal chemists, we are in a unique position to make fundamental advances in molecular parasitology and oncology specifically concerning mechanism of action aid improvedtherajoeutic aspects of easily prepared and relatively inexpensive new peroxides as antimalarial and anticancerdr jg candidates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI034885-17
Application #
7752591
Study Section
Special Emphasis Panel (ZRG1-DDR (01))
Program Officer
Rogers, Martin J
Project Start
1994-01-01
Project End
2010-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
17
Fiscal Year
2010
Total Cost
$422,039
Indirect Cost
Name
Johns Hopkins University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Fox, Jennifer M; Moynihan, James R; Mott, Bryan T et al. (2016) Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs. Oncotarget 7:7268-79
Conyers, Ryan C; Mazzone, Jennifer R; Tripathi, Abhai K et al. (2015) Antimalarial chemotherapy: orally curative artemisinin-derived trioxane dimer esters. Bioorg Med Chem Lett 25:245-8
Roy, Sujayita; He, Ran; Kapoor, Arun et al. (2015) Inhibition of human cytomegalovirus replication by artemisinins: effects mediated through cell cycle modulation. Antimicrob Agents Chemother 59:3870-9
Schultz, Tracey L; Hencken, Christopher P; Woodard, Lauren E et al. (2014) A thiazole derivative of artemisinin moderately reduces Toxoplasma gondii cyst burden in infected mice. J Parasitol 100:516-21
Conyers, Ryan C; Mazzone, Jennifer R; Siegler, Maxime A et al. (2014) The survival times of malaria-infected mice are prolonged more by several new two-carbon-linked artemisinin-derived dimer carbamates than by the trioxane antimalarial drug artemether. Bioorg Med Chem Lett 24:1285-9
Cai, Hongyi; Kapoor, Arun; He, Ran et al. (2014) In vitro combination of anti-cytomegalovirus compounds acting through different targets: role of the slope parameter and insights into mechanisms of Action. Antimicrob Agents Chemother 58:986-94
Mazzone, Jennifer R; Conyers, Ryan C; Tripathi, Abhai K et al. (2014) Antimalarial chemotherapy: artemisinin-derived dimer carbonates and thiocarbonates. Bioorg Med Chem Lett 24:2440-3
Mott, Bryan T; Tripathi, Abhai; Siegler, Maxime A et al. (2013) Synthesis and antimalarial efficacy of two-carbon-linked, artemisinin-derived trioxane dimers in combination with known antimalarial drugs. J Med Chem 56:2630-41
Mott, Bryan T; He, Ran; Chen, Xiaochun et al. (2013) Artemisinin-derived dimer phosphate esters as potent anti-cytomegalovirus (anti-CMV) and anti-cancer agents: a structure-activity study. Bioorg Med Chem 21:3702-7
He, Ran; Forman, Michael; Mott, Bryan T et al. (2013) Unique and highly selective anticytomegalovirus activities of artemisinin-derived dimer diphenyl phosphate stem from combination of dimer unit and a diphenyl phosphate moiety. Antimicrob Agents Chemother 57:4208-14

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