Synthesis and anti-HCMV activity of novel cyclopropyl phosphonic acid nucleosides

A simple synthetic route for novel acyclic phosphonate nucleosides is described. The characteristic cyclopropyl moiety 8 was constructed employing the Simmons-Smith reaction as key step starting from simple acyclic 2-butene-1,4-diol. The condensation of the mesylate 11 with natural nucleosidic bases (A,C,T,U) under nucleophilic substitution conditions (K₂CO₃, 18-Crown-6, DMF) and hydrolysis afforded the target nucleosides 16, 17, 18, and 19. In addition, the antiviral evaluations against various viruses were performed.     

Synthesis and anti-HCMV activity of novel acyclic nucleosides

A series of novel acyclic nucleosides 10, 11, 21, and 22 were synthesized efficiently starting from D-lactose. The condensation of the mesylate 5 and 16 with an adenine and cytosine base under standard nucleophilic substitution conditions (K2CO3, 18-Crown-6, DMF) afforded a series of acyclic novel nucleosides. Compound 21 displayed moderate anti-HCMV activity in the AD-169 cells (EC50 = 18.5 microg/mL) without exhibiting any cytotoxicity up to 100 microM.     

Synthesis and antiviral activity of novel exomethylene cyclopropyl nucleosides

Novel cyclopropyl nucleosides were synthesized as potential antiviral agents. The key intermediate 5, prepared from Feist's acid 1 was condensed with purine derivatives by the SN2 type reaction. All the synthesized compounds were evaluated for antiviral activity.     

Synthesis and antiviral evaluation of novel 5'-norcarboacyclic phosphonic acid nucleosides

This article describes a very simple route for synthesizing a novel 5'-norcarboacyclic nucleotides. The condensation of the mesylates 17 and 18 with the natural nucleosidic bases (A,U,T,C) under standard nucleophilic substitution (K2CO3, 18-Crown-6, DMF) and deprotection afforded the target nucleotide analogues 27-34. In addition, these compounds were evaluated for their antiviral properties against various viruses.     

Synthesis and anti-HCMV activity of novel 2',3', 4'-trimethyl branched carbocyclic nucleosides

This article reports the synthesis of novel 2',3',4'-trimethyl branched carbocyclic nucleosides. The introduction of a methyl group in the 2' and 3'-position was accomplished by sequential Horner-Wadsworth-Emmons reaction and isopropenyl magnesiumbromide addition, respectively. The construction of the 4'-quaternary carbon needed was carried out using a [3,3]-sigmatropic rearrangement. Bis-vinyls were successfully cyclized using a Grubbs catalyst II. The natural bases (adenine, cytosine) were efficiently coupled with the use of a Pd(O) catalyst.     

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 different novel nonclassical nucleosides

A series of different novel nonclassical nucleosides have been synthesised and evaluated for their inhibitory activity against human immunodeficiency virus (HIV) replication in MT-4 cells.     

Synthesis and anti-cancer activity of some novel 5-azacytosine nucleosides

1-O-Acetyl-2-deoxy-3,5-di-O-toluoyl-4-thio-D-erythro-pentofuranose and 2-deoxy-1,3,5-tri-O-acetyl-4-thio-L-threo-pentofuranose were coupled with 5-azacytosine to obtain alpha and beta anomers of nucleosides. All four nucleosides were reduced to the corresponding dihydro derivatives and deblocked to give target compounds. All eight target compounds were evaluated in a series of human cancer cell lines in culture. Only 2'-deoxy-4'-thio-5-azacytidine (3beta) was found to be cytotoxic in all the cell lines and was further evaluated in vivo. Details of the synthesis and biological activity are reported.     

Synthesis of novel nucleosides

A new spironucleoside structural type and two new bicyclic nucleoside structural types were synthesized from the reaction of ribose nitrile oxide with dimethyl acetylenedicarboxylate. Next, a synthetic method for novel meso-ionic nucleoside structual type is presented.     

Synthesis of novel 4'-cyclopropyl-5'-norcarbocyclic adenosine phosphonic acid analogues

Novel 4'-cyclopropyl-5'-norcarbocyclic adenosine phosphonic acid analogues were designed and racemically synthesized from propionaldehyde 5 through a de novo acyclic stereoselective route using triple Grignard addition and ring-closing metathesis (RCM) as key reactions. To improve cellular permeability and enhance the anti-HIV activity of this phosphonic acid, SATE phosphonodiester nucleoside prodrug 23 was prepared. The synthesized adenosine phosphonic acids analogues 17, 18, 19, 21, and 23 were subjected to antiviral screening against HIV-1. Compound 23 exhibits enhanced anti-HIV activity than its parent nucleoside phosphonic acid 18.     

Identification of novel nucleotide phosphonate analogs with potent anti-HCMV activity

We have recently described the discovery of new leads in the area of anti-HCMV research. Further structure - activity relationship studies have allowed us to identify potent and selective anti-HCMV nucleotide analogs. The synthesis as well as structure - activity relationship studies are described.     

Design and synthesis of a novel class of nucleotide analogs with anti-HCMV activity

A novel class of cyclic nucleotide analogs has shown anti-HCMV activity. The synthesis as well as structure - activity relationship studies are presented.     

Synthesis and in vitro growth inhibitory activity of novel silyl- and trityl-modified nucleosides

Seventeen silyl- and trityl-modified (5′-O- and 3′,5′-di-O-) nucleosides were synthesized with the aim of investigating the in vitro antiproliferative activities of these nucleoside derivatives. A subset of the compounds was evaluated at a fixed concentration of 100 μM against a small panel of tumor cell lines (HL-60, K-562, Jurkat, Caco-2 and HT-29). The entire set was also tested at varying concentrations against two human glioma lines (U373 and Hs683) to obtain GI₅₀ values, with the best results being values of ∼25 μM.     

Short synthesis and antiviral evaluation of C-fluoro-branched cyclopropyl nucleosides

A series of novel fluorocyclopropyl nucleosides were synthesized using the Simmons-Smith reaction as a key reaction starting from 1,3-dihydroxyacetone. All the nucleosides synthesized were assayed against several viruses. Among the compounds synthesized, the 5-fluorouracil analogue 15 showed significant anti-HCMV activity (9.22 microM).     

Synthesis and anti-HCMV activity of 1-acyl-beta-lactams and 1-acylazetidines derived from phenylalanine

Different Phe-derived 1-acyl-beta-lactams, analogous to a series of 2-azetidinones acting as HCMV serine protease inhibitors, were synthesized. Some of these compounds were modest inhibitors of the HCMV replication. Interestingly, removal of the carbonyl group of the beta-lactam ring, most likely acting as the serine trap, resulted in an azetidine derivative with anti-HCMV activity comparable to that of the reference compound ganciclovir.     

Synthesis of phosphonic analogues of carnitine and gamma-amino-beta-hydroxybutyric acid

The involvement of carnitine and gamma-amino-beta-hydroxybutyric acid in the biology of mammalian cells, the physiology of the human body, and some important aspects of medicinal treatment has induced many research groups to develop their pharmacologically potent analogues. Among them are the very important phosphonic analogues: phosphocarnitine and gamma-amino-beta-hydroxypropylphosphonic acid. This mini-review describes the various methodologies used for the synthesis of these compounds.     

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.     

Synthesis and anti-virus activity of some nucleosides analogues

New 3'-, 5'-, 5-bromo-2'-deoxyuridine (3a-g) and 3'-, 5'-thymidine (4a-i) analogues with amino acid and peptide residues were synthesized and evaluated for antiviral activity. The influence of long peptide chains, essential amino acids and the effect of this structural modification on the antiviral activity has been also reported. Three 5-bromo-2'-deoxyuridine derivatives containing glycyl-, glycyl-glycyl- and glycyl-glycyl-glycyl- residues (3a, 3b, 3c) showed a strong activity against the herpes virus PsRV and a moderate one vs. HSV-1. The corresponding thymidine analogues were considerably less effective, and only compounds 4d and 4h showed a borderline effect against PsRV.     

Synthesis and biological activity of 4'-thio-L-xylofuranosyl nucleosides

A series of 4'-thio-L-xylofuranosyl nucleosides were prepared and evaluated as potential anticancer and antiviral agents. The details of a convenient and high-yielding synthesis of the carbohydrate precursor 1-O-acetyl-2,3,5-tri-O-benzyl-4-thio-L-xylofuranose (6) are presented. Proof of structure and configuration at all chiral centers of the nucleosides was obtained by proton and carbon NMR. All target compounds were evaluated in a series of human cancer cell lines in culture and as antiviral agents.