New drugs are urgently needed for safe and effective 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 and safety. This interdisciplinary research characterizes our program at Hopkins for practical preclincial development of new drug candidates for chemotherapy of malaria and cancer. We are partnering with industry to move one or two of our lead peroxides along the drug development path. Based on our good mechanistic and synthetic progress with anti-infective and anticancer peroxides like the natural trioxane artemlslnin and some of its dimers, we propose the following research goals for the next flve years:. 1.. To continue to design, prepare, and evaluate new, structurally simple, easily prepared, inexpensive, potent and safe dimeric synthetic endoperoxides; 2. To continue lead optimization in developing safe and selective new semi-synthetic trioxanes having both antimalarial and anticancer activities, starting with (a) dihydroartemisinin acetate (b) artemisinin-9-en-lO-aldehyde; 3. To continue exploring mechanism of antimalarial and anticancer action of our most promising peroxides. 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 and improved therapeutic aspects of easily prepared and relatively inexpensive new peroxides as antimalarial and anticancer drug candidates. Progress covering 2006-2009 on NIH R37-AI-34885 and plans for 2011-2015 are detailed on the following pages.
Development of safe and efficacious antimalarial and anticancer peroxide drugs for improving human health.
|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|
|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|
|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|
|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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