Synthesis of telomere-mimic carbocyclic 5'-nor oligodeoxynucleotides.

Telomere-mimic S-ODNs have been synthesized and examined their effects on the proliferation of human tumor cell lines by XTT assay. Furthermore, the guanosine derivatives of carbocyclic 5'-nor nucleoside were synthesized.     

5'-nor carbocyclic ribavirin

An efficient synthesis of 5'-nor carbocyclic ribavirin (4) is described in 13 steps from conveniently available (+)-(IR,4S)-4-hydroxy-2-cyclopenten-1-yl acetate (6). Compound 4 was evaluated against the following viruses: herpes simplex type 1 and 2, vaccinia, cowpox, smallpox, Ebola, hepatitis B, hepatitis C, adenovirus type 1, influenza A (H1N1 and H3N2), influenza B, parainfluenza type 3, Pichinde, Punta Toro A, respiratory syncytial, rhinovirus type 2, Venezuelan equine encephalitis, yellow fever, and West Nile. No activity was found nor was there any cytotoxicity to the viral host cells.     

Synthesis of carbocyclic nucleosides bearing a cyclopropane ring.

A carbocyclic cyclopropane fused nucleoside, 9-(c-4-hydroxymethylbicyclo[3.1.0]hex-r-2-yl)-9H-adenine, has been efficiently synthesized from 2-azabicyclo-[2.2.1]hex-5-en-3-one (ABH) in 6 steps, namely cyclopropanation, -reductive amide cleavage (RAC) reaction and adenine ring construction.     

Synthesis and biological activity of novel carbocyclic nucleosides

The syntheses of several novel carbocyclic nucleosides which incorporate the cyclopentene moiety of neplanocin A will be presented. These include modified pyrimidine derivatives of the very potent antitumor agent cyclopentenyl cytosine and carbocyclic analogues of the ketohexose nucleosides psicofuranine and psicofuranosyl cytosine.     

Synthesis and anti-HIV activity of carbovir and related carbocyclic nucleosides.

(+/-) Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine (Carbovir) is an antiretroviral agent which is undergoing preclinical evaluation for the treatment of AIDS. Its hydrolytic stability and its ability to inhibit infectivity and replication of HIV in T-cells at concentrations of approximately 400-fold below toxic concentrations make Carbovir an excellent candidate for development as a potential antiretroviral agent.     

Synthesis of carbocyclic purine nucleosides using key intermediates, carbocyclic AICA-ribosides

Treating carbocyclic N1-methoxymethy-inosine and 2'-deoxy-inosine with 1N-NaOH/aq.EtOH gave the carbocyclic 5-amino-4-imidazolecarboxamide-riboside and -2'-deoxyriboside respectively. Reaction of both useful key intermediates with PhCONCS afforded the corresponding 5-(N-isothiocarbamoyl) derivatives in high yield. Methylation of the isothiocarbamoyl groups, followed by treatment with NaOH led to the purine ring-closure (guanine, isoguanine, and xanthosine) reaction.     

Synthesis of carbocyclic nucleosides and their SAH hydrolase inhibitory activities.

The cellular enzyme S-adenosyl-L-homocysteine (SAH) hydrolase has emerged as a target enzyme for the molecular design of anti-viral agents. Recently, SAH hydrolase has been considered as an attractive target in parasite chemotherapy for malaria. We report synthesis of several carbocyclic purine nucleosides and their inhibitory activities against human and malaria recombinant SAH hydrolases.     

New carbocyclic nucleosides derived from indan

Seven new carbocyclic nucleosides derived from indan (1a-g) were efficiently prepared from 1,2-indanedimethanol vía Mitsunobu reaction with 6-chloroadenine and subsequent introduction of the appropriate substituent.     

Synthesis of carbocyclic pyrimidine nucleosides and their inhibitory activities against Plasmodium falciparum thymidylate kinase

Plasmodium falciparum thymidylate kinase (PfTMK) is a promising antimalarial target due to its unique substrate specificity. Recently, we reported that 2′,3′-dideoxycarbocyclic thymidine showed moderate inhibitory activity and reported the related structure–activity relationship for inhibitors against PfTMK. In this study, we have designed and synthesized enantioselective 2′,3′-dideoxycarbocyclic pyrimidine nucleosides based on our previous results and screened them for inhibitory activity against PfTMK. The most potent inhibitor showed K_i^TMP and K_i^dGMP values of 14 and 20 μM, respectively. The fluorinated dideoxy derivative (-)-7, exhibited lower K_i^TMP and higher K_i^dGMP compared with that of the parent compound (K_i^TMP, K_i^dGMP equals 20 and 7 μM, respectively). The modification of carbocyclic pyrimidine nucleosides is a promising strategy for developing powerful PfTMK inhibitors.     

Synthesis and biological evaluation of novel homochiral carbocyclic nucleosides from 1-amino-2-indanols

New chiral purinyl and 8-azapurinyl carbanucleoside derivatives based on indanol were synthesized from commercial available (1S,2S)-trans-1-amino-2-indanol and (1R,2R)-trans-1-amino-2-indanol using a linear methodology. The antiviral activity and cytotoxicity of these compounds were evaluated against herpes simplex virus type 1 (HSV-1) in Vero cells, bovine viral diarrhea virus (BVDV) in Mardin-Darby bovine kidney (MDBK) cells and hepatitis B virus (HBV) in HepG2 2.2.15 cell line. Three compounds, showed an inhibition of the HBsAg levels similar to reference drug lamivudine. One chloropurinyl nucleoside, derived from the cis-1-amino-2-indanol, was cytotoxic on MDBK cells and it could be a lead for developing anticancer agents.     

Synthesis of novel carbocyclic nucleosides with a modified cyclopentane ring and evaluation of their antiviral activity.

New carbocyclic nucleosides with purine (compounds 2a-2c), 8-azapurine (compounds 2d and 2e) or pyrimidine (compound 3) as base were prepared and assayed for in vitro activity.     

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.     

New fluorinated carbocyclic nucleosides: synthesis and bioactivity

Novel fluorinated carbocyclic nucleosides, (+-)-3'-deoxy-3'-fluoroaristeromycin and (+-)-2',3'-dideoxy-3'-fluoroaristeromycin have been synthesized. The antitumor activities of these compounds were studied.     

Synthesis of chiral carbocyclic ribonucleotides.

The carbocyclic analogs of CMP, UMP, GMP, IMP, and ribo-TMP, of the same absolute configuration as the naturally occurring beta-D-ribofuranose-based ribonucleoside monophosphates, have been synthesized. The synthetic route employed Mitsunobu coupling of the heterocycles, appropriately protected where necessary, with a differentially protected, chiral carbocyclic core.     

Synthesis of 5'-thioalkyl, sulfoxide and sulfone pyrimidine nucleosides.

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 antiviral activity of carbocyclic nucleosides incorporating a modified cyclopentane ring. Part 3: Adenosine and uridine analogues

Six new carbocyclic nucleosides were prepared by mounting a purine (compounds 4-6), 8-azapurine (7 and 8) or uridine (9) base on the amino group of (1S,3R)-3-amino-2,2,3-trimethylcyclopentylmethanol (10). At subtoxic concentrations, compounds 5-9 showed at best marginal antiviral activity.     

The latest progress in the synthesis of carbocyclic nucleosides

This review presents the latest developments in the field of carba-nucleosides (1994-1998). Special attention is paid to the synthesis of key precursors to those carba-nucleosides that possess significant biological activities or have novel structures.     

Synthesis, antiviral and cytostatic activities, of carbocyclic nucleosides incorporating a modified cyclopentane ring. IV. Adenosine and uridine analogues

Eight new carbocyclic nucleosides were prepared by mounting a purine (compounds 8-10), 8-azapurine (12 and 13) or pyrimidine (15, 16 and 17b) on the amino group of (1S,3R)-3-aminomethyl-2,2,3-trimethylcyclopentylmethanol (6). All the compounds were evaluated as antiviral and antitumor agents in a variety of assay systems. Only compound 8 showed any cytostatic activity against the tumor cell lines examined.     

Asymmetric synthesis of carbocyclic pyrimidine nucleosides via pi-allylpalladium complex

Racemic and enantiomerically pure carbocyclic pyrimidine nucleosides were synthesized efficiently by a convergent approach using Trost nucleophilic addition of pi-allylpalladium complexes.