Synthesis of 2',3'-dideoxy-3'-fluoro-L-ribonucleosides as potential antiviral agents from D-sorbitol

2',3'-Dideoxy-3'-fluoro-L-ribonucleosides were synthesized as potential antiviral agents. The key intermediate, methyl 5-O-benzoyl-2,3-dideoxy-3-fluoro-L-ribofuranoside, which was prepared from D-sorbitol, was condensed with pyrimidine and purine bases to obtain the respective nucleosides. Among them, the cytosine analogue 2',3'-dideoxy-3'-fluoro-alpha-L-cytidine showed a moderate anti-HBV activity.     

Synthesis of 2',3'-dideoxy-3'-C-(hydroxymethyl)-4'-thiopentofuranosyl nucleosides as potential antiviral agent.

1-O-Acetyl-2,3-dideoxy-3-C-(hydroxymethyl)-4-thiofuranose derivative was synthesized from (S,S)-1,4-bis(benzyloxy)-2,3-epoxybutane derived from (+)-diethyl L-tartrate and the enantiomerically pure (E)-5-(2-bromovinyl)-1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-4'- thiopentofuranosyl]uracil 4 was obtained via coupling of silylated uracil followed by palladium-mediated coupling of methyl acrylate.     

Design and synthesis of novel 2',3'-dideoxy-4'-selenonucleosides as potential antiviral agents

On the basis of potent anti-HIV activity of 2',3'-dideoxynucleosides (ddNs), their bioisosteric analogues, 2',3'-dideoxy-4'-selenonucleosides (4'-seleno-ddNs) were first synthesized from a chiral template, d-glutamic acid using stereoselective ring-closure reaction of the dimesylate with Se(2-) and Pummerer type condensation of the selenoxide with nucleobases as key steps. X-ray crystallographic analysis indicated that 4'-seleno-ddNs adopted the same C2'-endo/C3'-exo (South) conformation as anti-HIV active ddNs, but did not show anti-HIV activity, indicating that RT seems to prefer the C2'-exo/C3'-endo (North) conformation on binding with their triphosphates.     

Synthesis and antiviral evaluation of 2',3'-dideoxy-2'-fluoro-3'- C-hydroxymethyl-beta-D-arabinofuranosyl pyrimidine nucleosides

The synthesis and anti-HBV and anti-HIV activity of a number of 2',3'-dideoxy-2'-fluoro-3'-C-hydroxymethyl-beta-D-arabinofuranosyl pyrimidine nucleosides are reported.     

Synthesis of 3'-trifluoromethyl nucleosides as potential antiviral agents

1,2-Di-O-acetyl-3-deoxy-3-trifluoromethyl-5-O-benzoyl-beta-D-ribofuranos e was synthesized from the precursor keto sugar by the use of Ruppert's reagent (CF3SiMe3) as the source of a nucleophilic trifluoromethyl group. Coupling of this trifluoromethyl sugar with nucleobases and elaboration gave novel deoxy and dideoxynucleosides. A single crystal X-ray analysis confirmed the structure and stereochemistry. The deoxynucleosides were converted through an elimination reaction to their dideoxydidehydro derivatives.     

Synthesis of 2',3'-dideoxy-2',3'-didehydro nucleosides via a serendipitous route

This paper describes a "green" synthesis of 2',3'-unsaturated 2',3'-dideoxynucleosides via an electrochemical reaction. Using this approach d4T, d4U, ddA and ddI can be synthesized in high yields.     

Synthesis and antiviral activity of D- and L-2'-azido-2',3'-dideoxy-4'-thiopyrimidine and purine nucleosides

Novel D- and L-2'-azido-2',3'-dideoxy-4'-thionucleosides were synthesized starting from L- and D-xylose via D- and L-4-thioarabitol derivative as key intermediates and evaluated for antiviral activity, respectively. When the final nucleosides were tested against HIV-1, HSV-1, HSV-2, and HCMV, they were found to be only active against HCMV without cytotoxicity up to 100 micrograms/ml.     

Synthesis and structure-activity relationships of 2',3'-dideoxypurine nucleosides as potential antiretroviral agents.

In order to study the structure-activity relationships of 2',3'-dideoxypurine nucleosides as potential anti-retroviral agents, various purine derivatives have been synthesized and tested against rous sarcoma virus (RSV) in chick embryo fibroblast (CEF) cells, and against human immunodeficiency virus (HIV) in human CD4+ T cells (ATH8). Some of the new purine derivatives found to be significant antiretroviral activities. And the correlations of activity between anti-RSV and anti-HIV have shown fairly good values so far.     

Synthesis of nucleosides having unusual branched sugars as potential antiviral agents.

Enantiomerically pure novel nucleosides having unusual branched sugars were synthesized in a stereospecific manner from a common chiral pool of (S, S)-1,4-bis(benzyloxy)-2,3-epoxybutane and evaluated for antiviral activity.     

Stereoselective synthesis of beta-L-2',3'-dideoxy- and L-2',3'-didehydro-2',3'-dideoxy purine nucleosides

beta-L-2',3'-Dideoxy- and L-2',3'-didehydro-2',3'-dideoxy purine nucleosides have been synthesized via a highly stereoselective method of glycosylation by the condensation of L-2-(phenylselenyl)-2,3-dideoxyribose derivative with silylated heterocyclic base.     

Synthesis of 2',3'-dideoxy-2'-monofluoromethyl azanucleosides

(2S,4S)-Methyl-N-tert-butoxycarbonyl-4-monofluoromethylpyroglutamate 6 was synthesized via a key dehydrofluorination followed by hydrogenation. Compound 6 was converted to (5S,3S)-N-benzyloxycarbonyl-5-tert-butyldimethylsilyloxymethyl-3-monofluoromethyl-2-pyrrolidone 12 over four steps in 62% yield, which was used as a precursor for the synthesis of 2',3'-dideoxy-2'-monofluoromethyl azanucleosides 17-18.     

Synthesis of novel 3'-deoxy-3'-C-hydroxymethyl nucleosides with conformationally rigid sugar moiety as potential antiviral agents

Based on the fact that the ring expanded 3'-C-hydroxymethyl analogue of oxetanocin A exhibited potent antiviral activity, two types of conformationally rigid 3'-C-hydroxymethyl derivatives in which 2'-hydroxyl group is linked to the 4'-position or to the 6'-position were synthesized starting from 1,2;5,6-di-O-isopropylidene-D-glucose, respectively.     

Structure-activity relationships of apio nucleosides as potential antiviral agents

Several types of novel apio nucleosides were synthesized starting from 1,3-dihydroxyacetone and evaluated for antiviral activity. Among compounds tested, amino substituted apio dideoxynucleosides exhibited anti-HBV activity, while thioapio dideoxynucleosides were found to be active against HIV-1. Apio dideoxydidehydro nucleosides showed moderate to potent anti-HCMV activity, but their bioisosteric thioapio dideoxydidehydro nucleosides did not exhibit any significant antiviral activity.     

Synthesis and biological evaluation of 2',3'-didehydro-2',3'-dideoxy-9-deazaguanosine, a monophosphate prodrug and two analogues, 2',3'-dideoxy-9-deazaguanosine and 2',3'-didehydro-2',3'-dideoxy-9-deazainosine

2',3'-Didehydro-2',3'-dideoxy-9-deazaguanosine (1), its monophosphate prodrug (2), and two analogues, 2',3'-dideoxy-9-deazaguanosine (3) and 2',3'-didehydro-2',3'-dideoxy-9-deazainosine (4), have been synthesized from benzoylated 9-deazaguanosine (5). Basic hydrolysis of 5, selective protection of the 2-amino and 5'-hydroxy functions with isobutyryl and silyl groups, respectively, followed by reaction with thiocarbonyldiimidazole gave the cyclic thiocarbonate, which, upon reaction with triethyl phosphite, followed by deprotection, afforded 1. Treatment of 1 with phenyl methoxyalaninylphosphochloridate and N-methylimidazole gave 2. Catalytic hydrogenation of 1 gave 3. Hydrodediazoniation of 1 with tert-butyl nitrite and tris(trimethylsilyl)silane gave 4. Compounds 1-4 were found to be inactive against the human immunodeficiency virus and exhibited minimal to no cytotoxic activity against the L1210 leukemia, CCRF-CEM lymphoblastic leukemia, and B16F10 melanoma in vitro.     

Synthesis of purine modified 2'-C-methyl nucleosides as potential anti-HCV agents

Based on the anti-hepatitis C activity of 2′-C-methyl-adenosine and 2′-C-methyl-guanosine, a series of new modified purine 2′-C-methyl nucleosides was prepared as potential anti-hepatitis C virus agents. Herein, we report the synthesis of both 6-modified and 2-modified purine 2′-C-methyl-nucleosides along with their anti-HCV replication activity and cytotoxicity in different cells.     

Synthesis of 2',3'-dideoxy-2'-fluoro-3'-thioarabinothymidine and its 3'-phosphoramidite derivative

An efficient method for the synthesis of 5'-O-monomethoxytrityl-2',3'-dideoxy-2'-fluoro-3'-thioarabinothymidine [(5'MMT)araF-T(3'SH), (5)] and its 3'-phosphoramidite derivative (6) suitable for automated incorporation into oligonucleotides, is demonstrated. A key step in the synthesis involves reaction of 5'-O-MMT-2,3'-O-anhydrothymidine (4) (Eleuteri, A.; Reese, C.B.; Song, Q. J. Chem. Soc. Perkin Trans. 1 1996, 2237 pp.) with sodium thioacetate to give (5'-MMT)araF-T(3'SAc) (5) (Elzagheid, M.I.; Mattila, K.; Oivanen, M.; Jones, B.C.N.M.; Cosstick, L?nnberg, H. Eur. J. Org. Chem. 2000, 1987-1991). This nucleoside was then converted to its corresponding phosphoramidite derivative, 6, as described previously ((a) Sun, S.; Yoshida, A.; Piccirilli, J.A. RNA, 1997, 3, 1352-1363; (b) Matulic-Adamic, J.; Beigelman, L. Helvetica Chemica Acta 1999, 82, 2141-2150: (c) Fettes, K.J.; O'Neil, I.; Roberts, S.M.; Cosstick, R. Nucleosides, Nucleotides and Nucl. Acids 2001, 20, 1351-1354).     

Synthesis and anti-HIV evaluation of new 2',3'-dideoxy-3'-thiacytidine prodrugs

A series of anti-HIV prodrugs possessing various polyaminated side arms have been developed. The incorporation of a N-Boc protected monoamine or diamine side arm into the backbone of the 2',3'-dideoxy-3'-thiacytidine 1 (BCH-189) provided an increase in antiviral potency, which could be several orders magnitude greater than the parent drug (1) depending on the cell culture systems used (MT-4 or MDMs). Twenty six 2',3'-dideoxy-3'-thiacytidine prodrugs which differ from each other by the length, the nature of the 5'-O function and the 5'-O or/and N-4 position on the nucleoside moiety were synthesized. Among this new series of prodrugs, several congeners (12c and 12a) were found to inhibit HIV-1 replication in cell culture with 50% effective concentrations EC50 of 10 and 50 nM respectively, in MT-4 cells. Compound 12c was found more active on infected MDMs cells with 50% effective concentration of 0.01 nM. The synthesis and the antiviral properties of these compounds are discussed.     

Synthesis and antiviral activity of novel 2',4'-doubly branched carbocyclic nucleosides

A series of 2' and 4'-doubly branched carbocyclic nucleosides 15, 16, 17 and 18 were synthesized starting from simple acyclic ketone derivatives. The required 4'-quatemary carbon was constructed using Claisen rearrangement. In addition, the installation of a methyl group in the 2'-position was accomplished using a Grignard carbonyl addition of isopropenylmagnesium bromide. Bis-vinyl was successfully cyclized using a Grubbs' catalyst II. Natural bases (adenine, cytosine) were efficiently coupled by using Pd(0) catalyst.     

Acyclic nucleoside analogues. III. 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. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 6; see also http://www.maik.ru.     

Synthesis of 3'-substituted-2',3'-deoxy-2'-methylidenepyrimidine nucleosides.

2'-deoxy-2'-methylideneuridine derivative 9 was converted into 2',3'-didehydro-2',3'-dideoxy-2'-phenyl-selenomethyl derivative 16, which was treated with NCS and tert-butyl carbamate to afford 3'-amino derivative 18 via a [2,3]-sigmatropic rearrangement. Treatment of 9 with DAST gave a mixture of 2',3'-didehydro-2', 3'-dideoxy-2'-fluoromethyl derivative 19 and 3'-"up"-fluoro-2'-methylidene derivative 20 in a ratio of 1.5 : 1. On the other hand, when 12 was treated with DAST, 19 and 3'-"down"-fluoro-2'-methylidene derivative 21 were obtained in a ratio of 1 : 1.6. These nucleosides were converted into the corresponding cytidine derivatives 4, 6, and 8, respectively. The reaction mechanisms as well as biological activity of these compounds will also be discussed.