Inhibition of Cellobiohydrolases from Trichoderma reesei. Synthesis and Evaluation of Some Glucose-, Cellobiose-, and Cellotriose-Derived Hydroximolactams and Imidazoles

摘要

The lactam 16,the hydroximolactams 8, 20, 23, and 27, and the imidazole 32 were prepared following known metods. They were tested together with the known tetrazole 35 and hydroximolactams 2 and 36 as inhibitors of the cellobiohydrolases Ce 17A and Ce16A from Trichoderma reesei. Ce17A is only wekly inhibited by these compounds. Comparing their inhibitory activity evidences the importance of occupying subsites +1 and +2. The results stronly suggest that the shape of none of the variants of the lactone-type inhibitor motif embodied by these inhibitors is complementary to the subsite-1,i.e., analogous to the transition state. Ce16A is rather strongly inhibited by the cellobiose analogues 20,23,and 32, and by the cellotriose analogue 27. Their relative inhibitory activities evidence that binding at subsite-2 depends upon the shape of the moiety occupying subsite-1. There is only a small difference between the inhibition by the hydroximolactams 20 and 23, which may be (partially) protonated by the catalytic acid of either anto-or syn-protonating glycosidases,and the imidazole 32, which can only be protonated by anti-protonating glycosidases. The results strongly suggest that shape requirements must be met by glycosidase inhibitors before they can be used to characterize the proton trajectory of glycosidases.