Studies on the Synthesis of S 5′,6-Methano-5′-Thiourldines

Abstract

Two approaches to the synthesis of the title compounds are described. In the first route, a reactive 5-oxo-6-methylene pyrimidine intermediate that is generated by treating the bis-acetylated or bis-benzoylated nucleosides 10 and 11 with sodium hydroxide undergoes intramolecular attack by the 5′-thiol group to afford the 5-hydroxy cyclonucleoside 12. In the second and higher yielding approach, the S_5′,6-methano linkage is established by an internal allylic displacement reaction that occurs when the 5-bromo-6-methyl nucleoside 24 is treated with base. The conformational properties of S_5′,6-methano-5′-thiouridine (3) and certain long-range spin-spin couplings observed in the NMR spectra of the intermediate nucleosides are discussed.     

Synthesis of 4-Substituted Pyrimidine 2′,3′-Dideoxynucleosides

Abstract

Reaction of 5′-0-(4,4′-dimethoxytriphenylmethyl)-3′-deoxythy-midine with triphenylphosphine/carbon tetrachloride, followed by deprotection of the 5′-hydroxyl group, afforded the 4-chloro derivative 3 from which some 4-substituted pyrimidin-2(1H)one-2′, 3′-dideoxyribosides were obtained by nucleo-philic substitution under very mild conditions.     

Synthesis of 3′,5′-Dithymidylyl-α-hydroxyphosphonate Dimer Building Blocks for Oligonucleotide Synthesis—A New Pro-oliguncleotide

Abstract

The synthesis of the dimer building blocks 1 and 2 and their introduction into (T)₁₅-oligonucleotides is described. The stability against 3′-exonuclease digestion (SVP) as well as the hybridization properties (T_m values) were examined.     

Synthesis and potato tuber-inducing activity of methyl 5′,5′,5′-trifluorojasmonate

Methyl 5′,5′,5′-trifluorojasmonate was synthesized as an antimetabolic analogue of methyl jasmonate. It induced potato tuber formation more effectively than methyl jasmonate and inhibited the growth of rice seedlings and the germination of lettuce and radish seeds. These results suggest that epijasmonic acid itself has potato tuber-inducing activity and that the hydroxyl group of tuberonic acid is not necessary for this activity.     

Synthesis of 5′-Thioalkyl,Sulfoxide and Sulfone Pyrimidine Nucleosides

Abstract

The preparation of 5′-thioalkyl, sulfoxide and sulfone pyrimidine nucleosides is [4–11] is described. The key steps of this synthesis are the nucleophilic displacements of a chlorine by a thioalkyl sodium salt or the direct introduction of the thioalkyl group under Mitsunobu conditions.     

Synthesis and Biological Evaluation of Pyrimidine and Purine α-L-2′,3′-Dideoxy Nucleosides

Abstract

A series of α-L-2′,3′-dideoxy nucleosides was prepared as potential antiviral agents. The pyrimidine nucleosides were prepared by standard Vorbrüggen coupling reactions. The purine analogues were prepared by enzymatic transfer of the dideoxy sugar from a pyrimidine to a purine base. These compounds were inactive against HIV-1, HBV, HSV-1 and -2, VZV, and HCMV.     

Studies Towards the Large Scale Chemical Synthesis of the Precursors of Ribonucleosides-3′,4′,5′,5″- 2H 4 and -2′,3′,4′,5′,5″- 2H 5

Abstract

A summary delineating the large scale synthetic studies to prepare labeled precursors of ribonucleosides-3′,4′,5′,5″- ²H ₄ and -2′,3′,4′,5′,5″- ²H ₅ from D-glucose is presented. The recycling of deuterium-labeled by-products has been devised to give a high overall yield of the intermediates and an expedient protocol has been elaborated for the conversion of 3-O-benzyl-α,β-D-allofuranose-3,4-d ₂ 6 to 1-O-methyl-3-O-benzyl-2-O-t-butyldimethylsilyl-α,β-D-ribofuranose-3,4,5,5′-d ₄ 16 (precursor of ribonucleosides-3′,4′,5′,5″- ²H ₄ ) or to 1-O-methyl-3,5-di-O-benzyl-α,β-D-ribofuranose-3,4,5,5′-d ₄ 18 (precursor of ribonucleosides-3′,4′,5′,5″- ²H ₄ ).     

Synthesis and Biological Evaluation of Pyrimidine Nucleosides Fused with 3′,4′-Tetrahydrofuran Ring

Abstract

Pyrimidine nucleosides fused with 3′,4′-tetrahydrofuran ring were synthesized, starting from 1,2;5,6-di-O-isopropylidene-D-glucose and assayed for antiviral activities. Thymine analogue 1 and its corresponding 2′-deoxy analogue 3 exhibited high cytotoxicity instead of giving antiviral activities.     

A Convenient Synthesis of N4,O3′, O5′-Triacetyl-2′-Ketocytidine

Abstract

A convenient synthesis of the title compound in four steps from cytidine is reported. Key transformations include differentiation of the 2′ position as N⁴,O^3′,O^5′-triacetyl-2,2′-anhydrocytidine, opening to the arabino derivative, and oxidation of the 2′ position with the Dess-Martin reagent.     

A New Synthesis of (—)-exo-Brevicomin

Rubusoside derivatives by transgalactosylation of various β-galactosidases were isolated and their structures were analyzed. Escherichia coli β-galactosidase produced mainly 13-O-β-d-glucosyl-19-O-[β-d-galactosyl-(1→6)-β-d-glucosyl]-steviol (RGal-2). Bacillus circulans β-galactosidase produced mainly 13-O-β-d-glucosyl-19-O-[β-d-galactosyl-(1→4)-β-d-glucosyl]-steviol (RGal-1a) in the early stage of the reaction and then produced 13-O-[β-d-galactosyl-(1→4)-β-d-glucosyl]-19-O-β-d-glucosyl-steviol (RGal-1b). With decreasing the amount of these products (RGal-1a and RGal-1b), RGal-2 was produced.     

Synthesis and Anti-viral Properties of 2′,3′-Dideoxy-3′,4′-dihydroxymethyl Substituted Pyrimidine Nucleoside Analogues

Abstract

Some 2′,3′-dideoxy-3′, 4′-dihydroxymethyl nucleoside analogues have been synthesised starting from diacetone-D-glucose. The 3-C-hydroxymethyl group was introduced by selective hydroboration-oxidation of the 3-C-methylene derivative. The 4-C-hydroxymethyl group was obtained by an aldol condensation followed by in situ cross Canizzaro reduction. Glycosylation using silylated pyrimidine bases furnished the 2′,3′-dideoxy-3′,4′-dihydroxymethyl nucleoside analogues.     

Conformational Studies of a Melittin—Inhibitor Complex

The conformation of a melittin—inhibitor complex was studied by solution NMR, solid-state NMR, and circular dichroism. In solution, binding was studied by titrating inhibitor against melittin in dimethyl sulfoxide, methanol, aqueous buffer, and dodecylphosphocholine micelles. The change in chemical shift of Trp19 resonances and the formation of a precipitate at 1:1 molar ratio indicated that the inhibitor was bound to melittin. Solid-state NMR also showed a change in chemical shift of two labeled carbons of melittin near Pro14 and a change in ¹H T ₁ relaxation times when complexed with inhibitor. Rotational resonance experiments of melittin labeled in the proline region indicated a change in conformation for melittin complexed with inhibitor. This observation was also supported by circular dichroism measurements, indicating a reduction in α-helical structure for increasing ratios of inhibitor bound to melittin.     

A Direct and Efficient Synthesis of 5′-Deoxy-2′, 3′-

Abstract

A direct and efficient synthesis of 5′-deoxy-2′,3′-O-isopropylideneinosine, 7, from readily available inosine is described. An example of a potentially general synthesis of N -substituted-5′-deoxyadenosines from 7 is also described.     

Glycosylations of Inosine and Uridine Nucleoside Bases and Synthesis of the New 1-(β-D-Glucopyranosyl)-Inosine-5′, 6″-diphosphate

Abstract

Gluco- and ribosylation of the bases of sugar protected inosine and uridine were investigated, obtaining only adducts with β-configuration at the new glycosidic carbon; stereospecific insertion of a sugar moiety at the 1-N of inosine was achieved either using a Mitsunobu approach (for ribosylation) or by direct coupling of 1-δ-bromoglucose 13 with 2′,3′,5′-tri-O-acetylinosine for glucosylation. 1-(β-D-glucosyl)-inosine, chosen as starting substrate for glucosylated analogs of cyclic IDP-ribose, was phosphorylated at the primary hydroxyls and tested in intramolecular pyrophosphate bond formation.     

Synthesis of 5, 6-Dichloro-Benzimidazole-(2′, 5′)-Nucleotide Trimer

Abstract

The chemical synthesis of the trimeric 5, 6-dichloro-1-β-D-ribofuranosylbenzimidazole-(2′, 5′)-diphosphate using the phosphotriester approach is described.     

Synthesis and Anticancer Activity of 3-(3-Oxoprop-1-enyl)-Substituted Analogues of Carbocyclic Pyrimidine Nucleosides and 2′,3′-Dideoxy Pyrimidine Nucleosides

Abstract

Various 2′, 3′ -dideoxy and carbocyclic pyrimidine nucleosides, and their corresponding 3-(3-oxoprop-1-enyl) derivatives, have been synthesized and evaluated against murine L1210 and P388 leukemias and Sarcoma 180 and human CCRF-CEM lymphoblastic leukemia. Among the compounds tested, 3-(3-oxoprop-1-enyl)-3′ -fluoro-3′ -deoxythymidine (17), 3-(3-oxoprop-1-enyl)-3′ -azido-3′ -deoxythymidine (15) and 3-(3-oxoprop-1-eny!)-(+)-1-[(lα, 3β, 4α)-3-hydroxy-4-(hydroxymethyl)cyclopentyl]-5-methyl-2,4 (lH,3H)pyrimidinedione (6) were found to be the most active with ED₅₀, values of 0.5,0.2,0.1, and 0.3 μM; 1.2, 0.5,1.0 and 1.0 μM; and 0.8,0.7,1.5, and 3.0μM, respectively. Our preliminary findings indicate that the 3-(3-oxoprop-1-enyl) derivative of carbocyclic thymidine is approximately 7 times more active than the 3-(3-oxoprop-1-enyl) derivative of carbocyclic thymine riboside against L1210 leukemia cells in vitro, with ED₅₀ values of 0.8 μM and 5.5 μM, respectively. These findings suggest that the cytotoxicity of these compounds not only is dependent upon the 3-(3-oxoprop-1-enyl)-substituted group, but also may vary with the sugar moiety.     

The enantiomers of the 1′,6′-isomer of neplanocin A: Synthesis and antiviral properties

Both enantiomers of 1′,6′-isoneplanocin have been prepared from a common substituted cyclopentane epoxide in 7 steps. Both compounds were subjected to DNA and RNA viral assessments with moderate to high activity found for both towards human cytomegalovirus, measles, Ebola, norovirus, and dengue. The D-like congener also showed vaccinia and HBV effectiveness. In many of the other antiviral assays both compounds showed cytotoxicity making, in some cases, an EC₅₀ determination not possible. The S-adenosylhomocysteine hydrolase inhibitory effects showed the D-like target to be equal that of neplanocin itself and better than 3-deazaneplanocin whereas the L-like analogue was 13 to 30 times less inhibitory than 3-deazaneplanocin and neplanocin, respectively.     

Synthesis and Antiviral Activity Evaluation of 2′,5′,5′-Trifluoro-Apiosyl Nucleoside Phosphonic Acid Analogs

Racemic synthesis of novel 2′,5′,5′-trifluoro-apiose nucleoside phosphonic acid analogs were performed as potent antiviral agents. Phosphonation was performed by direct displacement of triflate intermediate with diethyl (lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside analogs. An antiviral evaluation of the synthesized compounds against various viruses such as HIV, HSV-1, HSV-2, and HCMV revealed that the pyrimidine analogues have significant anti-HCMV activity.     

A Stereospecific Synthesis of Pyrimidine β-D-2′-Deoxyribonucleosides

Abstract

A stereospecific route for the synthesis of pyrimidine 2′-β-D-deoxyribonucleosides has been developed using suitably modified methyl 2-deoxy-D-ribofuranosides. The stereochemistry of the nucleoside bond is dictated by the chirality at C-4 of the pentofuranose. A novel palladium hydroxide catalyzed alcholysis of a nucleoside bond has been discovered. Preliminary studies of the mechanism and limitations of this reaction are described.