SYNTHESIS OF PENICILLAMINE-CONTAINING AND CYSTEINE-CONTAINING NUCLEOAMINO ACIDS AS POTENTIAL ANTIVIRALS AND AMINOPEPTIDASE-B INHIBITORS

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 alpha-amino-beta-mercapto acids, N,S-protected as N-formylthiazolidines, to 2',3'-O-isopropylideneuridine, 3'-O-acetylthymidine, 5'-O-tritylthy-midine, 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-(alpha-amino-beta-mercaptoacyl)thymidine derivatives were approximately twice as potent as the monoesters.