Toward a novel series of furanopyrimidine nucleoside analogues

Based on an unusual furanose ring opening of 1,2-O-isopropylidene pentofuranoside derivatives, a preparation scheme of a new series of furanopyrimidine nucleoside analogues has been devised.     

Asymmetric synthesis of thymine nucleoside analogues based on the isochroman core

Diastereoisomeric analogues of d4T having an isochroman core as the glycone moiety have been prepared in seven steps. Starting from phthalaldehyde, two chiral centres analogous to the α/β anomers of D/L sugars were created. The first was obtained enantiomerically pure via asymmetric dihydroxylation and the second via cyclisation of an aldehyde group with a primary hydroxyl group. Retention of chiral integrity at the C₄ site enabled enantiomerically pure nucleoside analogues to be obtained.     

Synthesis of 4-nitromethylene-1,4-dihydropyrimidine derivatives as pyrimidine nucleoside analogues

The synthesis of 4-nitromethylene-1,4-dihydropyrimidine derivatives as pyrimidine nucleoside analogues was developed, starting from 3-nitropyran-2-one N-functionalized amidines. Primary amines were reacted with amidines yielding 4-nitromethylene-1,4-dihydropyrimidine derivatives. In an initial survey, several 4-nitromethylene-1,4-dihydropyrimidines turned into 4-nitromethylene-1,2,3,4-tetrahydropyrimidine derivatives under different reduction conditions. The reduction reaction also induced a change in the exocyclic double bond configuration from (E) to (Z), due to an intramolecular hydrogen bond.     

Synthesis of novel 1,2,3-triazolyl nucleoside analogues bearing uracil, 6-methyluracil, 3,6-dimethyluracil,thymine, and quinazoline-2,4-dione moieties

A series of novel 1,2,3-triazolyl nucleoside analogues was synthesized via the CuAAC reaction of N1-alkynyl uracil, 6-methyluracil, 3,6-dimethyl uracil, thymine and quinazolin-2,4-dione with protected azido β-d-ribofuranose. The obtained compounds differ in both the nature of the pyrimidine-2,4-dione fragment and the length of the polymethylene linker connecting it with the β-d-ribofuranosyl-1,2,3-triazol-4-yl moiety. The 1,2,3-triazolyl nucleoside analogues were evaluated for their cytotoxicity in vitro.     

Synthesis of N-1 and ribose modified inosine analogues on solid support

Herein, we report the synthesis and the use of new N-1-dinitrophenyl-inosine based solid supports, in which the C-2 of the purine base is strongly activated toward the attack of N-nucleophiles. The synthesized supports, binding the nucleoside by a 5′-O-monomethoxytrityl function, have been used to accomplish the synthesis of a small library of N-1 alkylated inosine and AICAR derivatives. In addition, cleavage of the 2′-3′ ribose bond of N-1 alkylated inosine derivatives anchored to the supports allowed to prepare a new set of N-1 alkylated-2′,3′-secoinosine derivatives in high yields.     

Regioselective synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside analogues via TBS-directed 1,3-dipolar cycloaddition reaction

Herein described was a straightforward method for the highly regioselective synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside analogues, which featured the utilization of tert-butyldimethylsilyl (TBDMS) group as the directing group in the 1,3-dipolar cycloaddition reactions. 4-tert-Butyldimethylsilyl-5-trifluoromethyl-1,2,3-triazole nucleoside analogues were generated as the only cycloaddition products in moderate yields (15-79%) via the treatment of glycosyl azides with 3,3,3-trifluoro-1-tert-butyldimethylsilylpropyne 1 in toluene at 85 °C. Removal of TBS groups in these triazole cycloadducts with tetrabutylammonium fluoride (TBAF) smoothly afforded the various 5-trifluoromethyl-1,5-disubstituted 1,2,3-triazole nucleoside analogues in good yields (40-88%).     

Synthesis of 4-N-alkyl and ribose-modified AICAR analogues on solid support

Herein, we report the solid-phase synthesis of several 5-aminoimidazole-4-(N-alkyl)carboxamide-1-ribosides (4-N-alkyl AICARs) and the corresponding 2′,3′-secoriboside derivatives. The method uses the N-1-dinitrophenyl-inosine 5′-bonded to a solid support. This inosine derivative has the C-2 of the purine base strongly activated towards the attack of N-nucleophiles thus allowing the preparation of several N-1 alkylated inosine supports from which a small library of 4-N-alkyl AICAR derivatives has been synthesized. A set of new 4-N-alkyl AICA-2′,3′-secoriboside derivatives have also been obtained in high yields by solid-phase cleavage of the 2′,3′-ribose bond.     

Prolinol-based nucleoside phosphonic acids: new isosteric conformationally flexible nucleotide analogues

trans-4-Hydroxy-l-proline has been used as a starting material for the synthesis of prolinol-based nucleotide analogues with an N-phosphonomethyl moiety attached to the prolinol ring nitrogen atom. The synthetic methodology based on the inversion of configuration at both 1- and 4-position led to all diastereoisomeric O-protected 4-mesyloxyprolinol-N-phosphonates. Alkylation of nucleobases using the synthons in the l-series afforded the nucleotide analogues corresponding to α-l- and β-l-nucleotide. The NMR-based conformational study of these compounds in aqueous solution performed at two different pH values, showing either N-fully protonated or deprotonated forms, revealed the occurrence of the same mostly populated conformer in both cases. All final l-prolinol-based nucleoside phosphonic acids were tested for cytotoxic and antiviral properties, but no significant activity was found.     

Synthesis of unnatural 3′-phospha-2′-deoxyfuranose nucleoside analogues

This Letter describes the synthesis of racemic analogues of unnatural 2′-deoxy nucleoside with a phosphorus atom replacing the carbon atom in the 3′-position. A seven-step sequence was developed in racemic series to afford unnatural 3′-phospha-2′-deoxyfuranose nucleosides. The phospha nucleoside analogues were tested against HCV, but did not show any antiviral activity at a 10 μM maximum concentration used for the inhibition assays of analogues 2-T, 2-C and 4-Tα.     

An efficient synthesis of dienic nucleoside analogues via a Mitsunobu reaction

Nucleoside analogues 9 and 12 were obtained in good yields from alcohol 7 which, under Mitsunobu conditions, led to the title products after deprotection steps.     

Design and Synthesis of Some Novel Oxiconazole‐Like Carboacyclic Nucleoside Analogues,as Potential Chemotherapeutic Agents

The syntheses of some novel carboacyclic nucleosides, 17a – 17o , containing oxiconazole‐like scaffolds, are described (Schemes 1–3). In this series of carboacyclic nucleosides, pyrimidine as well as purine and other imidazole derivatives were employed as an imidazole successor in oxiconazole. These compounds could be prepared in good yields by using two different strategies (Schemes 1 and 2). Due to Scheme 1, the N‐coupling of nucleobases with 2‐bromoacetophenones was attained for 18a – 18e , and their subsequent oximation affording 19a – 19e and finally O‐alkylation with diverse alkylating sources resulted in the products 17a – 17g, 17n , and 17o . In Scheme 2, use of 2‐bromoacetophenone oximes 20 , followed by N‐coupling of nucleobases, provided 19f – 19j whose final O‐alkylation produced 17h – 17m (Scheme 2). For the rational interpretation of the dominant formation of (E)‐oxime ethers rather than (Z)‐oxime isomers, PM3 semiempirical quantum‐mechanic calculations were discussed and the calculations indicated a lower heat of formation for (E)‐isomers.     

Novel oligonucleotide analogues containing a morpholinoamidine unit

Morpholinoamidines were devised as new cationic units in oligonucleotides, by combining morpholino-nucleosides (to simplify the nomenclature, we will use the term morpholino-nucleosides to refer to nucleoside analogues in which the ribose ring was transformed into a morpholine) with internucleoside guanidines. Here, methodology was developed to synthesize oligonucleotides containing morpholinoamidines formed by morpholino-uridine and 5′-amino-5′-deoxythymidine. Morpholinoamidine was produced by solid-phase reaction of Alloc-morpholinocarbothioamide with 5′-aminonucleoside resin and Mukaiyama's reagent activation. Two 14-mer oligonucleotides containing a single morpholinoamidine were synthesized and their affinity properties were investigated by forming DNA double and triple helices. Duplexes were slightly stabilized by a 3′ unit, but were less stable if internally positioned. Notably, triplexes were significantly stabilized at pH 7.0.     

Synthesis of nucleoside aminooxy acids

First nucleoside aminooxy acids were synthesized from furanoid sugar phthalimidooxy acids by N-glycosylation with uracil, thymine, N-benzoylcytosine, 6-N-benzoyladenine and 2-N-acetyl-6-O-diphenylcarbamoylguanine. Boc or Fmoc protected uridine aminooxy acid derivatives have also been prepared. As oxyamine protecting group, the phthalimido group was shown to be instable in MeOH, leading to the imide ring-opening product in a reversible way. This reaction was accelerated under acid or basic conditions. A uridine dimer linked by N-oxy amide has also been prepared by coupling of uridine aminooxy ester with uridine phthalimidooxy acid. These nucleoside aminooxy acids might constitute useful building blocks for the development of novel RNA mimics and conjugates with other biomolecules or reporter compounds.     

Synthesis of mono- and polyhydroxylated cyclobutane nucleoside analogs

Enantiomerically enriched cyclobutene compounds 13 and 24 are good precursors of several cyclobutane nucleoside analogs. The synthetic ways involve, in the key step, either hydroboration or dihydroxylation.     

Synthesis of novel pyrimidine nucleoside analogues

Two new tetrazolopyrimidinedeoxynucleosides were synthesized and their physico-chemical data are described. Results of preliminary analyses of their biological properties are also reported.     

Synthesis and N-functionalization of isoxazolidines: a new approach to nucleoside analogues

A straightforward synthetic approach for the preparation of non N-functionalized isoxazolidines from BF₃-catalyzed 1,3-cycloaddition reactions between methyl glyoxylate oxime and alkenes is described. Subsequently, isoxazolidines were N-functionalized with three chemically active groups (2-chloroethyl, cyanomethyl and 2-acetoxyethyl), thus allowing the preparation of a wide array of N-functionalized isoxazolidines. The compounds were characterized by means of ¹H and ¹³C NMR spectroscopy and mass spectrometry. X-ray analysis was used for stereochemical elucidation.     

Pyrrolidine N-alkylphosphonates and related nucleotide analogues: synthesis and stereochemistry

N-Phosphonoalkyl-trans-3,4-dihydroxypyrrolidine derivatives were synthesized and exploited as synthons for the preparation of hydroxypyrrolidine nucleoside phosphonic acids, the 3′-deoxynucleoside 5′-phosphate analogues. Simultaneously, an alternative route, the N-phosphoalkylation of the preformed pyrrolidine nucleosides employing Mannich- and Michael-type reactions, was investigated to obtain desired nucleotide analogues. In contrast to the latter approach, the former resulted in the formation of two diastereoisomers very likely due to the existence of two possible S_N2 transition states during a nucleophilic displacement. The stereochemistry of the prepared nucleotide analogues was studied by NMR spectroscopy.     

Synthesis of a new family of acyclic nucleoside phosphonates, analogues of TPases transition states

A 6-step procedure was developed for the synthesis of a new family of acyclic nucleoside phosphonates (ANPs), "PHEEPA" [(2-pyrimidinyl-2-(2-hydroxyethoxy)ethyl)phosphonic acids] in overall yields ranging from 4.5% to 32%. These compounds, which possess on one side a hydroxy function and on the other side a phosphonate group, can be considered either as potential antiviral agents or as transition state analogues of nucleoside phosphorylases such as thymidine phosphorylase.     

Synthesis of new boron analogues of cyclic carboxylic α-amino acids using ring-closing metathesis reactions

Ruthenium catalyzed ring-closing metathesis has been used as a key step for the synthesis of cyclic α-aminoboronic esters as, for example, boron-containing mimics of pipecolic, 2-azepanecarboxylic acid or baikiain.