Polycyclic cage compounds as carrier molecules for neuroprotective non-steroidal anti-inflammatory drugs
Prins, Louis Hendrik Albertus
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The blood brain barrier is formed by the brain capillary endothelium and plays the predominant role in controlling the passage of substances between the blood and the brain. For a compound with low blood-brain barrier permeability to be able to cross this barrier, certain physicochemical characteristics thereof need to be altered. Recent studies on polycyclic structures, pentacyclo[220.127.116.11 2,6.0 2,10.0 5,9]undecane and amantadine, indicate favorable distribution thereof to the brain and it was concluded that these polycyclic structures and their derivatives penetrate the blood-brain barrier readily. Neuroprotection can be afforded by a variety of mechanisms, including the inhibition of oxidative stress. The neuroprotective activity of certain non-steroidal anti-inflammatory drugs (NSAIDs) can be attributed to their antioxidant properties. Acetylsalicylic acid and ibuprofen used in this study, are both weak organic acids with low blood-brain barrier permeation. No known transport mechanisms are present at the blood-brain barrier that are able to transport these drugs into the central nervous system (CNS). If these drugs could be delivered into the brain, they would demonstrate potent neuroprotective activity as a result of their anti-inflammatory and antioxidant properties. It was therefore hypothesised that the polycyclic cage compounds described above could be used as carrier molecules to deliver neuroprotective drugs into the CNS and the aim of this study was to design novel polycyclic structures incorporating selected NSAIDs in order to improve their blood-brain barrier permeability. The well-described Cookson’s diketone, pentacyclo[18.104.22.168 2,6.0 2,10.0 5,9]undecane-8, 11-dione, was reacted with 3-aminopropanol to obtain the rearranged oxazinane cage structure. Acetylsalicylic acid and ibuprofen were subsequently conjugated to this cage structure by esterification, yielding the respective ester prodrugs. Amine prodrugs were synthesised by conjugating the NSAIDs to amantadine. The structures were confirmed by 1H and 13C NMR, MS and IR. An in vivo blood-brain barrier permeability assay employing HPLC and LC-MS/MS analytical procedures was used to compare brain and blood concentrations of the relevant drugs 1 hour after administration to male C57BL/6 mice. The antioxidant activities of the compounds were assessed with an in vitro lipid peroxidation assay. Both NSAIDs were detected in the brain tissue of the test mice after administering the synthesised prodrugs, indicating blood-brain barrier permeation. The ester prodrugs were found to be very labile and significant amounts of it were hydrolysed within the 1 hour time period. This was evident as neither of the intact ester prodrugs was detected in quantifiable amounts 1 hour after administration to the test mice. When administering these ester prodrugs (compound 22 and 23), the free NSAIDs were detected at higher concentrations compared to when the free drugs were administered. The amide prodrugs (compounds 25 and 26), exhibited lower free drug concentrations than that obtained after the NSAIDs were administered on their own. This observation could be attributed to incomplete hydrolysis of the amide bond at 1 hour after administration and might also explain the lower brain concentration of the free drug observed for both prodrugs. However, the novel prodrugs synthesised exhibited favorable blood-brain barrier penetration, and the more efficient delivery of the drug to the brain would afford higher concentrations of the neuroprotectant and thus better neuroprotection. Lipid peroxidation results indicated that the ester and amide prodrugs, significantly increased the ability of free drugs to attenuate lipid peroxidation. This was aspecailly true for compounds 22 and 26, with 22 being in the range of the model antioxidant, Trolox. The novel prodrugs therefore present with a multiple drug targeting action as the blood-brain barrier permeability and the antioxidant activity of the free NSAIDs were increased.
- Health Sciences