Branched-chain sugar nucleosides: Stereocontrolled synthesis and bioevaluation of novel 3΄-C-trifluoromethyl and 3΄-C-methyl pyranonucleosides (original) (raw)
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European Journal of Medicinal Chemistry, 2008
The protected b-nucleosides 1-(2,4,6-tri-O-acetyl-3-deoxy-3-fluoro-b-D-glucopyranosyl)-N 4 -benzoyl cytosine (2a) and 9-(2,4,6-tri-O-acetyl-3-deoxy-3-fluoro-b-D-glucopyranosyl)-N 6 -benzoyl adenine (2b), were synthesized by the coupling of peracetylated 3-deoxy-3-fluoro-D-glucopyranose (1) with silylated N 4 -benzoyl cytosine and N 6 -benzoyl adenine, respectively. The nucleosides were deacetylated and several subsequent protection and deprotection steps afforded the partially acetylated nucleosides of cytosine 7a and adenine 7b, respectively. Finally, direct oxidation of the free hydroxyl group at 4 0 -position of 7a and 7b, and simultaneous elimination reaction of the b-acetoxyl group, afforded the desired unsaturated 3-fluoro-4-keto-b-D-glucopyranosyl derivatives. These newly synthesized compounds were evaluated for their potential antitumor and antiviral activities. Compared to 5FU, the newly synthesized derivatives showed to be more efficient as antitumor growth inhibitors and they exhibited direct antiviral effect toward rotavirus.
Nucleosides Nucleotides & Nucleic Acids, 2012
This article describes the synthesis of (3 ′S) and (3 ′R)-3 ′-amino-3 ′-deoxy pyranonucleosides and their precursors (3 ′S) and (3 ′R)-3 ′-azido-3 ′-deoxy pyranonucleosides. Azidation of 1,2:5,6-di-O-isopropylidene-3-O-toluenesulfonyl-α-D-allofuranose followed by hydrolysis and subsequent acetylation afforded 3-azido-3-deoxy-1,2,4,6-tetra-O-acetyl-D-glucopyranose, which upon coupling with the proper silylated bases, deacetylation, and catalytic hydrogenation, obtained the target 3 ′-amino-3 ′-deoxy-β-D-glucopyranonucleosides. The desired 1-(3 ′-amino-3 ′-deoxy-β-D-allopyranosyl)5-fluorouracil was readily prepared from the suitable imidazylate sugar after azidation followed by a protection/deprotection sequence and reduction of the unprotected azido precursor. No antiviral activity was observed for the novel nucleosides. Moderate cytostatic activity was recorded for the 5-fluorouracil derivatives.
Trifluoromethyl derivatives of canonical nucleosides: synthesis and bioactivity studies
The use of the system CF 3 SO 2 Na/tert-butyl-hydroperoxide (tert-ButOOH), recently reported for the efficient trifluoromethylation of a variety of heterocyclic aromatic compounds, has been here profitably exploited for the synthesis of 5-CF 3 -2 0 -deoxycytidine, 8-CF 3 -2 0 -deoxyadenosine, 8-CF 3 -2 0 -deoxyguanosine and 8-CF 3inosine, regioselectively obtained in good to acceptable yields following a very simple protocol. The bioactivity of these modified nucleosides, and particularly of the novel 8-CF 3 -2 0 -deoxyguanosine and 8-CF 3 -inosine, has been evaluated on a panel of tumour and non-tumour cell lines in preliminary in vitro cytotoxicity assays.
Synthesis of unsaturated fluoride containing d- and l-pyranosyl nucleosides
Tetrahedron: Asymmetry, 2002
A series of fluorinated pyranosyl nucleosides in D-and L-configurations, 16, 19-20, 25, 28-29, have been synthesized. Starting from 1,2-O-isopropylidene-D-glyceraldehyde, homologated templates (3S)-6 and (3R)-6 were prepared by vinylation of fluoroenal 3, which were transformed to give allylic alcohols, 8 and 21, in three steps, respectively. The key intermediate triols 9 and 22 were obtained by O-benzoyl group migration from the primary hydroxyl group to the neighboring secondary hydroxyl group. Under basic conditions, ring closure reaction of 9 and 22 afforded unsaturated pyranosyl derivatives 10 and 23, respectively, while under acidic conditions unsaturated furanosyl compounds 12 were formed. N-Glycosylation of the pyranosyl acetates with silylated bases under Vorbrü ggen conditions then gave the protected nucleosides, which were converted to the free nucleosides. However, condensation of the unsaturated furanosyl intermediate 12 did not provide the desired nucleosides. Structural and stereochemical assignments of the synthesized compounds were based on the NOESY spectra of 16a and 16b, as well as the X-ray crystal structure of 19a.
Synthesis of 6′‐Methyl‐2′‐ O ,4′‐ C ‐methylene‐ α ‐L‐ ribofuranosyl‐pyrimidine Nucleosides
ChemistrySelect, 2019
Herein, we report the efficient synthesis of (6'R)-and (6'S)-6'methyl-2'-O,4'-C-methylene-α-L-ribofuranosyl-thymine, and (6'R)-and (6'S)-6'-methyl-2'-O,4'-C-methylene-α-L-ribofuranosyluracil starting from diacetone glucofuranose in overall yields of 6.3, 4.7, 5.4 and 4.0%, respectively. The key step in the synthesis of stereochemically defined 6'-Me-bicyclic-nucleosides is the nucleophilic addition of methyl group at methylene carbon of 4-C-CH 2 OH moiety of the 4-C-tert-butyldiphenylsilyloxymethylated sugar precursor. Thus, the methyl group was added on the aldehyde obtained from Dess-Martin periodinane oxidation of the precursor alcohol employing AlMe 3 in hexane. Both (6'R)and (6'S)-stereoisomers of bicyclic nucleosides T and U were successfully synthesized following Vorbrüggen nucleobase coupling of T and U with triacetylated glycosyl donor obtained from acetolysis of (5R)-and (5 S)-4-C-(tert-butyldiphenylsilyloxymethyl)-5-C-methyl-1,2-O-isopropylidene-3-O-(2-naphthylmethyl)-α-D-xylofuranoses and further cyclization and deprotection of the resulted nucleoside. One of the nucleosides, (6'R)-6'-methyl-2'-O,4'-C-methylene-α-L-ribofuranosyl-uracil has been reported earlier in 1.8% yield, while the present methodology yielded the nucleoside in 5.4% yield. All the synthesized 6'-Me-bicyclic-nucleosides showed no significant anti-viral activity against H1 N1 strain of influenza A virus (A/Puerto Rico/ 8/1934). Experimental procedures including materials, reagents and solvents used for the synthesis of compounds 1, 2, 3 a, 3 b, (5R)-4, (5S)-5, (5R)-6, (5S)-7, 8 ad , 9 ad , 10 ad , 11 ad , 12 ad and 13 ad and their characterization data along with their 1 H and 13 C NMR spectra are given in the supplementary information.
European journal of medicinal chemistry, 2011
This report describes the total and facile synthesis of 3 0-C-cyano & 3 0-C-cyano-3 0-deoxy pyrimidine pyranonucleosides. Reaction of 3-keto glucoside 1 with sodium cyanide gave the desired precursor 3-C-cyano-1,2:5,6-di-O-isopropylidene-aD -glucofuranose (2). Hydrolysis followed by acetylation led to the 1,2,3,4,6-penta-O-acetyl-3-C-cyano-D-glucopyranose (4). Compound 4 was condensed with silylated 5-fluorouracil, uracil, thymine and N 4-benzoylcytosine, respectively and deacetylated to afford the target 1-(3 0-C-cyano-b-D-glucopyranosyl)nucleosides 6aed. Routine deoxygenation at position 3 0 of cyanohydrin 2, followed by hydrolysis and acetylation led to the 3-C-cyano-3-deoxy-1,2,4,6-tetra-O-acetyl-D-allopyranose (10). Coupling of sugar 10 with silylated pyrimidines and subsequent deacetylation yielded the target 1-(3 0-C-cyano-3 0-deoxy-b-D-allopyranosyl)nucleosides 12aed. The new analogues were evaluated for their antiviral and cytostatic activities. It was found that 6a was endowed with a pronounced anti-proliferative activity that was only 2-to 8-fold less potent than that shown for the parental base 5-fluorouracil. None of the compounds showed activity against a broad panel of DNA and RNA viruses.
Bioorganic Chemistry, 2010
The synthesis of the unsaturated 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl nucleosides of 5-fluorouracil (6a), N6-benzoyl adenine (6b), uracil (6c), thymine (6d) and N4-benzoyl cytosine (6e), is described. Monoiodination of compounds 1a,b, followed by acetylation, catalytic hydrogenation and finally regioselective 2′-O-deacylation afforded the partially acetylated dideoxynucleoside analogues of 5-fluorouracil (5a) and N6-benzoyl adenine (5b), respectively. Direct oxidation of the free hydroxyl group at the 2′-position of 5a,b, with simultaneous elimination reaction of the β-acetoxyl group, afforded the desired unsaturated 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl derivatives 6a,b. Compounds 1c–e were used as starting materials for the synthesis of the dideoxy unsaturated carbonyl nucleosides of uracil (6c), thymine (6d) and N4-benzoyl cytosine (6e). Similarly a protection-selective deprotection sequence followed by oxidation of the free hydroxyl group at the 2′-position of the dideoxy benzoylated analogues 9c–e with simultaneous elimination reaction of the β-benzoyl group, gave the desired nucleosides 6c–e. None of the compounds was inhibitory to a broad spectrum of DNA and RNA viruses at subtoxic concentrations. The 5-fluorouracil derivative 6a was more cytostatic (50% inhibitory concentration ranging between 0.2 and 12 μM) than the other compounds.The synthesis of the unsaturated 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl nucleosides of 5-fluorouracil (6a), N6-benzoyl adenine (6b), uracil (6c), thymine (6d) and N4-benzoyl cytosine (6e), is described. The newly synthesized 2′-ketopyranosyl derivatives were not potent antivirals at subtoxic concentrations. The 5-fluorouracil derivative 6a was more cytostatic (50% inhibitory concentration ranging between 0.2 and 12 μM) than the other compounds.
European Journal of Medicinal Chemistry
This report describes the total and facile synthesis of 3′-C-cyano & 3′-C-cyano-3′-deoxy pyrimidine pyranonucleosides. Reaction of 3-keto glucoside 1 with sodium cyanide gave the desired precursor 3-C-cyano-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (2). Hydrolysis followed by acetylation led to the 1,2,3,4,6-penta-O-acetyl-3-C-cyano-D-glucopyranose (4). Compound 4 was condensed with silylated 5-fluorouracil, uracil, thymine and N4-benzoylcytosine, respectively and deacetylated to afford the target 1-(3′-C-cyano-β-D-glucopyranosyl)nucleosides 6a–d. Routine deoxygenation at position 3′ of cyanohydrin 2, followed by hydrolysis and acetylation led to the 3-C-cyano-3-deoxy-1,2,4,6-tetra-O-acetyl-D-allopyranose (10). Coupling of sugar 10 with silylated pyrimidines and subsequent deacetylation yielded the target 1-(3′-C-cyano-3′-deoxy-β-D-allopyranosyl)nucleosides 12a–d. The new analogues were evaluated for their antiviral and cytostatic activities. It was found that 6a was endowed with a pronounced anti-proliferative activity that was only 2- to 8-fold less potent than that shown for the parental base 5-fluorouracil. None of the compounds showed activity against a broad panel of DNA and RNA viruses.Synthesis of 3′-C-cyano-β-D-glucopyranosyl 6a–d & 3′-C-cyano-3′-deoxy-β-D-allopyranosyl nucleosides 12a–d, is reported. Derivative 6a was highly cytostatic against a panel of tumor cell lines at an IC50 between 1.9 and 32 μM.► A stereoselective synthesis of 3'-C-branched chain nucleosides was accomplished. ► 3'-C-branched chain nucleosides was prepared and chemically characterized. ► The novel compounds were evaluated for their antitumor and antiviral activity. ► The 5-fluorouracil derivative, proved to be highly cytostatic.
Synthesis of Novel Fluorinated 2′,3′-Dideoxynucleosides
Nucleosides & nucleotides
The synthesis of various 2′,3′-dideoxypyrimidine nucleosides, starting from 5-(2,2,2-trifluoroethoxymethyl) (10) and 5-(bis-2,2,2-trifluoroethoxy)methyl-2′-deoxyuridine (11), is described. These compounds were synthesized for screening against herpes simplex virus type-1 and type-2, and HIV virus.