Neu5Ac2en, analogues

The synthesis of C-5-substituted Neu5Ac2en analogues has been approached both from the saturated analogues [172] and by de-N-acetylation of Neu5Ac2en (148) with hydrazine [184] or by hydrogenolytic cleavage of Neu5CBz2en (156)... 

Scheme 12 Completion of the synthesis of zanamivir and 2,3-unsaturated sialic acid (Neu5Ac2en) analogues. Reagents and conditions a) Me3SiN3 (1.5 equiv), t-BuOH, 90 °C, 13 h 96% b) i) ln(0) (2 equiv), NH4CI, EtOH, 80 °C, 12 h ii) LiOH, THE, rt, 2 h 90% for the 2 steps c) aminoiminomethanesulfonic acid, K2CO3, water, 77% d) LiOH (2 equiv), THE, rt, 2 h 90%.

Andrews DM, Cherry PC, Humber DC, Jones PS, Keeling SP, Martin PE, Shaw CD, Swanson S (1999) Synthesis and influenza virus siahdase inhibitory activity of analogues of 4-guanidino-Neu5Ac2en (Zanamivir) modified in the glycerol side-chain. Eur J Med Chem 34 563-574... 

A series of fourteen 4-triazole-modified Zanamivir analogues were synthesized from the 4-azido-4-deoxy-Neu5Ac2en derivative using click chemistry, and their inhibitory potencies against influenza virus sialidase were determined. These modifications were not that successful as 33-35 demonstrated only 6-40% protective rate at a concentration of 50 pM against the virus infection compared to Zanamivir which shows 86% at the same concentration. The best result was obtained for compound 36, which showed a protective rate of >61%.76... 

Fig. 10. Analogues of 4-amino-4-deoxy-Neu5Ac2en (9) and 4-deoxy-4-guanidino-Neu5Ac2en (1) modified by removal of C-9 through C-7. IC50 values for 85-90 against isolated influenza A virus sialidase are given in parentheses.

A number of C-6 carboxamide analogues were prepared in which the stereo-chemically complex glycerol side-chain of Zanamivir or 4-amino-4-deoxy-Neu5Ac2en was replaced entirely by secondary or tertiary amides with the general structure of 94 or 95.95,96 These series of compounds were prepared from the C-6 carboxylate 92 (prepared by periodate oxidation of the glycerol side-chain of 91) by amide couling via the activated pentafluorophenyl ester 93 (Scheme 3). 

Chandler, M. et al. Approaches to Carbocyclic Analogues of the Potent Neuraminidase Inhibitor 4-Guanidino-Neu5Ac2en. X-Ray Molecular Structure of N-[(/ S,2S, 6R)-2-azido-6-benzyloxy-methyl-4-formylcyclohex-3-enyl]acetamide. 3.4.1 1995 [112]... 

Vorwerk, S. et al. Carbocyclic Analogues oj H-Acetyl-2,3-didehydro-2-deoxy-D-Neuraminic Acid (Neu5Ac2en, DANA) Synthesis and Inhibition of Viral and Bacterial Neuraminidase. 3.4.4 1998 [187]... 

The discovery, in the early 1990s, that zanamivir was a potent and selective inhibitor of influenza virus sialidase prompted several researchers to investigate the synthesis of Neu5Ac2en based analogues of zanamivir. Much of this effort was a consequence of the fact that zanamivir (12) must be administered as a nasal spray, due to its poor oral bioavailability and rapid excretion [101,102], and the desire to identify new sialidase inhibitors with modified physicochemical properties. Several researchers have described structure-activity relationship studies based on zanamivir (vide infra), with most modifications reported at C-4, C-5, and the glycerol side-chain. 

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