Nucleosides and Nucleotides. 192. Toward the Total Synthesis of Cyclic ADP-Carbocyclic-Ribose. Formation of the Intramolecular Pyrophosphate Linkage by a Conformation-Restriction Strategy in a Syn-form Using a Halogen Substitution at the 8-Position of the Adenine Ring

Abstract

The synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was investigated. Construction of the 18-membered backbone structure was successfully achieved by condensation of the two phosphate groups of 19, possibly due to restriction of the conformation of the substrate in a syn-form using an 8-chloro substituent at the adenine moiety. SN2 reactions between an optically active carbocyclic unit 8, which was constructed by a previously developed method, and 8-bromo-N ⁶-trichloroacetyl-2′,3′-O-isopropylideneadenosine 9c gave N-1-carbocyclic derivative, which was deprotected to give 5′,5′-diol derivatives 18. When 18 was treated with POCl₃ in PO(OEt)₃, the bromo group at the 8-position was replaced to give N-1-carbocyclic-8-chloroadenosine 5′,5′-diphosphate derivative 19 in 43% yield. Treatment of 19 with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride gave the desired intramolecular condensation product 20 in 10% yield. This is the first chemical construction of the 18-membered backbone structure containing an intramolecular pyrophosphate linkage of a cADPR-related compound with an adenine base.     

Novel Synthesis of 4′C-Aryl-Branched Acyclic Nucleoside Using [3,3]-Sigmatropic Rearrangement

Abstract

A very efficient synthetic route for preparing a novel 4′-C-aryl branched-1′,2′-seco-2′,3′-dideoxy-2′,3′-didehydro-nucleoside is described. Mesylate 7 was successfully synthesized via a Horner-Wadsworth-Emmons reaction and a [3,3]-sigmatropic rearrangement, with which an adenine base was coupled by nucleophilic substitution conditions (K₂CO₃, 18-Crown-6, DMF) to give the target nucleoside 9.     

Enantioselective Synthesis and Conformational Analysis of Cyclohexene Carbocyclic Nucleosides

Abstract

An enantioselective approach towards the synthesis of optically pure cyclohexene nucleosides 3 has been developed starting from (R)-carvone. The key steps are the regio- and stereoselective hydroboration of an exo double bond, the selective reduction of an enone intermediate and introduction of a base moiety by Mitsunobu reaction. Conformational analysis showed that the adenine base adopts predominantly in a pseudo-axial position.     

Synthesis of Methylenecyclobutyl- and Cyclobutenyl Adenine,Potent Antiviral Carbocyclic Analogues of Oxetanocin A

Abstract

9-Cyclobutyladenines bearing both methylene and hydroxymethyl groups, 3 and 4, were prepared by dehydration of carbocyclic oxetanocin A (1a). Introduction of a double bond into cyclobutane ring was achieved by allylic oxidation of N ⁶-benzoyl-9-[3-methylenecyclobutyl]adenine (12), which after several steps, afforded 9-[3-(hydroxy-methyl)-2-cyclobutenyl)adenine (5).     

A Novel Method for the Synthesis of ddA and F-ddA Via Regioselective 2′-O-Deacetylation of 9-(2,5-DI-O-Acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl)adenine

Abstract

Regioselective 2′-O-deacetylation of 9-(2,5-di-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl)adenine (1) is achieved by treatment of 1 with β-cyclodextrin (β-CyD) / aq. NaHCO₃ or N₂H₄·H₂O / EtOH. The 9-(5-O-Acetyl-3-bromo-3-deoxy-β-D-xylo-furanosyl)adenine (2) obtained is a common intermediate for the synthesis of 2′,3′-dideoxy-adenosine (ddA) (7) and 9-(2-fluoro-2,3-dideoxy-β-D-threo-pentofuranosyl)-adenine (F-ddA) (9).     

Conformational Preferences of Modified Nucleic Acid Bases N6-Methyl-N6-(N-Threonylcarbonyl) Adenine and 2-Methylthio-N6-(N-Threonylcarbonyl) Adenine by the Quantum Chemical PCILO Calculations

Abstract

Conformational preferences of the hypermodified nucleic acid bases N⁶-methyl-N⁶-(N- threonylcarbonyl) Adenine, m⁶ tc⁶ Ade, and 2-methylthio-N⁶-(N-threonylcarbonyl) Adenine, mS² tc⁶ Ade, have been studied theoretically using the quantum chemical PCILO (Perturbative Configuration Interaction using Localized Orbitals) method. The multidimensional conformational space has been searched using selected grid points formed by combining the various torsion angles which take the favoured values obtained from energy variation with respect to each torsion angle individually. In m⁶ tc⁶ Ade and mS² tc⁶ Ade alike the threonylcar- bonyl substituent preferably orients away (distal) from the imidazole moiety of the adenine ring. And as in the simpler N⁶-(N-threonylcarbonyl) Adenine, tc⁶ Ade, the atoms in the ureido group as well as the amino acid carbon atoms C(12) and C(13) remain coplanar with the purine base. As in tc⁶ Ade, this conformation is stabilized by the intramolecular hydrogen bond between N(11)H of the amino acid and N(l) of the adenine base.

The N⁶-methyl protons, in m⁶ tc⁶ Ade, take trans-staggered orientation with respect to the C(6)-N(6) bond. The preferred orientation of the 2-methylthio group is cis to the C(2)-N(3) bond in mS² tc⁶ Ade. This is in marked contrast to the modified nucleic acid base 2-methylthio-N⁶-(Δ²-isopentenyl) Adenine, mS² i⁶ Ade, where the 2-methylthio group orients trans to the C(2)- N(3) bond, causing a change in the preferred orientation of the isopentenyl component on methylthiolation. The present results thus indicate that unlike in the isopentenyl adenine the role of further chemical substitutions in threonylcarbonyl adenine may be indirect and less pronounced.     

SYNTHESIS AND ANTI-HCMV ACTIVITY OF NOVEL ACYCLIC NUCLEOSIDES

ABSTRACT

A series of novel acyclic nucleosides 10, 11, 21, and 22 were synthesized efficiently starting from D-lactose. The condensation of the mesylate 5 and 16 with an adenine and cytosine base under standard nucleophilic substitution conditions (K₂CO₃, 18-Crown-6, DMF) afforded a series of acyclic novel nucleosides. Compound 21 displayed moderate anti-HCMV activity in the AD-169 cells (EC₅₀=18.5 µg/mL) without exhibiting any cytotoxicity up to 100 µM.     

Synthesis and Evaluation of Acyclic Nucleotide Analogs

Abstract

Acyclic nucleotide analogs derived from antiviral 9-(2-phosphonylmethoxyethyl)adenine by modification at the side chain or by alternation of the heterocyclic base were synthesized and investigated for their antiviral activity.     

Synthesis of 2′,3′-Dideoxy-3′-C-Hydroxymethyl Nucleosides Having the L-Configuration as Potential Inhibitors of HIV

Abstract

Synthesis of 2′,3′-Dideoxy-3′-C-(hydroxymethyl)-α- and β-L-erythro-pentofuranosyl nucleosides of thymine, cytosine and adenine is reported.     

Synthesis of a Base-Protected xylo-LNA Adenine Nucleoside

Abstract

Synthesis of (1S,3R,4R,7R)-7-hydroxy-1-hydroxymethyl-3-(6-N-benzoyl-adenin-9-yl)-2,5-dioxabicyclo[2.2.1]heptane (2), a base-protected xylo-LNA adenine nucleoside, has been accomplished using a convergent synthetic strategy starting from 1,2-di-O-acetylfuranose 3.     

Open-Chain Carbocyclic Analogs of Adenosine with Dihalovinyl Unit as Potential Inhibitors of S-Adenosyl-L-homocysteine Hydrolase

Abstract

Vinylogously extended deoxyeritadenine derivatives were synthesized as acyclic/carbocyclic analogues of the 6′-halo(homovinyl)adenosines, which are known to be potent inhibitors of S-adenosyl-L-homocysteine hydrolase. Swern oxidation of 9-[3-(t-butyldimethylsilyloxy)-4-hydroxybutyl]adenine (4) followed by Wittig olefination and desilylation gave access to ethyl 6-(adenin-9-yl)-4-hydroxy-2(E)-hexenoate (7) and 5-(adenin-9-yl)-1,1-dibromo-1-penten-3-ol (9). No inhibition of AdoHcy Hydrolase was observed with 7 and 9.     

Perturbation of Hydrogen Bonds in the Adenine…Thymine Base Pair by Na+, Mg2+, Ca2+ and NH4 + Cations

Abstract

Perturbation of the hydrogen bonds in the adenine…thymine base pair by Na⁺, Mg²⁺, Ca²⁺ and NH₄ ⁺ cations has been investigated by means of ab initio SCF calculations with the STO-3G basis set. The geometry of adenine…thymine, as well as those of the perturbed pairs were optimized. Approach of any cation to thymine at 06 leads to destabilization of the adenine…thy mine pair; divalent cations (Mg²⁺, Ca²⁺) have a profound effect on the structure of the base pair. The approach of a cation to other available sites (thymine: O2, adenine N1 and N3) leads, on the other hand, to stabilization of the base pair. If a water molecule is placed between the cation and the base pair, the structure and stability of the base pair are changed only negligibly.     

The Z-Conformation of Poly(dA-dT) · Poly(dA-dT) in Solution as Studied by Ultraviolet Resonance Raman Spectroscopy

Abstract

Poly(dA-dT) poly(dA-dT) structures in aqueous solutions with high NaCl concentrations and in the presence of Ni²⁺ ions have been studied with resonance Raman spectroscopy (RRS). In low water activity the effects of added 95 mM NiCl₂ in solution stabilize the syn geometry of the purines and reorganize the water distribution via local interactions of Ni-water charged complexes with the adenine N7 position. It is shown that RRS provides good marker bands for a left-handed helix: i) a purine ring breathing mode around 630 cm″^?1coupled to the deoxyribose vibration in the syn geometry, ii) a 1300-1340 cm^?1 region characterizing local chemical interactions of the Ni²⁺ ions with the adenien N7 position, iii) lines at about 1483-and 1582 cm^?1 correlated to the anti/syn reorientation of the adenine residues on B-Z structure transition, iv) marker bands of the thymidine carbonyl group couplings at 1680-and 1733 cm^?1 due to the disposition of the thymidine residues in the Z helix specific geometry. Hence poly(dA-dT) poly(dA-dT) can adopt a Z form in solution. The Z form observed in alternate purine-pyrimidine sequences does not require G-C base pairs.     

Evaluation of the Kinetics of Hydrolysis of Monoamino Analogues of 2′- or 3′-Deoxyadenosine and of 9-(2-Deoxy-β-D-Threo-pentofuranosyl)Adenine or 9-(3-Deoxy-β-D-threo-pentofuranosyl)Adenine by Liquid Chromatography

Abstract

Liquid chromatography was used to follow the degradation of monoamino analogues of 2′- or 3′-deoxyadenosine and of 9-(2-deoxy-β-D-threo-pentofuranosyl) adenine or 9-(3-deoxy-β-D-threo-pentofuranosyl) adenine in buffers of different pH and constant ionic strength (μ). Comparison of stabilities of some of the compounds under study with those of corresponding hydroxyl analogues showed that at acid pH the aminated compounds are more stable than the corresponding hydroxyl compounds. The higher stability associated with the presence of an amino group in the sugar is explained in function of pK_a values, which were determined by ¹³C NMR.     

1,5-Anhydro-2-Deoxy-D-Altritol Oligonucleotides as Conformationally Restricted Analogues of Rna

Abstract

As part of a project concerning the investigation of new hexitol nucleic acids (HNA), the 1,5-anhydro-2-deoxy-D-altritol nucleoside building blocks with a uracil, cytosine, adenine and guanine base moiety were synthesized. The uracil analogue was used for the automated synthesis of corresponding oligonucleotides. Hybridization capabilities of these altritol nucleic acids (ANA) are illustrated by the Tm values obtained for the (a ^hU)₁₃/(dA)₁₃ duplex.     

Synthesis of 3′,4′-C-Bishydroxymethyl-2′,3′,4′-trideoxy-β-L-threo-pentopyranosyl Nucleosides as Potential Inhibitors of HIV

Abstract

The synthesis of 3′,4′-bishydroxymethyl-2′,3′,4′-trideoxy pentopyranosyl derivatives of thymine, uracil, cytosine, and adenine is described. trans-(3S,4S)-Bis(methoxycarbonyl)cyclopentanone (3) was converted to 1-O-acetyl-3,4-C-bis[(tert-butyldiphenylsiloxy)methyl]-2,3,4-trideoxy-α,β-L-threo-pentopyranose (6), which was subsequently condensed with the silylated purine and pyrimidine bases.     

Oligonucleotides with 2,6-Diaminopurine Base Replacing for Adenine: Synthesis and Properties

Abstract

Synthesis of three nucleoside building blocks with a benzoyl protected diaminopurine (DAP) base and their incorporation at different positions of DNA, RNA and hexitol oligomers (HNA) have been accomplished. DNA hairpins with a DAP substituted for one (or more) adenine in the loop structure were not found to be more stable. But the stability of RNA-hexitol as well as hexitol-hexitol duplexes improved when the adenine base was replaced with DAP.     

Therapeutic Potential of HPMPC (Cidofovir), PMEA (Adefovir) and Related Acyclic Nucleoside Phosphonate Analogues as Broad-Spectrum Anttviral Agents

Abstract

This article reviews the antiviral features of the acyclic nucleoside phosphonate (ANP) analogues, with a special focus on the most recent findings concerning the biochemistry and clinical efficacy of HPMPC [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; cidofovir; Vistide®] and PMEA [9-(2-phosphonyl-methoxyethyl)adenine; adefovir].     

How does modification of adenine by hydroxyl radical influence the stability and the nature of stacking interactions in adenine-cytosine complex?

This study reports on ab initio calculations of adenine - cytosine complexes in two different context alignments appearing in B-DNA. The influence of adenine modification by hydroxyl radical on the stability of the complexes is also discussed. The analysis was performed on over 40 crystallographic structures for each of the sequence contexts. In most cases, modification of adenine by hydroxyl radical leads to less negative intermolecular interaction energies. The issue of the influence of alteration of structural base step parameters on the stability of modified and unmodified adenine - cytosine complexes is also addressed. Analysis of the dependence of intermolecular interaction energy on base step parameters reveals that for twist and shift modification of adenine by hydroxyl radical leads to quite different interaction energy profiles in comparison with unmodified complexes. In order to elucidate the physical origins of this phenomenon, i.e. to analyze how the modification of adenine by hydroxyl radical is reflected in the change of intermolecular interaction energy components, a variational-perturbational decomposition scheme was applied at the MP2/aug-cc-pVDZ level of theory.     

SYNTHESIS AND IN VITRO ANTIVIRAL ACTIVITY EVALUATION OF 9-(2-AZIDO-2,3-DIDEOXY-β-D-THREO-PENTOFURANOSYL)ADENINE DERIVATIVES

9-(2-Azido-2,3-dideoxy-β-D-threo-pentofuranosyl)adenine derivatives (1a–e) containing a lipophilic function at the N-6 position in the purine ring were prepared and evaluated for their antiviral activity. The compounds 1a–e turned out to be inactive as antiviral agents.