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1 2007

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Chemiczno-enzymatyczna strategia konstrukcji proleków nukleozydowych

Kaczmarek R., Kulik K., Baraniak J.

Wiadomości Chemiczne

2007

[Z] 61, 5-6

417-443

Several nucleoside analogues have found successful application as antiviral and anticancer agents. Their mode of action differs, but in the most general terms they have been developed as inhibitors or competitors of natural 2'-deoxynucleosides in the process of their conversion to the corresponding nucleoside-5'-triphosphates. As such, they can be incorporated into a growing viral DNA strand by a DNA polymerase resulting in chain termination. In cancer therapy, modified nucleosides, after being phosphorylated to the corresponding monophosphates, block DNA biosynthesis by deactivating nucleoside syntheses. Hence biological activity of nucleoside analogues in most cases depends on the intracellular phosphorylation by viral and/or cellular kinases to their respective mono-, di-, and triphosphate derivatives. Among the three successive activating phosphorylation steps the first one has fundamental importance as the rate-limiting step. Several different enzymes can perform this initial phosphorylation, depending on the nature of the aglycone. Also, the presence and activity of the intracellular enzymes necessary for the activation of nucleoside analogues are highly dependent on the host species, the cell type, and the stage in the cell cycle. Moreover, in many cases, nucleoside analogues are poor substrates for the cellular kinases needed for their activation. For all these reasons, intracellular nucleoside monophosphate (NMP) delivery has been considered for overcoming the first phosphorylation step. Unfortunately, NMPs themselves cannot be used as potential chemotherapeutic agents. Owing to their high polarity, these compounds are not able to penetrate cellular membrane or the blood-brain barrier easily. Therefore, in order to reduce the phosphate negative charge and enable the modified nucleotide to enter the cell, many nucleotides modified on the phos-phate moiety by so-called masking group have been synthesized. A suitable nucleotide prodrug (so-called pronucleotide) has to fulfill two requirements: i) it has to be lipophilic enough for passive diffusion of the membrane and the blood-brain barrier; ii) it should be able to deliver the nucleoside by chemical or enzymatic hydrolysis leaving a non-toxic masking group. Many strategies using various protecting groups for the phosphate moiety have been deve-loped to achieve this goal. The majority of strategies for unmasking pronucleotides that have been examined to date have involved substrate-nonspecific enzymes to remove one or more groups that are attached to the 5'MP moiety. Carboxylesterases (CEs) have attracted considerable attention, since they include bis(pivaloyloxymethyl) [(bis(POM)] and S-acyl-2-thioethyl (SATE) moieties which are initially unmasked by CE-mediated cleavage. A combination of aryl ester and amino acid phosphoramidate groups as a particular class of enzyme-labile protecting groups was developed for the delivery of antiviral nucleoside prodrugs. An endogenous phosphoramidase was responsible and necessary for the biological activity of those compounds in living cells. On the other side almost all approaches based on chemical hydrolysis reported so far were unable to deliver the nucleotide selectively exept the cycloSal approach. This review will predominantly concentrate on the different approaches to the design of nucleotide prodrugs. Keywords: prodrug, pronucleotide, nucleoside analogues, antiviral activity, anticancer acti-vity, masking groups.