RESUMO
The structure-activity relationships and molecular modeling of the uracil nucleotide activated P2Y6 receptor have been studied. Uridine 5'-diphosphate (UDP) analogues bearing substitutions of the ribose moiety, the uracil ring, and the diphosphate group were synthesized and assayed for activity at the human P2Y6 receptor. The uracil ring was modified at the 4 position, with the synthesis of 4-substituted-thiouridine 5'-diphosphate analogues, as well as at positions 2, 3, and 5. The effect of modifications at the level of the phosphate chain was studied by preparing a cyclic 3',5'-diphosphate analogue, a 3'-diphosphate analogue, and several dinucleotide diphosphates. 5-Iodo-UDP 32 (EC50 = 0.15 microM) was equipotent to UDP, while substitutions of the 2'-hydroxyl (amino, azido) greatly reduce potency. The 2- and 4-thio analogues, 20 and 21, respectively, were also relatively potent in comparison to UDP. However, most other modifications greatly reduced potency. Molecular modeling indicates that the beta-phosphate of 5'-UDP and analogues is essential for the establishment of electrostatic interactions with two of the three conserved cationic residues of the receptor. Among 4-thioether derivatives, a 4-ethylthio analogue 23 displayed an EC50 of 0.28 microM, indicative of favorable interactions predicted for a small 4-alkylthio moiety with the aromatic ring of Y33 in TM1. The activity of analogue 19 in which the ribose was substituted with a 2-oxabicyclohexane ring in a rigid (S)-conformation (P = 126 degrees , 1'-exo) was consistent with molecular modeling. These results provide a better understanding of molecular recognition at the P2Y6 receptor and will be helpful in designing selective and potent P2Y6 receptor ligands.
Assuntos
Receptores Purinérgicos P2/efeitos dos fármacos , Difosfato de Uridina/análogos & derivados , Difosfato de Uridina/síntese química , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Agonistas do Receptor Purinérgico P2 , Estereoisomerismo , Relação Estrutura-Atividade , Difosfato de Uridina/farmacologiaRESUMO
Hitherto unknown restricted 3'-deoxy-3',4'-exo-methylene nucleoside derivatives bearing the nucleic acid naturally occurring pyrimidine bases have been synthesized. The compounds were tested for their activity against HIV, HBV, and several RNA viruses, but they did not show significant antiviral effect.
Assuntos
Antivirais/síntese química , Metano/análogos & derivados , Conformação de Ácido Nucleico , Nucleosídeos/síntese química , Fármacos Anti-HIV/farmacologia , Antivirais/farmacologia , HIV/metabolismo , Infecções por HIV/tratamento farmacológico , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/metabolismo , Hidrocarbonetos/síntese química , Hidrocarbonetos/química , Técnicas In Vitro , Metano/síntese química , Metano/química , Modelos Químicos , Nucleosídeos/química , Vírus de RNA/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
Hitherto unknown nucleoside analogues incorporating the five naturally occurring nucleic acid bases built on a 2-oxabicyclo[3.1.0]hexane template were synthesized. The synthesis of these new conformationally restricted nucleoside analogues involved the preparation of a suitable sugar precursor bearing the 2-oxabicyclo[3.1.0]hexane scaffold. This sugar was readily obtained from [(3aS,6aS)-2,2-dimethyl-3a,6a-dihydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether (4) following a Simons-Smith-type cyclopropanation reaction. Finally, glycosylation reactions and deprotection provided the nucleoside analogues. Using nucleoside 14 bearing thymine base as a model, we found that the conformation of such nucleoside analogue was restricted toward a (0)T(1) conformation.