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.
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