Phosphonic‐Acid Analogues of the N‐Acetyl‐2‐deoxyneiiraniinic Acids: Synthesis and Inhibition of Vibrio cholerae Sialidase

Abstract

The phosphonic acids 3 and 4 were prepared to compare their inhibitory activity on Vibrio cholerae sialidase with the one of the corresponding N‐acetyl‐2‐deoxyneuraminic acids 5 and 6. Thus, hydrogenation and benzylation of methyl N‐acetyl‐2,3‐didehydro‐2‐deoxyneuraminate (1MeNeu2en5Ac; 7) gave a mixture of the fully O‐benzylated benzyl and methyl esters 9 and 10, the partially O‐benzylated benzyl and methyl esters 11 and 12, and the fully O‐and N‐benzylated benzyl and methyl esters 13 and 14 (Scheme 1). Transesterification of 9 to 10 and hydrolysis of 10 gave the acid 15. Oxidative decarboxylation of 15 with Pb(OAc)4 gave a 1:9 mixture of the α‐and β‐D‐glycero‐D‐galacto‐acetates 16 and 17. Phosphonoylation of 17 with P(OMe)3 and Me3SiOTf gave a 1.3:1 mixture of the phosphonates 18 and 19, which were deprotected to give the (4‐acetamido‐2,4‐dideoxy‐D‐glycero‐α‐and β‐D‐galacto‐octopyranosyl)phosphonic acids 3 and 4, respectively. The acid 6 was obtained by epimerization of the tert‐butyl ester 23 with lithium N‐cyclohexylisoproylamide and deprotection. The phosphonic acids 3 (Ki 5.5 10‐5 M) and 4 (Ki 2.3.10−4 M) are stronger inhibitors of Vibrio cholerae sialidase than the anomeric N‐acetyl‐2‐deoxyneuraminic acids 5(Ki 2.3 10−3 M) and 6. Both 3 and 4 inhibit the Vibrio cholerae sialidase, while only the carboxylic acid 5, possessing an equatorial COOH group is an inhibitor.

C‐Glykoside der N‐Acetylneuraminsäure. Synthese und Untersuchung ihrer Wirkung auf die Vibrio cholerae Sialidase

“…178,53, 175,37 20a) [7] 175,40, 173,21 22b) [7] 175,34, 175,20 05, 72,19, 70,04,68,30 73,15, 72,75, 70,21,68,68 78,19, 75,25, 71,66, 71,03,70,36 76,09, 73,92, 70,61, 69,99, 68,74 75,49,72,65, 70,18, 68,91 75,65,72,84, 70,09, 69,12 73,84,72,16, 69,22, 68,71 75,75, 74,09, 73,05, 70,44, 68,86 74,01, 72,39, 71,53, 68,61, 67,87 C (9) C ( …”

“…Der Vergleich mit den 2-Desoxy-Analogen 22 und 23 [7] zeigt, dass 8 ein schwacher Hemmer ist, wahrend fur 22 keine Hemm-Wirkung gefunden wird, und dass 15 um eine Grossenordnung schwacher hemmt als 23. Bemerkenswert ist die Wirkung der P-Aminosaure 9: anstelle einer Hemmung wird eine Aktivierung (ca.…”

“…Acetylierung fuhrt zum Verschwinden der OH-Signale, zur Tieffeldverschiebung der AcOCH,-Signale und zum Auftreten der CH,CO-Resonanzen bei 1,96 (11) und 1,42 1,50 2,17 2,39 2,20 2,23 2,46 2,49 2,56 2,51 2,51 2,63 2,63 2, 12 3,98-3,89 4,14 4,20 3,65 3,60 3,77 337 3,65 4,05-3,96 3,56 3,9O-3,79 3,52 3,22 3,32 3,81 3,82 3,65 39-3,77 3,7? 3,26 4,13 3,90-3,79 3,98-3,89 4,32 4,3 1 4,32 4,25 4,30 4,2 1 4,34 4,5 1 4,39 4,16 3,77 3,98-3,89 3,82 4,05 3,78 3,96 3,78 3,97 3,74 3,97 3,73 3,98 3,71 39-3,17 3,72 4,O 1 3,69-3,65 4,05-3,96 3,69 4,09 4,47 3,90-3,79 H-C(9) H-C(9) CH,(l') NH 5d) [7] 3,65 3,90-3,79 3,61, 3,49 6,OO ") CDCI,. b)CDC13/D20. '…”

Chemistry, biochemistry and biology of sialic acids

“…[344]). Furthermore, variants of 2d-2Ha-NeuSAc and 2d-2He,-NeuSAc, in which the carboxyl function has been replaced by a phosphono (PO3H2) group [449], and a phosphonic acid analogue of Neu2en5Ac [450], have been synthesized. Table 12 Survey of radiolabelled sialic acidsa Several interesting sialic acid variants and sialic acid derivatives have been synthesized, and a list is presented in Table .…”

Synthesis of Glycosylphosphine Oxides and Related Compounds

“…3 and Tables 3 and 4 ) . The P-B bond length is not significantly different to that observed in triphenylphosphine borane (1.93(1) and 1.90(2) A) [SOa] and trimethylphosphine borane (1.901 (7) A) [50b]. The pyranose ring adopts a slightly flattened 4C, conformation (Table 5 ) , which differs from the solution conformation, for which NMR spectra suggest a &, quite similar to the conformation of the corresponding phosphine sulfide 19.…”