Synthesis of enantiomeric-pure cyclohexenyl nucleoside building blocks for oligonucleotide synthesis

Lipases were used for the resolution of (±) (4aR, 7R, 8aS)-2-phenyl-4a,7,8,8a-tetrahydro-4H-1,3-benzodioxine. This separation was carried out on preparative scale and used for the synthesis of eight phosphoramidites of cyclohexenyl nucleosides (d- and l-series).     

Synthesis of homoceramides, novel ceramide analogues, and their lack of effect on the growth of hippocampal neurons

The synthesis of a new series of D-erythro-homoceramide analogues is described. Several synthetic approaches were investigated. Homoceramides can be successfully synthesized from L-homoserine as chiral building block and a protected Weinreb-amide as a key intermediate. The synthesis of short-chain analogues with a heptyl side chain, as well as with a phenyl residue in the sphingoid part (instead of the naturally occurring tridecyl side chain), was effected. The homoceramides 15-17 and 24 were investigated for their potential to reverse the inhibitory effect of fumonisin B(1) on axonal growth. Unfortunately, none of the tested compounds showed any biological activity due to their lack of metabolism to glucosylhomoceramide.     

Synthesis of 2′-Deoxy-5-(isothiazol-5-yl)uridine and Its Interaction with the HSV-1 Thymidine Kinase

2′-Deoxy-5-(isothiazol-5-yl)uridine ( 12 ) was synthesized starting from 2′-deoxy-5-iodouridine using a Pd-catalysed cross-coupling reaction with propiolaldehyde diethyl acetal followed by deprotection and ring closure using thiosulfate. 2′-Deoxyuridine 12 has a particular place among the 5-heteroaryl-substituted 2′-deoxyuridines in that it has a high affinity for herpes simplex virus type 1 (HSV-1)-encoded thymidine kinase (TK) without antiviral activity. Biochemical studies revealed that 12 is a substrate for viral TK. We further investigated the interaction of 12 with the HSV-1 thymidine kinase. The conformation of 12 in solution was established by NMR spectroscopy. The most stable conformer 12A has the S-atom of the isothiazole ring placed in the neighbourhood of the C(4)?O group of the pyrimidine moiety. The compound was docked in its most stable conformation in the active site of HSV-1 TK and subjected to energy minimization. This demonstrated that the isothiazole moiety binds in a cavity lined by the side chains of Tyr-132, Arg-163, Ala-167, and Ala-168 and that the C(3) atom of the isothiazole moiety is located in close proximity of the phenolic O-atom of Tyr-132 and the aliphatic part of the Arg-163 side chain.     

Synthesis of 3′-fluoro-4′-amino-hexitol nucleosides with a pyrimidine nucleobase as building blocks for oligonucleotides

The synthesis of 3′-fluoro-4′-amino-hexitol nucleosides with a uracil and cytosine nucleobase was performed. The synthesis started from 1,5:2,3-dianhydro-4,6-benzylidene-allitol and afforded the target compounds in 15 steps. These protected hexitol nucleosides are valuable building blocks for the preparation of a new class of oligonucleotides.     

A Synthetic Substrate of DNA Polymerase Deviating from the Bases,Sugar, and Leaving Group of Canonical Deoxynucleoside Triphosphates

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Highlights? A highly modified nucleotide as substrate for polymerases ? The reversibility of the polymerase reaction at the template level ? Synthesis of a nucleoside with two anomeric centers