RESUMEN
A novel concept of nonhydrolytic enzyme sensing based on aggregation-induced emission is described. As a proof of principle, fluorogenic probes for methionine sulfoxide reductases have been developed. Changes in the polarity and electronic nature upon reduction of sulfoxide to sulfide are translated to the aggregation potential of the probe. The new probes enable sensitive and highly spatially resolved imaging of the enzymatic activity.
Asunto(s)
Metionina Sulfóxido Reductasas , Sulfóxidos , Metionina/metabolismo , Metionina Sulfóxido Reductasas/metabolismo , Oxidación-Reducción , Estereoisomerismo , SulfurosRESUMEN
Three series of isomeric pyrrolo- and furo-fused 7-deazapurine ribonucleosides were synthesized and screened for cytostatic and antiviral activity. The synthesis was based on heterocyclizations of hetaryl-azidopyrimidines to form the tricyclic heterocyclic bases, followed by glycosylation and final derivatizations through cross-coupling reactions or nucleophilic substitutions. The pyrrolo[2',3':4,5]pyrrolo[2,3- d]pyrimidine and furo[2',3':4,5]pyrrolo[2,3- d]pyrimidine ribonucleosides were found to be potent cytostatics, whereas the isomeric pyrrolo[3',2',4,5]pyrrolo[2,3- d]pyrimidine nucleosides were inactive. The most active were the methyl, methoxy, and methylsulfanyl derivatives exerting submicromolar cytostatic effects and good selectivity toward cancer cells. We have shown that the nucleosides are activated by intracellular phosphorylation and the nucleotides get incorporated to both RNA and DNA, where they cause DNA damage. They represent a new type of promising candidates for preclinical development toward antitumor agents.
