Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
J Med Chem. 2010 Nov 25;53(22):8202-6. doi: 10.1021/jm1009567. Epub 2010 Oct 27.
We extend our approach of combination chemotherapy through a single prodrug entity (O'Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonyl-masking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target "heme", we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.
我们通过使用 1,2,4-三恶烷作为蛋白酶抑制剂羰基掩蔽基团，扩展了我们的组合化疗单一前药实体方法（O'Neill 等人，Angew. Chem., Int. Ed. 2004, 43, 4193）。这些分子旨在通过两种独立的作用机制靶向疟原虫：铁(II)分解释放羰基蛋白酶抑制剂和潜在细胞毒性的 C-自由基。使用拟议的靶标“血红素”，我们还证明了血红素烷基化/羰基抑制剂释放，并定量测量了寄生虫红细胞中环氧化物的周转率。
