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The synthesis of aminodeoxybestatin and epi-aminodeoxybestatin [(2S,3R)- and (2R,3R)-2,3-di-amino-4-phenylbutanoyl-L-leucine; (2S,3R)- and (2R,3R)-DAPBA-L-Leu)], bestatin and epi-bestatin analogues, respectively, in which the hydroxy group has been replaced with an amino group, is described by two different methods. The first one involves the synthesis of bis-(N-Z)-DAPBA, by homologation of N-Z-phenylalanine, via a modified Strecker synthesis followed by subsequent coupling with the methyl ester of L-leucine and removal of the protecting groups. Following this procedure, 25% racemization at the C-3 centre of the DAPBA derivatives took place during the homologation reaction. The second method involves the stereospecific SN2 nucleophilic substitution of the 2-hydroxy group of (2R,3R)- and (2S,3R)-3-(benzyloxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl-L-leucine methyl esters [(2R,3R)- and (2S,3R)-N-Z-AHPBA-L-Leu-OMe], and subsequent saponification, azido reduction and removal of the N-Z-protecting group. Replacement of the hydroxy group of bestatin and epi-bestatin with an amino group results in a decrease in their aminopeptidase (AP-B, AP-M and Leu-AP)-inhibitory potencies.

Nucleoamino acids, wherein D- and L-penicillamine and D-and L-cysteine are attached to uridine or thymidine through a carboxylic ester linkage, have been synthesized and evaluated as antivirals and aminopeptidase B (AP-B) inhibitors. The coupling of the α-amino-β-mercapto acids, N,S-protected as N-formylthiazolidines, to 2′,3′-O-isopropylideneuridine, 3′-O-acetylthymidine, 5′-O-tritylthymidine, and thymidine was achieved via the mixed anhydride formed from N,N-bis-(2-oxooxazolidin-3-yl)phosphorodiamidic chloride and the corresponding protected amino acid in the presence of 4-(dimethylamino)pyridine. Treatment of the protected compounds with 1 mol dm–3-HCl in refluxing MeOH, under argon, afforded the corresponding deprotected nucleoamino acids free of racemization. Neither the compounds herein described nor D-penicillamine showed anti-HIV-1 activity in MT-4 cells or antiviral activity against some other viruses at concentrations below the cytotoxicity threshold. Penicillamine and cysteine monoesters were equipotent with the corresponding free amino acid in inhibiting AP-B with an IC50 in the 10–4 mol dm–3 range, while the bis-(α-amino-β-mercaptoacyl)thymidine derivatives were approximately twice as potent as the monoesters.

Analogues of the potent anti-influenza A and B compound, 4-guanidino-Neu5Ac2en, are described in which the stereochemically demanding C-6-glycerol side-chain is truncated. Syntheses of the one- and two-carbon side-chain analogues, of both 4-guanidino- and 4-amino-Neu5Ac2en, are presented, as well as the syntheses of analogues lacking any side-chain. Whilst complete removal of the C-6 side-chain abolishes activity, a stepwise increase in inhibition of influenza neuraminidase and influenza A and B in cell culture with increasing C-6 chain length is observed. The one-carbon, hydroxymethyl derivative retains significant activity to represent a suitable lead in the search for neuraminidase inhibitors of reduced stereochemical demand and synthetic complexity.

Boron trifluoride-diethyl ether mediated addition of trimethylsilylcyanide (TMSCN) to the chiral acetals derived from Z-L- and Z-D-phenyl alaninal, (Z=N-benzyloxycarbonyl), and (+)-(2S,4S)- and (–)-(2R,4R)-2,4-pentanediol stereoselectively gave the four stereoisomers of the 3-amino-2-hydroxy-4-phenylbutanoic acid, key intermediates for bestatin and bestatin analogues.