Peroxides for Chemotherapy of Malaria and Cancer

描述（申请人提供）：迫切需要新药，用于疟疾、癌症等广泛存在的人类疾病的有效、无毒的化疗。我们将化学见解和合成技能与体外生物测试相结合，然后，对于最有前途的新化学实体，在体内建立疗效和安全性。这项跨学科研究是我们在霍普金斯大学为疟疾和癌症化疗的新候选药物的实际临床前开发项目的特点。基于我们在抗感染和抗癌过氧化物（如天然三氧环青蒿素及其部分晚餐物）的机理和合成方面取得的良好进展，我们提出了未来5年的五大研究目标：(1)设计、制备和评价结构简单、制备方便、价格低廉、有效且安全的新型内过氧化物(a)单体合成内过氧化物；(b)二聚体合成过氧化物(2)设计、制备和评价从(a)醋酸双氢青蒿素制备的新的、有效的和安全的半合成二聚体；(b)从青蒿素-9-烯-10-醛(3)确定我们最有希望的二聚体内过氧化物和三氧烷的分子作用机制。作为合成和药物化学家，我们在分子寄生虫学和肿瘤学方面具有独特的地位，特别是在容易制备且相对便宜的新型过氧化物作为抗疟疾和抗癌候选药物的作用机制方面取得了根本性的进展。

DESCRIPTION (provided by applicant): 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 and safety. This interdisciplinary research characterizes our program at Hopkins for practical preclincial development of new drug candidates for chemotherapy of malaria and cancer. Based on our good mechanistic and synthetic progress with anti-infective and anticancer peroxides like the natural trioxane artemisinin and some of its dinners, we propose the following five research goals for the next five years: (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 prepared (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 improved therapeutic aspects of easily prepared and relatively inexpensive new peroxides as antimalarial and anticancer drug candidates.