HDS Inhibition

The superior potency vs GSK-3 led to the exploration of effects on tau phosphorylation, both in a natural substrate kinase assay and in Sf9 cells. In the former, HD inhibited tau phosphorylation in a dose-dependent manner with an IC50 of 33 nM. In Sf9 cells expressing human tau23, HD was shown to inhibit tau phosphorylation at the ATS, ATIOO, AT180 and PHFl site [55]. However, since these sites are not restricted to GSK-3 phosphorylation and the fact that these experiments were done with a single very high dose (50 xM), a concentration at which HD inhibits several other kinases besides GSK-3, the physiological relevance of this observation, in the context of GSK-3 inhibition, needs to be validated. 

The results are shown in Figure 6. It can clearly be seen that 3-methylindole and 1,4-dimethylcarbazole are not major inhibitors, whereas acridine is. The three component blend behaves essentially as an additive combination of the three different N-compounds. There are also indications to the effect that acridine strongly inhibits the conversion of 1,4-dimethylcarbazole. In the absence of acridine, a high degree of conversion was obtained even for this low reactivity alkylcarbazole. The results indicate that alkylcarbazoles are not the major species of concern in HDS inhibition, even though they are the major species detected in hydrotreated diesel fuels. This suggests that there may be some components of diesel fuels that inhibit both HDN of alkylcarbazoles and HDS of alkyldibenzothiophenes. To see whether or not this is the case, additional studies were conducted on the N-free diesel fuel. 

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