Synthesis and Antiviral Evaluation of 3′-Fluoro-5′-norcarbocyclic Nucleoside Phosphonates Bearing Uracil and Cytosine as Potential Antiviral Agents

Carbocyclic nucleoside analogues are an essential class of antiviral agents and are commonly used in the treatment of viral diseases (hepatitis B, AIDS). Recently, we reported the racemic synthesis and the anti-human immunodeficiency virus activities (HIV) of 3′-fluoro-5′-norcarbocyclic nucleoside phosphonates bearing purines as heterocyclic base. Based on these results, the corresponding racemic norcarbocyclic nucleoside phosphonates bearing pyrimidine bases were synthesized. The prepared compounds were evaluated against HIV, but none of them showed marked antiviral activity compared to their purine counterparts.

Synthesis and anti-HBV activity of carbocyclic nucleoside hybrids with salient features of entecavir and aristeromycin

A new carbocyclic nucleoside with the salient features of entecavir and aristeromycin identified as the anti-HBV lead candidate.

Synthesis of Cyclobutane Analogue 4: Preparation of Purine and Pyrimidine Carbocyclic Nucleoside Derivatives

The coupling of 2-bromo-3-benzoyloxycyclobutanone with purine under basic conditions produces two regioisomers consisting of the N-7 and N-9 alkylated products in equal amounts in their racemic forms. The distribution of the isomers is consistent with the charge delocalization between the N-7 and N-9 positions of the purinyl anion. The structural assignments and relative stereochemistry of each regioisomer were based on 1 and 2D NMR techniques. The relative stereochemistry of the C-2 and C-3 substituents in each regioisomer was the trans orientation consistent with steric factors in the coupling step. The N-9 regioisomer was reduced with sodium borohydride to give the all trans cyclobutanol as the major product in a stereoselective manner. The alcohol was debenzoylated with sodium methoxide in a transesterification step to give the nucleoside analogue. The regioisomeric pyrimidine nucleosides were prepared by Vorbrüggen coupling of the 3-hydroxymethylcyclobutanone triflate with either thymine or uracil followed by stereoselective hydride addition. Regiospecificity of the coupling at the N-1 position was observed and stereoselective reduction to the trans-disubstituted cyclobutanol structure assignments was based on NMR data.

Synthesis and Anticancer Properties of Novel Truncated Carbocyclic Nucleoside Analogues

Background: Modified nucleosides established a prime role as therapeutic drugs. Objective: Design and synthesis of novel truncated carbocyclic nucleoside with modified nucleobases and evaluation of their anticancer properties. Methods: Novel truncated carbocyclic nucleoside analogues were synthesized from a versatile starting material D-ribose. The synthetic route includes stereoselective Grignard reaction, Wittig olefination, ring closing metathesis, double bond hydrogenation and Mitsunobu nucleobase condensation as the key steps. Cytotoxicity was measured using MTT assay in breast cancer cell lines (MCF7 and MDA-MB-231), ovarian cancer cell lines (IGROV1 and OVCAR8). Result & Conclusion: The synthesized compounds were characterized using spectroscopy techniques. The synthesized compounds induced cytotoxicity in breast cancer cell lines (MCF7 and MDA-MB-231), ovarian cancer cell lines (IGROV1 and OVCAR8) while minimal effect on primary cell line. Among the eight analogues, 1b and 1d showed the highest cytotoxicity effect and induced autophagy mode of cell death. These compounds induced autophagy by inactivating AKT and mTOR pathway. In addition, PARP1 was found to be stabilized upon treatment with compound 1b and 1d and is one of the known markers associated with induction of autophagy through the AMPK/mTOR pathway after DNA damage. Taken together, these results suggest that compounds 1b and 1d inhibit cancer cell proliferation through mTOR inactivation-mediated induction of autophagy.

Alicyclic β- and γ-Amino Acids: Useful Scaffolds for the Stereocontrolled Access to Amino Acid-Based Carbocyclic Nucleoside Analogs

Stereocontrolled synthesis of some amino acid-based carbocyclic nucleoside analogs containing ring C=C bond has been performed on β- and γ-lactam basis. Key steps were N-arylation of readily available β- or γ-lactam-derived amino ester isomers and amino alcohols with 5-amino-4,6-dichloropyrimidine; ring closure of the formed adduct with HC(OMe)3 and nucleophilic displacement of chlorine with various N-nucleophiles in the resulting 6-chloropurine moiety.