Fontaine Shaun D, Spangler Benjamin, Gut Jiri, Lauterwasser Erica M W, Rosenthal Philip J, Renslo Adam R
Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th Street, San Francisco, CA 94158 (USA).
ChemMedChem. 2015 Jan;10(1):47-51. doi: 10.1002/cmdc.201402362. Epub 2014 Oct 14.
Antimalarial agents artemisinin and arterolane act via initial reduction of a peroxide bond in a process likely mediated by ferrous iron sources in the parasite. Here, we report the synthesis and antiplasmodial activity of arterolane-like 1,2,4-trioxolanes specifically designed to release a tethered drug species within the malaria parasite. Compared with our earlier drug delivery scaffolds, these new arterolane-inspired systems are of significantly decreased molecular weight and possess superior metabolic stability. We describe an efficient, concise and scalable synthesis of the new systems, and demonstrate the use of the aminonucleoside antibiotic puromycin as a chemo/biomarker to validate successful drug release in live Plasmodium falciparum parasites. Together, the improved drug-like properties, more efficient synthesis, and proof of concept using puromycin, suggests these new molecules as improved vehicles for targeted drug delivery to the malaria parasite.
抗疟药物青蒿素和蒿甲醚通过寄生虫中可能由亚铁源介导的过程首先还原过氧化物键来发挥作用。在此，我们报告了专门设计用于在疟原虫内释放连接药物物种的蒿甲醚样1,2,4-三氧杂环戊烷的合成及其抗疟原虫活性。与我们早期的药物递送支架相比，这些受蒿甲醚启发的新系统分子量显著降低且具有优异的代谢稳定性。我们描述了新系统的高效、简洁且可扩展的合成方法，并证明使用氨基核苷抗生素嘌呤霉素作为化学/生物标志物来验证在活的恶性疟原虫中药物的成功释放。综合起来，这些新分子具有改善的类药物性质、更高效的合成方法以及使用嘌呤霉素的概念验证，表明它们是用于向疟原虫进行靶向药物递送的改进载体。
