RESUMO
A group of arabinouridines (TMSEAU, EAU, IEAU-TA) and 2'-deoxyuridines (TMSEDU, EDU, IEDU) having a variety of substituents at the uracil C-5 position (trimethylsilylethynyl, TMSE; ethynyl, E; or iodoethynyl, IE), and the sugar C-2' position (2'-arabino OH in arabinouridine, AU; or 2'-deoxyribo H in 2'-deoxyuridine, DU) were prepared to acquire antiviral structure-activity relationships. A broad-spectrum viral panel screen showed that these 5-alkynylarabino/deoxy-uridines exhibit moderate anti-HSV-1 activity, with no difference in potency between arabinouridines and 2'-deoxyuridines. The 2'-deoxyuridines TMSEDU, EDU, and IEDU, unlike the arabinouridines, exhibited potent antiviral activity against cytomegalovirus, but they were also highly cytostatic. The abilities of the 5-alkynylarabino/deoxy-uridines to inhibit nontransfected (wild-type or thymidine kinase-deficient, tk-) and viral gene transfected (HSV-1, HSV-2, or VZV thymidine kinase-positive, tk+) FM3A and OST (osteosarcoma) cells were determined. This group of 5-alkynylarabino/deoxy-uridines showed an enhanced ability to inhibit cells transfected with a viral thymidine kinase gene (HSV-1tk+, HSV-2tk+, VZVtk+) relative to wild-type or thymidine kinase-deficient (tk-) cells.
Assuntos
Alcinos/síntese química , Antivirais/síntese química , Herpesvirus Humano 3/enzimologia , Simplexvirus/enzimologia , Timidina Quinase/genética , Uridina/análogos & derivados , Uridina/síntese química , Alcinos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Desoxiuridina/análogos & derivados , Desoxiuridina/síntese química , Desoxiuridina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Herpesvirus Humano 3/efeitos dos fármacos , Humanos , Camundongos , Simplexvirus/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Timidina Quinase/biossíntese , Transfecção , Uridina/farmacologiaRESUMO
The solution-phase parallel synthesis of tethered dimers was employed to identify lead inhibitors of bacterial NAD synthetase. Active dimers contained two aromatic end groups joined by a polymethylene linker, with one end group containing a permanent positive charge. Effective inhibitors of NAD synthetase also inhibited the growth of Gram-positive (but not Gram-negative) bacteria, including antibiotic-resistant strains. The desmethyl precursors of active inhibitors lacked a permanent positive charge and were inactive as either enzyme inhibitors or antibacterial agents. Similarly, a close structural analogue of the most active inhibitors contained two additional ether oxygens in the tether and was inactive in both assays. These results are consistent with the premise that NAD synthetase inhibition is responsible for the antibacterial actions and support further studies on NAD synthetase as a new target for antibacterial agents.