Carbocyclic Nucleoside Analogues Research Articles

AIM study of pyrimidyl carbocyclic analogues of nucleosides based on cyclopentene rings

AbstractA topological charge electron density analysis using the atoms in molecules (AIM) theory with HF/6‐31++G**// HF/6‐31G* wave functions was performed on cis‐pyrimidyl and cis‐5/6‐halopyrimidyl derivatives of 1,2‐disubstituted analogues of carbocyclic nucleosides. In these analogues, which belong to an important class of antiviral or antitumoral compounds, the usual ribose or deoxyribose is replaced by a carbocycle with a hydroxymethyl group and a heterocyclic base on adjacent carbons and a double bond between positions 2 and 3 of the carbocycle. The results obtained demonstrate that 5‐halogenation does not alter the relative energy sequence of the conformers and gives rise to no meaningful distortion of the electron distribution in the cyclopentene ring. In fact, the difference in the total electron population of this cycle between the parent and any of the halogenated molecules is never larger than 7×10−3 a.u. It has been found that the electron population of the αC atom in the chloro derivatives is enlarged with respect to the unhalogenated species. The 5‐halogenation results in a destabilization of the C4, C5, and C6 atoms of the heterocyclic base. According to the AIM computed energy properties this destabilization originates from larger interelectronic repulsions in the C5 basin that are consistent with its reduced volume and its lower first moment of the electron density. On the other hand, 6‐halogenation produces a significant modification of the conformational equilibrium, modifying the relative energy sequence of conformers. The electronic properties are also significantly modified by 6‐halogenation. The charge transfer from the cyclopentene ring to the base reaches 0.71 a.u. in the 6‐fluoro derivative and 0.69 a.u. in the 6‐chloro derivative. © 2002 John Wiley & Sons, Inc. Int J Quantum Chem 86: 67–78, 2002

A new stereoselective route to the carbocyclic nucleoside cyclobut-A

A new synthesis of cyclobut-A, a carbocyclic nucleoside analogue of oxetanocin is described. The key step involves a stereoselective intramolecular [2+2] photocycloaddition to provide a trisubstituted cyclobutane derivative with the desired stereochemistry. The nucleoside linkage was established through nucleophilic displacement of an acetate group by adenine.

Synthesis of Aucubovir II, a New Carbocyclic Nucleoside Analog

The synthesis of a new carbocyclic nucleoside starting from aucubin, a natural methylcyclopentanoid monoterpene, has been performed, allowing the preparation of aucubovir II, a carbocyclic nucleoside analog with a highly functionalized cyclopentane ring. The stereocontrol of the coupling reaction was complete, utilizing the procedure described by Vorbruggen with a purinic base.

ChemInform Abstract: Synthesis of (1R,3R)-3-[2-(Aminoethyl)-2,2-dimethylcyclobutyl]methanol and (1S,3R)-(3-Amino-2,2-dimethylcyclobutyl)methanol from (+)-Nopinone.

The title amino alcohols 6 and 7, which are of interest as intermediates in the synthesis of carbocyclic analogs of nucleosides, were synthesized from (+)-nopinone (8). Ring opening of α-isonitrosonopinone leads to a cyanoester which can be directly reduced to 6. Alternatively, a longer route from the lactam 12, one of the Beckmann rearrangement products of 8, leads also to 6, in a higher overall yield. Besides this the isomeric lactam 13 was transformed, upon hydrolytic opening, oxidative degradation of the lateral chain and reduction, into 7.

New Route to 4-Aminocyclopent-2-en-1-ols: Synthesis and Enantioselective Rearrangement of 4-Amino-substituted Cyclopentene Oxides

A new route for the asymmetric synthesis of 4-aminocyclopent-2-en-1-ols (90% ee) for carbocyclic nucleoside analogue synthesis is described. The approach involves the stereoselective preparation of cis 4-amino-substituted cyclopentene oxides and subsequent chiral base-mediated rearrangement to the corresponding allylic alcohols. Full details on the synthesis and stereoselectivity of epoxidation of 4-amino-substituted cyclopentenes are presented.

Structure of an 11-mer DNA Duplex Containing the Carbocyclic Nucleotide Analog: 2′-Deoxyaristeromycin

2′-deoxyaristeromycin (dAr) is a nucleoside analogue that is resistant to the action of DNA glycosylases. High-resolution NMR spectroscopy and molecular dynamics simulations were used to determine the three-dimensional structure of an 11-mer DNA containing a single dAr•T base pair at its center. Analysis of the spectra revealed the existence of a right-handed duplex in solution, stabilized by Watson-Crick hydrogen bonding and base-stacking interactions. The carbocyclic sugar adopted a C1′-exo conformation and sugars of the 3′-flanking base pair had puckers in the O4′—endo range. The dAr•T base pair was mildly propeller twisted, and the dAr analogue showed a positive roll with the 3′-flanking base. Our findings indicate that the observed resistance of dAr-containing oligodeoxynucleotides to the catalytic action of DNA glycosylases relates to its electronic properties rather than structure, and validate the use of dAr and related carbocyclic nucleoside analogues for biological and structure/function relationship studies.

102 Inhibition of measles virus replication by 5′-nor carbocyclic nucleoside analogs : D.L. Barnard 1, V. Stowell 1, K.L. Seley 2, V.R. Hegde 2, S.W. Schneller 2, and R.W. Sidwell 1. 1Inst. for Antiviral Research, Utah State Univ., Logan, UT, USA and 2Auburn University, Auburn University, AL, USA

102 Inhibition of measles virus replication by 5′-nor carbocyclic nucleoside analogs : D.L. Barnard 1, V. Stowell 1, K.L. Seley 2, V.R. Hegde 2, S.W. Schneller 2, and R.W. Sidwell 1. 1Inst. for Antiviral Research, Utah State Univ., Logan, UT, USA and 2Auburn University, Auburn University, AL, USA

Synthesis of (1R,3R)-3-[2-(Aminoethyl)-2,2-dimethylcyclobutyl]methanol and (1S,3R)-(3-Amino-2,2-dimethylcyclobutyl)methanol from (+)-Nopinone

The title amino alcohols 6 and 7, which are of interest as intermediates in the synthesis of carbocyclic analogs of nucleosides, were synthesized from (+)-nopinone (8). Ring opening of α-isonitrosonopinone leads to a cyanoester which can be directly reduced to 6. Alternatively, a longer route from the lactam 12, one of the Beckmann rearrangement products of 8, leads also to 6, in a higher overall yield. Besides this the isomeric lactam 13 was transformed, upon hydrolytic opening, oxidative degradation of the lateral chain and reduction, into 7.

ChemInform Abstract: Racemic Synthesis of Carbocyclic Purine Nucleoside Analogues with Restricted Glycosyl Conformation.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Stereoselective Hydrogenation and Ozonolysis of Iridoids. Conversion into Carbocyclic Nucleoside Analogues

Stereoselective hydrogenation of the iridoids geniposide (9) and aucubin (19) was achieved by using the 1-methyl-1-methoxyethyl ether as a protecting group for the allylic alcohol, as it enhanced the stereoselectivity and prevented undesired hydrogenolysis. Ozonolysis of the hydrogenation product from 9, adoxoside (11), with reductive workup, afforded either a chiral lactone (25) or a chiral polyol (26), depending on the reduction conditions. Polyol 26 was subjected to protecting-group manipulation and subsequent oxidation and reductions to yield cyclopentane building blocks (29−34), which, by Mitsunobu couplings with purines, afforded carbocyclic nucleoside analogues (7, 8, and 35).

ChemInform Abstract: Synthesis of (.+‐.)‐cis‐3‐Aminomethyl‐1‐indanylmethanol as a Precursor of Carbocyclic Analogues of Nucleosides

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of (±)-cis-3-Aminomethyl-1-indanylmethanol as a Precursor of Carbocyclic Analogues of Nucleosides

Aminoalcohol precursor of carbocyclic analogues of nucleosides (±)-cis-3-aminomethyl-1-indanylmethanol was efficiently synthesized starting from benzonorbornadiene (5) previously prepared by addition of cyclopentadiene to 1-bromo-2-fluorobenzene.

Synthesis of Novel Carbocyclic Adenosine Analogues as Inhibitors of Adenosine Kinase

Several new 4‘-amino substituted carbocyclic adenosine analogues (6, 7, 31) were prepared as potential inhibitors of the enzyme adenosine kinase. Three different heterocyclic base moieties (adenine, 8-azaadenine, and pyrazolo[3,4-d]pyrimidine) were incorporated into carbocyclic nucleoside analogues through the use of two different synthetic strategies. In both strategies, bicyclic isoxazolidine 9 (prepared through a hetero Diels−Alder reaction with cyclopentadiene) was used as the starting material. In one route, the N−O bond was reductively cleaved, and the hydroxyl group (after inversion and ring functionalization) was used as a leaving group to incorporate the heterocyclic base moiety as the key bond-forming step. A second, more efficient and higher yielding synthetic route was developed as a general solution to the synthesis of the target 4‘-amino substituted carbocyclic adenosine analogues. In this methodology, the allylic C−O bond in the bicyclic isoxazolidine 9 was cleaved with double stereoinversi...

Chiral Carbocyclic Nucleosides from d-Glucose: Enantiodivergent Synthesis and One-Pot Entry of Dimethylamino Functionality in the Purine Rings

Cyclization of appropriately designed enose−nitrones derived from d-glucose, having nitrone at C-5 or C-1 and allylic/homoallylic functionalities at C-3 of the sugar backbone, afforded polyhydroxylated aminocarbocycles which were subsequently used as the precursors for carbocyclic nucleoside analogues (11, 13, 16, 21, and 23). The enantiodirecting synthesis of both the enantiomeric pairs of nucleoside analogues 11 and 13, 21a and 23a, and 21c and 23c, has also been demonstrated by judiciously applying intramolecular nitrone cycloaddition (INC) reaction. An interesting observation was that in the cyclization reaction of pyrimidine ring to purine ring in DMF solvent, the substitution of C-6 chloro group with a dimethylamino functionality also occurred spontaneously under mild condition, though similar reactions are reported to occur at higher temperature. The hydrogen bonding between N-3 of the purine ring and an appropriate hydroxy substituent in the carbocycle seems to play a crucial role in this reaction.

Racemic synthesis of carbocyclic purine nucleoside analogues with restricted glycosyl conformation

Carbocyclic purine nucleoside analogues which have restricted glycosyl conformation at χ ≈ 180° were designed, based on the conformational features of the L-nucleotide residue in heterochiral DNA, and synthesized. The synthesis of (±)-carbocyclic 8,6′-O-anhydro-8,6′-dihydroxy-2′-deoxyadenosine 3 was achieved by intramolecular cyclization of the 8-bromo-6′-O-tosyl-2′-deoxyadenosine derivative. (±)-Carbocyclic 8,6′-O-anhydro-8,6′-dihydroxy-2′-deoxyguanosine 4 was synthesized from the carbocyclic 2,6-diaminopurine nucleoside derivative via the carbocyclic 8-bromo-6′-O-mesyl-2′-deoxyguanosine derivative.

The Residence Time of the Bound Water in the Hydrophobic Minor Groove of the Carbocyclic-Nucleoside Analogs of Dickerson-Drew Dodecamers

Summary The residence time of the bound water molecules in the antisense oligodeoxyribonucleotides containing 7′-α-methyl (TMe). carbocyclic thymidines in duplex (I), d5′(1C2G3C4G5A6A7TMc 8TMc 9C10G11C12G)2 3′, and 6′-a-hydroxy (TOH) carbocyclic thymidines in duplex (II), d5′(1C3G3C4G5AOH 6 AOH 7TOH 8 TOH 9C10G11C12G)23, have been investigated using a combination of NOESY and ROESY experiments. Because of the presence of 7′-α-methyl groups of TMe in the centre of the minor groove in duplex (I), the residence time of the bound water molecule is shorter than 0.3 ns. The dramatic reduction of the residence time of the water molecule in the minor groove in duplex (I) compared with the natural counterpart has been attributed to the replacement of second shell of hydration and disruption of hydrogen-bonding with 04′ in the minor groove by hydrophobic α-methyl groups, as originally observed in the X-ray study. This effect could not be attributed to the change of the width of the minor groove because a comparative NMR study of the duplex (I) and its natural counterpart showed that the widths of their minor grooves are more or less unchanged (r.m.s.d change in the core part is <0.63Å). For duplex (II) with polar 6′-α-hydroxyl groups pointed to the minor groove, the correlation time is much longer than 0.36ns as a result of the stabilising hydrogen-bonding interaction with N3 or 02 of the neighbouring nucleotides.

Optically Active Cyclobutanone Chemistry: Synthesis of (−)-Cyclobut-A and (±)-3‘-Epi-Cyclobut-A

The carbocyclic nucleoside analogues (−)-cyclobut-A and (±)-3‘-epi-cyclobut-A were synthesized utilizing photolysis of the (benzyloxymethyl)(methoxy) chromium carbene complex 4 with optically active ene-carbamate 5 to produce the corresponding optically active α,α-disubstituted cyclobutanone 6. Stereoselective removal of the α-ethoxy group with inversion gave cyclobutanone 7, which was converted by existing methodology to the title compounds.

A Carbocyclic Nucleoside Analogue Is a TNF-α Inhibitor with Immunosuppressive Action: Role of Prostaglandin E2and Protein Kinase C and Comparison with Pentoxifylline

Tumor necrosis factor-α (TNF-α) is associated with several acute and chronic inflammatory conditions. New therapies directed at inhibiting TNF-α will be important in treating pathological processes mediated by TNF-α. In this study, we studied and compared the effect of the carbocyclic nucleoside analogue (9-[(1R,3R)-trans-cyclopentan-3-ol] adenine) with pentoxifylline on modulating TNF-α production. The carbocyclic nucleoside analogue inhibited TNF-α production in a dose-dependent manner (1 μM–1 mM) by stimulated peripheral blood mononuclear cells and cell lines of both monocyte (THP-1) and T-lymphocyte phenotypes (CEM × 174). The drug potently inhibited TNF production in cells stimulated by endotoxin, the superantigen (staphylococci enterotoxin A), the mitogen (phytohemagglutinin), and the protein kinase C activator (phorbol myristate acetate) with ED50ranging from 5 to 30 μM. At moderate concentrations, the carbocyclic nucleoside analogue inhibited superantigen (ED50= 300 μM) and alloantigen (mixed lymphocyte reaction) T cell proliferative responses (ED50= 150 μM). The involvement of protein kinase C and prostaglandin E2(PGE2), mediators that regulate TNF-α production, was also investigated. Unlike PTX, the nucleoside analogue did not upregulate PGE2production. The inhibition of TNF-α production appeared to be mediated at least partly by PKC, since the nucleoside analogue caused suppression of PKC activity in stimulated cells. The results show that the carbocyclic nucleoside analogue is a TNF-α inhibitor that may be appropriate in the therapy of TNF-α-associated complications. The suppressive properties of the carbocyclic nucleoside analogue on antigen and alloantigen (mixed lymphocyte reaction) responses may be appropriate in disease conditions in which inhibiting both TNF-α and T-cell reactivity is desirable.

Synthetic approaches to (1 S,3 R)-3-aminomethyl-2,2,3-trimethylcyclopentylmethanol and (1 S,3 R)-3-amino-2,2,3-trimethylcyclopentylmethanol from (+)-camphoric acid

The title aminomethyl ( 5) and amino ( 6) alcohols, which are of interest as intermediates in the synthesis of carbocyclic analogues of nucleosides, were prepared from (+)-camphoric acid via methyl (1 S,3 R)-3-carbamoyl-2,3,3-trimethylcyclopentane carboxylate ( 8). Direct reduction of 8 gave 5 in 26% yield. Amino alcohol 6 was prepared in 11–53% overall yields by several approaches, each involving oxidative degradation of 8 followed by a reduction step.

Synthesis and biological evaluation of 1,2-disubstituted carbonucleosides of 2-amino-6-substituted purine and 8-azapurine.

One, two-disubstituted carbocyclic nucleoside analogues bearing a 2-amino-6-substituted (chloro, hydroxy or amino) purine or 8-azapurine base were prepared by constructing the base about (+/-)-2-aminocyclopentane methanol, and their activities against a selection of viruses and tumor cells were determined in vitro.