Synthesis of a Nucleobase-Modified ProTide Library

A new method for the construction of (aryloxy)­phosphoramidate nucleoside prodrugs is presented. An (aryloxy)­phosphoramidate ribose derivative as key building block was used for coupling with a number of nucleobases under Vorbrüggen reaction conditions yielding the protected ProTides in excellent yields. Selective hydrolysis of the acetoxy groups on the sugar moiety afforded a series of the desired ProTides. The advantage of this approach, when compared to classical procedures, is the greater flexibility for achieving structural variety of the nucleobase moiety

Synthesis of α‑l‑Threose Nucleoside Phosphonates via Regioselective Sugar Protection

A new synthesis route to α-l-threose nucleoside phosphonates via 2-<i>O</i> and 3-<i>O</i> selectively protected l-threose is developed. The key intermediates 2-<i>O</i>-benzoyl-l-threonolactone and 1-<i>O</i>-acetyl-2-<i>O</i>-benzoyl-3-<i>O</i>-<i>t</i>-butyldiphenylsilyl-l-threofuranose were functionalized to synthesize 2′-deoxy-2′-fluoro- and 3′-<i>C</i>-ethynyl l-threose 3′-<i>O</i>-phosphonate nucleosides. The key intermediates developed are important intermediates for the synthesis of new l-threose-based nucleoside analogues, TNA phosphoramidites, and TNA triphosphates

Potential energy plots of a cyclohexenyl nucleoside, a 2′-ribo-OH cyclohexenyl nucleoside and a 2′-ara-OH cyclohexenyl nucleoside

<p><b>Copyright information:</b></p><p>Taken from "Cyclohexenyl nucleic acids: conformationally flexible oligonucleotides"</p><p>Nucleic Acids Research 2005;33(8):2452-2463.</p><p>Published online 29 Apr 2005</p><p>PMCID:PMC1087899.</p><p>© The Author 2005. Published by Oxford University Press. All rights reserved</p

Important NOE contacts observed in the thymine cyclohexenyl residue (T*) in a DNA duplex consisting of d(5′-GCGT*GCG-3′) hybridized with d(5′-CGCACGC-3′)

<p><b>Copyright information:</b></p><p>Taken from "Cyclohexenyl nucleic acids: conformationally flexible oligonucleotides"</p><p>Nucleic Acids Research 2005;33(8):2452-2463.</p><p>Published online 29 Apr 2005</p><p>PMCID:PMC1087899.</p><p>© The Author 2005. Published by Oxford University Press. All rights reserved</p

Synthesis of a C‑Nucleoside Phosphonate by Base-Promoted Epimerization

The efficient synthesis of a [2′S] C-nucleoside phosphonate and its corresponding prodrug has been realized. A phosphonomethoxy group was stereoselectively introduced at the anomeric 5′-carbon atom through glycosylation of a benzoyl protected [5′R]-acetoxy-[2′R]-9-deazaadenine. An unexpected epimerization at the 2′-position of the sugar moiety occurred upon removal of the protecting groups, but this was further exploited as a key reaction for improved synthesis of the target compound

Molecular Dynamics of Double Stranded Xylo-Nucleic Acid

Xylo-nucleic acid (XyloNA) is a synthetic analogue of ribo-nucleic acid (RNA), where the ribose sugar has been replaced by xylose. We present a molecular dynamics study of the conformational evolution of XyloNA double strand oligomers derived from A-RNA through the substitution of β-d-ribofuranose by β-d-xylofuranose and having lengths of 8, 16, and 29 base pairs, using a set of independent all-atom simulations performed at various time scales ranging from 55 to 100 ns, with one long 500 ns simulation of the 29-mer. In order to validate the robustness of XyloNA conformation, a set of simulations using various cutoff distances and solvation box dimensions has also been performed. These independent simulations reveal the uncoiling or elongation of the initial conformation to form an open ladder type transient state conformation and the subsequent formation of a highly flexible duplex with a tendency to coil in a left-handed fashion. The observed open ladder conformation is in line with recently obtained NMR data on the XyloNA 8-mer derived using 5′-d­(GU­GUA­CAC)-3′. The observed negative interbase pair twist leads to the observed highly flexible left-handed duplex, which is significantly less rigid than the stable left-handed dXyloNA duplex having a strong negative twist. A comparison between the xylo-analogues of DNA and RNA shows a clear distinction between the helical parameters, with implications for the pairing mechanism

Stereo overlay of the 20 lowest energy structures fitted to all residues except those in the closing base pair (U27–A43)

<p><b>Copyright information:</b></p><p>Taken from "The naturally occurring N6-threonyl adenine in anticodon loop of tRNA causes formation of a unique U-turn motif"</p><p>Nucleic Acids Research 2006;34(10):2878-2886.</p><p>Published online 31 May 2006</p><p>PMCID:PMC1474066.</p><p>© The Author 2006. Published by Oxford University Press. All rights reserved</p

Amidate Prodrugs of Cyclic 9‑(<i>S</i>)‑[3-Hydroxy-2-(phosphonomethoxy)propyl]adenine with Potent Anti-Herpesvirus Activity

A series of amidate prodrugs of cyclic 9-[3-hydroxy-2-(phosphonomethoxy)­propyl]­adenine (cHPMPA) featuring different amino acid motifs were synthesized. All phosphonamidates derived from (<i>S</i>)-cHPMPA displayed a broad spectrum activity against herpesviruses with EC₅₀ values in the low nanomolar range. A phosphonobisamidate prodrug of (<i>S</i>)-HPMPA also exhibited a remarkably potent antiviral activity. In addition, the leucine ester prodrug of (<i>S</i>)-cHPMPA and phosphonobisamidate valine ester prodrug of (<i>S</i>)-HPMPA proved stable in human plasma. These data warrant further development of cHPMPA prodrugs, especially against human cytomegalovirus (HCMV), for which there is a high need for treatment in transplant recipients

Synthesis of Modified Peptidoglycan Precursor Analogues for the Inhibition of Glycosyltransferase

The peptidoglycan glycosyltransferases (GTs) are essential enzymes that catalyze the polymerization of glycan chains of the bacterial cell wall from lipid II and thus constitute a validated antibacterial target. Their enzymatic cavity is composed of a donor site for the growing glycan chain (where the inhibitor moenomycin binds) and an acceptor site for lipid II substrate. In order to find lead inhibitors able to fill this large active site, we have synthesized a series of substrate analogues of lipid I and lipid II with variations in the lipid, the pyrophosphate, and the peptide moieties and evaluated their biological effect on the GT activity of E. coli PBP1b and their antibacterial potential. We found several compounds able to inhibit the GT activity in vitro and cause growth defect in Bacillus subtilis. The more active was C16-phosphoglycerate-MurNAc-(l-Ala-d-Glu)-GlcNAc, which also showed antibacterial activity. These molecules are promising leads for the design of new antibacterial GT inhibitors

1′,5′-Anhydro‑l-<i>ribo</i>-hexitol Adenine Nucleic Acids (α‑l‑HNA-A): Synthesis and Chiral Selection Properties in the Mirror Image World

The synthesis and a preliminary investigation of the base pairing properties of (6′ → 4′)-linked 1′,5′-anhydro-l-<i>ribo</i>-hexitol nucleic acids (α-l-HNA) have herein been reported through the study of a model oligoadenylate system in the mirror image world. Despite its considerable preorganization due to the rigidity of the “all equatorial” pyranyl sugar backbone, α-l-HNA represents a versatile informational biopolymer, in view of its capability to cross-communicate with natural and unnatural complements in both enantiomeric forms. This seems the result of an inherent flexibility of the oligonucleotide system, as witnessed by the singular formation of iso- and heterochiral associations composed of regular, enantiomorphic helical structures. The peculiar properties of α-l-HNA (and most generally of the α-HNA system) provide new elements in our understanding of the structural prerequisites ruling the stereoselectivity of the hybridization processes of nucleic acids