Stereoselective synthesis of D- and L-carbocyclic nucleosides by enzymatically catalyzed kinetic resolution.
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Stereoselective synthesis of D- and L-carbocyclic nucleosides by enzymatically catalyzed kinetic resolution. / Mahler, Miriam; Reichardt, Bastian; Hartjen, Philip; van Lunzen, Jan; Meier, Chris.
in: CHEM-EUR J, Jahrgang 18, Nr. 35, 35, 2012, S. 11046-11062.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Stereoselective synthesis of D- and L-carbocyclic nucleosides by enzymatically catalyzed kinetic resolution.
AU - Mahler, Miriam
AU - Reichardt, Bastian
AU - Hartjen, Philip
AU - van Lunzen, Jan
AU - Meier, Chris
PY - 2012
Y1 - 2012
N2 - An efficient synthesis of (S)- or (R)-3-(benzyloxy-methyl)-cyclopent-3-enol was developed by appling an enzyme-catalyzed kinetic-resolution approach. This procedure allowed the syntheses of the enantiomeric building blocks (S)- and (R)-cyclopentenol with high optical purity (>98 % ee). In contrast to previous approaches, the key advantage of this procedure is that the resolution is done on the level of enantiomers that only contain one stereogenic center. Owing to this feature, it was possible to chemically convert the enantiomers into each other. By using this route, the starting materials for the syntheses of carbocyclic D- and L-nucleoside analogues were readily accessible. 3',4'-Unsaturated D- or L-carbocyclic nucleosides were obtained from the condensation of various nucleobases with (S)- or (R)-cyclopentenol. Functionalization of the double bond in 3'-deoxy-3',4'-didehydro-carba-D-thymidine led to a variety of new nucleoside analogues. By using the cycloSal approach, their corresponding phosphorylated metabolites were readily accessable. Moreover, a new synthetic route to carbocyclic 2'-deoxy-nucleosides was developed, thereby leading to D- and L-carba-dT. D-Carba-dT was tested for antiviral activity against multidrug-resistance HIV-1 strain E2-2 and compared to the known antiviral agent d4T, as well as L-carba-dT. Whilst L-carba-dT was found to be inactive, its D-analogue showed remarkably high activity against the resistant virus and significantly better than that of d4T. However, against the wild-type virus strain NL4/3, d4T was found to be more-active than D-carba-dT.
AB - An efficient synthesis of (S)- or (R)-3-(benzyloxy-methyl)-cyclopent-3-enol was developed by appling an enzyme-catalyzed kinetic-resolution approach. This procedure allowed the syntheses of the enantiomeric building blocks (S)- and (R)-cyclopentenol with high optical purity (>98 % ee). In contrast to previous approaches, the key advantage of this procedure is that the resolution is done on the level of enantiomers that only contain one stereogenic center. Owing to this feature, it was possible to chemically convert the enantiomers into each other. By using this route, the starting materials for the syntheses of carbocyclic D- and L-nucleoside analogues were readily accessible. 3',4'-Unsaturated D- or L-carbocyclic nucleosides were obtained from the condensation of various nucleobases with (S)- or (R)-cyclopentenol. Functionalization of the double bond in 3'-deoxy-3',4'-didehydro-carba-D-thymidine led to a variety of new nucleoside analogues. By using the cycloSal approach, their corresponding phosphorylated metabolites were readily accessable. Moreover, a new synthetic route to carbocyclic 2'-deoxy-nucleosides was developed, thereby leading to D- and L-carba-dT. D-Carba-dT was tested for antiviral activity against multidrug-resistance HIV-1 strain E2-2 and compared to the known antiviral agent d4T, as well as L-carba-dT. Whilst L-carba-dT was found to be inactive, its D-analogue showed remarkably high activity against the resistant virus and significantly better than that of d4T. However, against the wild-type virus strain NL4/3, d4T was found to be more-active than D-carba-dT.
KW - Humans
KW - Kinetics
KW - Cell Line
KW - Drug Resistance, Multiple, Viral
KW - Cell Survival/drug effects
KW - Stereoisomerism
KW - Inhibitory Concentration 50
KW - Virus Replication/drug effects
KW - Anti-HIV Agents/chemical synthesis/pharmacology
KW - Catalysis
KW - Cyclization
KW - Cyclopentanes/chemical synthesis/pharmacology
KW - HIV Reverse Transcriptase/antagonists & inhibitors/chemistry
KW - HIV-1/drug effects
KW - Nucleosides/chemical synthesis/pharmacology
KW - Pancreatin/chemistry/metabolism
KW - Reverse Transcriptase Inhibitors/chemical synthesis/pharmacology
KW - Stavudine/pharmacology
KW - Humans
KW - Kinetics
KW - Cell Line
KW - Drug Resistance, Multiple, Viral
KW - Cell Survival/drug effects
KW - Stereoisomerism
KW - Inhibitory Concentration 50
KW - Virus Replication/drug effects
KW - Anti-HIV Agents/chemical synthesis/pharmacology
KW - Catalysis
KW - Cyclization
KW - Cyclopentanes/chemical synthesis/pharmacology
KW - HIV Reverse Transcriptase/antagonists & inhibitors/chemistry
KW - HIV-1/drug effects
KW - Nucleosides/chemical synthesis/pharmacology
KW - Pancreatin/chemistry/metabolism
KW - Reverse Transcriptase Inhibitors/chemical synthesis/pharmacology
KW - Stavudine/pharmacology
M3 - SCORING: Journal article
VL - 18
SP - 11046
EP - 11062
JO - CHEM-EUR J
JF - CHEM-EUR J
SN - 0947-6539
IS - 35
M1 - 35
ER -
