Creek Darren J, Charman William N, Chiu Francis C K, Prankerd Richard J, McCullough Kevin J, Dong Yuxiang, Vennerstrom Jonathan L, Charman Susan A
Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
J Pharm Sci. 2007 Nov;96(11):2945-56. doi: 10.1002/jps.20958.
The iron-mediated reactivity of various dispiro-1,2,4-trioxolanes was determined by automated kinetic analysis under standard reaction conditions. The active antimalarial compounds underwent peroxide bond cleavage by Fe(II) resulting in products indicative of carbon-centered radical formation. The rate of reaction was heavily influenced by the presence of spiro-substituted adamantane and cyclohexane rings, and was also significantly affected by cyclohexane ring substitution. Steric hindrance around the peroxide oxygen atoms appeared to be the major determinant of reaction rate, however polar substituents also affected reactivity by an independent mechanism. A wide range of reaction rates was observed within this class of peroxide antimalarials, however iron-mediated reactivity did not directly correlate with in vitro antimalarial activity.
在标准反应条件下，通过自动动力学分析测定了各种双螺-1,2,4-三氧杂环戊烷的铁介导反应活性。活性抗疟化合物通过Fe(II)使过氧化物键断裂，生成表明形成碳中心自由基的产物。反应速率受螺取代金刚烷和环己烷环的存在的严重影响，也受到环己烷环取代的显著影响。过氧化物氧原子周围的空间位阻似乎是反应速率的主要决定因素，然而极性取代基也通过独立机制影响反应活性。在这类过氧化物抗疟药中观察到了广泛的反应速率范围，然而铁介导的反应活性与体外抗疟活性没有直接关联。
