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Synthesis of New Sialidase Inhibitors, 6‐Amino‐6‐Deoxysialic Acids
Author(s) -
Baumberger Franz,
Vasella Andrea,
Schauer Roland
Publication year - 1988
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19880710216
Subject(s) - chemistry , sialidase , azide , stereochemistry , mitsunobu reaction , sialic acid , ether , diol , reagent , ozonolysis , enzyme , biochemistry , neuraminidase , organic chemistry
The synthesis of the 6‐amino‐6‐deoxysialic‐acid analogues 4, 5 , and 6 , is described. Mitsunobu reaction of the 1‐ C ‐nitroglycal 8 , (PPh 3 , HCOOH, DEAD) gave the formiate 10 with inversion of configuration at C(3) ( Scheme 2 ). Treatment of 10 with aq. NH 3 and subsequent protection of the amino function gave the imines 14 and 15 ( Scheme 3 ), which were transformed into the triflates 17 . Substitution by azide, deprotection, and N ‐acetylation gave the anormeric 2‐acetamido‐3‐azido‐1‐deoxy‐1‐nitro‐ D ‐mannoses 16 and the enol ether 18 . Chain elongation of the nitro azides 16 followed by hydroylsis gave the nonulosonates 20/22 , which upon reduction yielded the diols 23 and 24 , respectively ( Scheme 4 ). The diol 23 was transformed into the sialic‐acid analogues 5, 6 , and 32 by ozonolysis, transfer hydrogenation, hydorgenolysis, and deprotection ( Scheme 5 ), and the diol 24 into 4 by a similar reaction sequence. The sialic‐acid analogues 4 and 6 inhibit bacterial and viral sialidases competitively. The inbibitor constants for this enzyme from Vibrio cholerae are 0.12 mm for 4 and 0.19 mm for 6 , respectively. The activity of fowl plague virus sialidase was reduced by 17% and 36% under the influence of 4 and 6 , respectively, at a concentration of 0.1 m M . Compound 5 was inactive.