Fibre and molecular structure of thymidylyl-3′,5′-deoxyadenosine

X-ray diffraction and molecular model building studies of an ordered structure of thymidylyl-3′,5′-deoxyadenosine which gives fibre-type diffraction patterns, are consistent with a seven-residues per turn, left-handed structure in which the adenine of one molecule and the thymine of the next are linked together by Hoogsteen type of hydrogen bonds. The structure thus resembles a macromolecule in which units are linked together by hydrogen bonds and stabilized by base stocking. Both nucleosides in the basic molecule are in the anti conformation and both sugar rings have C3′-endo puckers. The C5′-05′ bond of the deoxyadenosine is trans relative to C4′-C3′ and the conformations about the P-03′ and P-05′ bond are gauche^?, trans.     

Acyclic Nucleoside Analogues: III. A Synthesis of New 2′,3′-Dideoxy-2′,3′-Didehydronucleoside Analogues

The coupling of 5-acetoxy-1,1-dimethoxypent-2-ene with cytosine and thymine trimethylsilyl derivatives, as well as the reaction of 5-acetoxy-1-bromopent-2-ene with adenine sodium salt, yielded acyclic analogues of the corresponding nucleosides containing 5-acetoxy groups. They were deprotected with a saturated methanolic solution of ammonia to the target analogues of nucleosides, which were characterized with ¹H NMR, IR, and UV spectra.     

Study on Disulfur-Backboned Nucleic Acids: Part 3. Efficient Synthesis of 3′,5′-Dithio-2′-Deoxyuridine and Deoxycytidine

A general method is described for synthesizing 3′,5′-dithio-2′-deoxypyrimidine nucleosides 6 and 13 from normal 2′-deoxynucleosides. 2,3′-Anhydronucleosides 2 and 9 are applied as intermediates in the process to reverse the conformation of 3′-position on sugar rings. The intramolecular rings of 2,3′-anhydrothymidine and uridine are opened by thioacetic acid directly to produce 3′-S-acetyl-3′-thio-2′-deoxynucleosides 3 or 5. To cytidine, OH^? ion exchange resin was used to open the ring and 2′-deoxycytidine 10 was abtained in which 3′-OH group is in threo-conformation. The 3′-OH is activated by MsCl, and then substituted by potassium thioacetate to form the S,S′-diacetyl-3′,5′-dithio-2′-deoxycytidine 12. The acetyl groups in 3′,5′ position are removed rapidly by EtSNa in EtSH solution to afford the target molecules 6 and 13. The differences of synthetic routes between uridine and cytidine are also discusssed.     

Synthesis and Binding Properties of a Homopyrimidine 2′,5′-Linked Xylose Nucleic Acid (2′,5′-XNA)

Abstract

The synthesis and hybridization properties of pyrimidine 2′,5′-RNA and 2′,5′-Xylose Nucleic Acid (2′,5′-XNA) are described.     

Intramolecular Radical Reactions of 5′-O-Modified 2′,3′-Didehydro-2′,3′-Dideoxyuridine Derivatives

Abstract

Radical reactions of 5′-O-(2-bromo-1-methoxy)ethyl- and 5′-O-(2-propynyl)-2′,3′-dideoxy-2′,3′-didehydrouridines were investigated. Both reactions proceeded in a 6-exo-trig manner to give products cyclized regio- and stereospecifically at the 3′-position. The structures of these products were analyzed by X-ray crystallography.

     

Synthesis of 2′,3′-Didehydro-2′,3′-Dideoxy-3′-C-Methyl Substituted Nucleosides

Abstract

1-(2,3-Dideoxy-3-C-hydroxmethyl-β-D-threo-pentofuranosyl) -,1- (2,3-didehydro-2,3-dideoxy-3-C-hydroxymethyl-β-D-glycero- pentofuranosyl) -and 1-(3-C-azidomethyl-2,3-dideoxy-3-C-hydroxymethyl-β-D-glycero- pentofuranosyl)uracil, thymine and cytosine were synthesized and evaluated for anti-HIV activity. The synthetic strategy was based on an allylic alcohol transposition of the corresponding 3′-C-methylene-nucleoside analogues.     

Phosphonates Derivatives of 2′,3′-Dideoxy-2′,3′-didehydro-pentopyranosyl Nucleosides

Abstract

Adenine and thymine derivatives of 2′,3′-dideoxy-2′,3′-didehydropento-pyranosyl nucleosides carrying a phosphonomethyl moiety at their 4′-O-position and in a cis relationship with the heterocyclic base have been synthesized.     

Acyclic 2′, 3′-Dideoxy-2′,3′-didehydronucleoside 5′-Triphosphates as Termination Substrates of Broad Set of DNA Polymerases

Abstract

O4′-Nor-2′,3′-dideoxy-2′,3′-didehydronucleoside 5′-triphosphates (acyclo-d₄NTP) have been shown to have the properties of effective termination substrates for DNA biosynthesis, catalyzed by several different DNA polymerases.     

DNA tandem lesion: 5′,8-cyclo-2′-deoxyadenosine. The influence on human health

Nucleic acids are the targets for various endogenous and exogenous genotoxic agents, including reactive oxygen species. The appearance of a hydroxyl racial (^?OH), the most harmful molecule, next to an oligonucleotide can lead to two types of DNA damage: strand breaks or nucleobase modifications. Since clustered DNA damage is defined as the presence of two or more lesions in one helix turn, purine 5′,8-cyclo-2′-deoxynucleosides are recognized as tandem lesions: both sugar moieties and base have been modified within one nucleoside/nucleotide. The hydrogen abstraction from the C5′ group of nucleosides/nucleotides by ^?OH, with subsequent C8 C5′ cyclisation results in purine 5′,8-cyclonucleoside formation. Due to its unusual 3D structure and the fact that only one radical hit is needed for purine 5′,8-cyclonucleoside formation their influence on genome stability/integrity and DNA repair processes are subjects of medical interest. In the present work the influence of 5′,8-cyclo-2′-deoxyadenosine on DNA spatial geometry and DNA repair hinder in connection with human health, such as neurological disorders is discussed.     

Synthesis and Structure of 2′,3′-Dideoxy-3′-fluoro-5-cyanouridine

Abstract

The title compound was prepared by reaction of the 5-bromo congener with potassium cyanide in DMF. X-ray analysis revealed its solid state structure and the obtained conformation was compared to the con-formation of 3′-azido-3′-deoxythymidine (AZT) and of 2′,3′-dideoxy-3′-fluoro-5-chlorouridine, respectively, two very selective anti-HIV agents. They both show two separate molecules in their asymmetric unit, one of each fairly resembling the conformation of the title compound 4. The latter, however, displayed only very moderate activity.     

Enzymatic synthesis of 2′-deoxyadenosine

Summary The title compound was prepared by a two step enzymatic procedure consisting of DNA hydrolysis to the mixture of 2-deoxynucleosides followed by a transdeoxyribosilation of exogenous adenine.     

Synthesis of 2′,3′-Dideoxyribavirin

Abstract

A synthesis of 1-(2,3-dideoxy-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (2′,3′-dideoxyribavirin, ddR) is described. Glycosylation of the sodium salt of 1,2,4-triazole-3-carbonitrile (5) with 1-chloro-2-deoxy-3,5-di-0-p-toluoyl-α-D-erythro-pentofuranose (1) gave exclusively the corresponding N-1 glycosyl derivative with β-anomeric configuration (6), which on ammonolysis provided a convenient synthesis of 2′-deoxyribavirin (7). Similar glycosylation of the sodium salt of methyl 1,2,4-triazole-3-carboxylate (2) with 1 gave a mixture of corresponding N-1 and N-2 glycosyl derivatives (3) and (4), respectively. Ammonolysis of 3 furnished yet another route to 7. A four-step deoxygenation procedure using imidazolylthiocarbonylation of the 3′-hydroxy group of 5′-0-toluoyl derivative (9a) gave ddR (11). The structure of 11 was proven by single crystal X-ray studies. In a preliminary in vitro study ddR was found to be inactive against HIV retrovirus.     

Synthesis and Evaluation of Anti-HIV-1 and Antitumor Activity of 2′,3′-didehydro-2′,3′-dideoxy-3-deazaadenosine, 2′,3′-dideoxy-3-Deazaadenosine and Some 2′,3′-dideoxy-3-deaza-adenosine 5′-dialkyl Phosphates1

Abstract

- The 4-amino-1-(2.3-dideoxy-β-D-glycero-pent-2-enofurano-syl)-1H-irnidazo[4,5-c]pyridine (1) and 4-amino-1-(2,3-dideoxy-β-D-gfycero-pentofuranosyl)-1H-imidazo[4,5-c]pyridine (2), 3-deaza analogues of the anti-HIV agents 2′.3′-didehydro-2′,3′-dideoxyadenosine (d4A) and 2′,3′-dideoxy-adenosine (ddA), have been synthesized. The reaction of 3-deazaadenosine (3) with 2-acetoxyisobutyryl bromide yielded a mixture of cis and trans 2′,3′-ha-lo acetates which was convertcd into olefinic nucleoside (1) on treatment with a Zn/Cu couplc and then with methanolic ammonia. The 2′,3′-dideoxy-3-deazaadenosine (2) was obtained by catalytic reduction of 1. A number of phosphate triester derivatives of 2 have also been prepared. The diethyl-, dipropyl- and dibutylpliospliates 7a-c and 3-deazaadenosine have shown anti-HIV activity at non-cytotoxic doses. Compounds 7a-c have also shown significant cytostatic activity against murine colon adenocarcinoma cells.     

SYNTHESIS of 2′-DEOXY-2′-FLUOROGUANYL-(3′,5′)-GUANOSINE

ABSTRACT

The protected analogue of 2-amnio-6-chloropurine arabinoside (3b) was subjected to reaction with diethylaminosulfur trifluoride (DAST) and subsequently treated with NaOAc in Ac₂O/AcOH to give N ²,O ^3′,O ^5′-triacetyl-2′-deoxy-2′-fluoroguanosine (5a). After deacetylation of the sugar moiety and protection of 5′-OH by a 4,4′-dimethoxytrityl group, this nucleoside component was converted to 2′-deoxy-2′-fluoroguanyl-(3′,5′)-guanosine (6c, GfpG).     

Influence of Acetyl and Bromine Substitutions on Stacking. Crystal and Molecular Structures of 8-Bromo 2′,3′,5′-Triacetyl Adenosine and 8-Bromo 2′,3′,5′-Triacetyl Guanosine

Abstract

The three dimensional structures of 8-bromo 2′,3′,5′-triacetyl adenosine (8-Br Tri A) and 8-bromo 2′,3′,5′-triacetyl guanosine (8-Br Tri G) have been determined by single crystal X-ray diffraction methods to study the combined effect of bromine and acetyl substitutions on molecular conformation and interactions. The ribose puckers differ from those found in unbrominated Tri A and Tri G and unacetylated 8-Br A and 8-Br G analogues. The adenine bases in 8-Br Tri A form A.A.A base triplets using both Watson-Crick and Hoogsteen sites. Br atoms are not involved in stacking unlike most halogenated structures. The ‘scorpion tail’ positioning of acetyl over base in 8-Br Tri G is different from Tri G and is an interesting consequence of bromine substitution.     

Reaction of 3′,5′-di-O-acetyl-2′-deoxyguansoine with hypobromous acid

Hypobromous acid (HOBr) is formed by eosinophil peroxidase and myeloperoxidase in the presence of H₂O₂, Cl^?, and Br^? in the host defense system of humans, protecting against invading bacteria. However, the formed HOBr may cause damage to DNA and its components in the host. When a guanine nucleoside (3′,5′-di-O-acetyl-2′-deoxyguansoine) was treated with HOBr at pH 7.4, spiroiminodihydantoin, guanidinohydantoin/iminoallantoin, dehydro-iminoallantoin, diimino-imidazole, amino-imidazolone, and diamino-oxazolone nucleosides were generated in addition to an 8-bromoguanine nucleoside. The major products were spiroiminodihydantoin under neutral conditions and guanidinohydantoin/iminoallantoin under mildly acidic conditions. All the products were formed in the reaction with HOCl in the presence of Br^?. These products were also produced by eosinophil peroxidase or myeloperoxidase in the presence of H₂O₂, Cl^?, and Br^?. The results suggest that the products other than 8-bromoguanine may also have importance for mutagenesis by the reaction of HOBr with guanine residues in nucleotides and DNA.     

Flexibility of 3′,5′ Deoxyribonucleooside Diphosphates

Abstract

In 3′,5′ deoxyribonucleoside diphosphates, in addition to the nature of the base and the sugar puckering, there are six single bond rotations. However, from the analysis of crystal structure data on the constituents of nucleic acids, only three rotational angles, that are about glycosyl bond, about C4′-C5′ and about C3′-O3′ bonds, are flexible. For a given sugar puckering and a base, potential energy calculations using non-bonded, electrostatic and torsional functions were carried out by varying the three torsion angles. The energies are represented as isopotential energy surfaces. Since the availability of the real-time color graphics, it is possible to analyse these isopotential energy surfaces. The calculations were carried out for C3′ exo and C3′ endo puckerings for deoxyribose and also for four bases. These calculations throw more light not only on the allowed regions for the three rotational angles but also on the relationships among them. The dependence of base and the puckering of the sugar on these rotational angles and thereby the flexibility of the 3′,5′ deoxyribonucleoside diphosphates is discussed. From our calculations, it is now possible to follow minimum energy path for interconversion among various conformers.     

Synthesis and Biological Evaluation of Some 5-Nitro- and 5-Amino Derivatives of 2′-Deoxycytidine, 2′,3′-Dideoxyuridine,and 2′,3′-Dideoxycytidine

Abstract

In this article, we describe the synthesis of 5-nitro-1-(2-deoxy-α-D-erythro-pentofuranosyl)cytosine (4α), 5-nitro-1-(2-deoxy-β-D-erythro-pentofuranosyl)cytosine (4β), 5-amino-1-(2-deoxy-α-D-erythro-pentofuranosyl)cytosine (5α), 5-nitro-1- (2-deoxy-β-D-erythro-pentofuranosyl)cytosine (5β), 5-nitro-1-(2,3-dideoxy-β- D-ribofuranosyl)uracil (6β), 5-amino-1-(2,3-dideoxy-α,β-D-ribofuranosyl)uracil (7), 5-nitro-1-(2,3-dideoxy-α,β-D-ribofuranosyl)cytosine (8) and 5-amino-1-(2,3-dideoxy-β-D-ribofuranosyl)cytosine (9β). The prepared compounds were tested for their activity against HIV and HBV viruses, but they did not show significant activity.     

Synthesis and Biological Properties of the Four Optical Isomers of 5-o-Carboranyl-2′,3′-didehydro-2′,3′-dideoxyuridine

Abstract

The four isomers of the 5-o-carboranyl-2′,3′-didehydro-2′,3′-dideoxyuridine (d4CU) were synthesized and their antiviral activity and cytotoxicity in normal and cancer human cells determined. Coupling of silylated 5-o-carboranyluracil with the protected D/L 2,3-dideoxy-2-phenylselenenylribosylacetates provided after oxidative elimination and deprotection, the desired compounds. The presence of the electron deficient 5-o-carboranyl moiety on uracil influenced the yield of the various isomers. In general, the compounds demonstrated weak anti-human immunodeficiency virus activity in primary human lymphocytes. No marked difference in the biological profile was noted for the various optical isomers, suggesting that the high lipophilicity of these nucleosides imparted by the carboranyl moiety overrides stereochemical considerations in the 2′,3′-didehydro-2′,3′-dideoxy-aglycon moiety.     

Stannylation Approach to the Synthesis of 2′- and 3′-Substituted Analogues of 2′,3′-Didehydro-2′,3′-dideoxynucleosides

Abstract

Three methods are described for the introduction of a tributylstannyl group to the sp²-carbon of 2′,3′-didehydro-2′,3′-dideoxy nucleosides (d44Ns). The resulting stannylated products serve as versatile intermediates for the synthesis of d4Ns having various types of carbon-substituent.