are systems which allow the delivery of the nucleoside monophosphate into cells.
Due to the high polarity of nucleotides at physiological pH-value, these compounds are unable to penetrate the hydrophobic/lipophilic cell membrane. A number of prodrug systems have been
developed in order to mask the two negative charges of the phosphate group. Inside the cell the lipophilic
mask should be cleaved by chemical or enzymatical means. The cyclo
developed by us uses salicylalcohol derivatives as lipophilic mask (Figure 1).,
Figure 1: Synthesis of cyclo
Due to the non-stereoselective
synthesis routes A or B (Figure 1), the available cyclo
Sal-prodrugs are always obtained as mixtures of two
diastereomers because of the newly formed chiral center at the phosphorus atom.
The two diastereomers have different chemical and physical properties and
possess different biological activity. In one particular case it was found that
-isomer of 3-Methyl-cyclo
-Sal-d4TMP has a
10-fold higher activity than the SP
Figure 2: (RP
diastereomers can be separated chromatographically. However, this approach often
fails. For this reason we are developing a diastereoselective synthesis route
to yield diastereomerically pure cycloSal-prodrugs.
One synthetical approach is based on the use of the chiral auxiliary 7, which causes an asymmetric induction
at the phosphorus atom that leads to the preferred formation of the
diastereomer (RP)-8. The following conversion of the
diastereomer yields the diastereomerically pure cycloSal-prodrug (SP)-9 (Figure 3).
approach affords the synthesis not only of the (SP
)- but also of the (RP
Sal-prodrug. The chloridate rac
reacts with the chiral auxiliary under the formation of the diastereomers (SP
. After the column chromatography of
the diastereomers, each individual reaction with the nucleoside analog leads to
the diastereomerically pure cyclo
prodrug compound (Figure 4).
Figure 4: Diastereospecific synthesis of
diastereomerically pure cyclo
- C. Meier, cycloSal Phosphates as Chemical Trojan
Horses for Intracellular Nucleotide and Glycosylmonophosphate
Delivery-Chemistry Meets Biology, Eur. J.
Org. Chem. 2006, 5, 1081-1102.
- C. Meier, M. Ruppel, D. Vukadinovic, J. Balzarini,
„Lock-in“-cycloSal-Pronucleotides- A New Generation of Chemical Trojan
Horses?, Mini Rev. Med. Chem. 2004, 4, 383-394.
- C. Meier, cycloSal-Pronucleotides-Design of the
Concept, Chemistry, and Antiviral Activity, Advances
in Antiviral Drug Design 2004,
- a) E. H. Rios Morales, C. Arbelo Román, J. O. Thomann, C. Meier, Linear Synthesis of Chiral cycloSal-Pronucleotides, Eur. J. Org. Chem. 2011, 4397-4408. b) E. H. Rios Morales, J. Balzarini, C. Meier, Diastereoselective Synthesis of cycloSaligenyl-Nucleosyl-Phosphotriesters, Chem. Eur. J. 2011, 17, 1649-1659
- E. H. Rios Morales, J. Balzarini, C. Meier, Stereoselective Synthesis and Antiviral Activity of Methyl-Substituted cycloSal-Pronucleotides, J. Med. Chem. 2012, 55, 7245-7252.