Synthesis, α-mannosidase inhibition studies and molecular modeling of 1,4-imino-á´
-lyxitols and their C-5-altered N-arylalkyl derivatives.
Beilstein J Org Chem
; 19: 282-293, 2023.
Article
em En
| MEDLINE
| ID: mdl-36925565
ABSTRACT
A synthesis of 1,4-imino-á´
-lyxitols and their N-arylalkyl derivatives altered at C-5 is reported. Their inhibitory activity and selectivity toward four GH38 α-mannosidases (two Golgi types GMIIb from Drosophila melanogaster and AMAN-2 from Caenorhabditis elegans, and two lysosomal types LManII from Drosophila melanogaster and JBMan from Canavalia ensiformis) were investigated. 6-Deoxy-DIM was found to be the most potent inhibitor of AMAN-2 (K i = 0.19 µM), whose amino acid sequence and 3D structure of the active site are almost identical to the human α-mannosidase II (GMII). Although 6-deoxy-DIM was 3.5 times more potent toward AMAN-2 than DIM, their selectivity profiles were almost the same. N-Arylalkylation of 6-deoxy-DIM resulted only in a partial improvement as the selectivity was enhanced at the expense of potency. Structural and physicochemical properties of the corresponding inhibitorenzyme complexes were analyzed by molecular modeling.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Beilstein J Org Chem
Ano de publicação:
2023
Tipo de documento:
Article