RESUMO
5'-N-(alpha-Amino-beta-mercaptoacyl)amino-5'-deoxynucleosides have been synthesized by coupling of N-formylthiazolidines derived from D- and L-penicillamine, and D- and L-cysteine to 5'-amino-5'-deoxynucleosides using the DCC/HOSu method, followed by deprotection in N HCl in MeOH under argon. Although these compounds were designed as potential anti-HIV-1 agents, none of them showed anti-HIV-1 activity in MT-4 cells or antiviral effect against some other viruses, at concentrations below the cytotoxicity threshold.
Assuntos
Antivirais/síntese química , Desoxirribonucleosídeos/síntese química , Compostos de Sulfidrila/síntese química , Antivirais/farmacologia , Células Cultivadas , Efeito Citopatogênico Viral/efeitos dos fármacos , Desoxirribonucleosídeos/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Compostos de Sulfidrila/farmacologiaRESUMO
The synthesis of (6R,5S,2RS)-6-amino-5-hydroxy-2-isobutyl-4-oxo-7- phenylheptanoic acid (9), a carbaanalogue of the aminopeptidase (AP) inhibitor bestatin (1) is described. This synthesis was carried out by a malonic ester alkylation with the suitably protected halomethyl ketone of (2S,3R)-AHPBA*), followed by a second alkylation with isobutyl bromide of the resulting 4-ketodiester, and subsequent decarboxylation and deprotection. The inhibitory potencies of the 1:1 diastereomeric mixture 9 against AP-B, AP-M and Leu-AP were approximately 10-fold lower than those of bestatin.
Assuntos
Aminopeptidases/antagonistas & inibidores , Ácidos Heptanoicos/síntese química , Animais , Ácidos Heptanoicos/farmacologia , Técnicas In Vitro , Leucina/análogos & derivados , Leucina/farmacologia , SuínosRESUMO
5'-O-[N-(Aminoacyl or isobutyryl)sulfamoyl]uridines 4a-e, 5a-e and 5'-O-[N-(isopropyl)sulfamoyl]cytidines 7-9 have been synthesized and tested against herpes simplex virus type 2. Condensation of 2',3'-O-isopropylidene-5'-O-sulfamoyluridine with the N-hydroxysuccinimide esters of Boc-Gly, Boc-L-Ala, Boc-D-Ala and Boc-L-Phe, gave 4a-d which, on deprotection under acidic conditions, provided 5a-d. A similar condensation of 2',3'-di-O-acetyl-5'-O-sulfamoyluridine with the N-hydroxysuccinimide ester of isobutyric acid afforded 4e which on deacylation led to 5e. 5'-O-[N-(Isopropyl)sulfamoyl]-2',3'-O-isopropylidenecytidine (7) was prepared by reaction of 2',3'-O-isopropylidene-4-N-[(dimethylamino)methylene] cytidine with N-isopropylsulfamoyl chloride. Acidic hydrolysis of 7 provided 8 which, upon acetylation, gave the corresponding 2',3'-di-O-acetyl derivative 9. Compounds 7-9 show antiviral effect. Structure-activity relationships are discussed.