Inhibition of Cellobiohydrolases from Trichoderma reesei. Synthesis and Evaluation of Some Glucose-, Cellobiose-, and Cellotriose-Derived Hydroximolactams and Imidazoles
✍ Scribed by Stefan Vonhoff; Kathleen Piens; Muriel Pipelier; Christophe Braet; Marc Claeyssens; Andrea Vasella
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- German
- Weight
- 229 KB
- Volume
- 82
- Category
- Article
- ISSN
- 0018-019X
No coin nor oath required. For personal study only.
✦ Synopsis
The lactam 16, the hydroximolactams 8, 20, 23, and 27, and the imidazole 32 were prepared following known methods. They were tested together with the known tetrazole 35 and the hydroximolactams 2 and 36 as inhibitors of the cellobiohydrolases Cel7A and Cel6A from Trichoderma reesei. Cel7A is only weakly inhibited by these compounds. Comparing their inhibitory activity evidences the importance of occupying subsites 1 and 2. The results strongly suggest that the shape of none of the variants of the lactone-type inhibitor motif embodied by these inhibitors is complementary to the subsite À 1, i. e., analogous to the transition state. Cel6A 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 À 2 depends upon the shape of the moiety occupying subsite À 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 anti-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.
1 ) On a 20-g scale, the Dess-Martin oxidation proceeded in higher yields and more reproducibly than the Swern oxidation. 2 ) Oxidation of 11 with DMSO/Ac 2 O, pyridine ´SO 3 complex, or pyridinium chlorochromate ( PCC ) was incomplete. Swern oxidation gave a less polar product than 12 or 13, which was not isolated. Oxidation with Dess-Martin periodinane led a product with a higher R f value than 12 and 13.
13 with NaBH 4 in HCO 2 H [17] or with Et 3 SiH and BF 3 ´OEt 2 [13] was lower yielding and less diastereoselective 3 ). The d-glucono-and l-idonolactams 14 and 15 were separated by MPLC. Hydrogenolytic debenzylation of 14 in the presence of Pd(OH ) 2 yielded 69% of the cellobionolactam 16 4 ).
The d-gluco-and l-ido-configured hydroxylactams 12 and 13 are characterized by J (2,3) 6.7 and