1,3-Dioxolanylpurine nucleosides (2R,4R) and (2R,4S) with selective anti-HIV-1 activity in human lymphocytes (original) (raw)

Asymmetric synthesis of 1,3-dioxolane-pyrimidine nucleosides and their anti-HIV activity

Journal of Medicinal Chemistry, 1992

In order to study the structureactivity relationships of dioxolane nucleosides as potential anti-HIV agents, various enantiomerically pure dioxolane-pyrimidine nucleosides have been synthesized and evaluated against HIV-1 in human peripheral blood mononuclear cells. The enantiomerically pure key intermediate 8 has been synthesized in nine steps from 1,6-anhydro-~-mannose (l), which was condensed with 5-substituted pyrimidines to obtain various dioxolane-pyrimidine nucleosides. Upon evaluation of these compounds, cytosine derivative 19 was found to exhibit the moat potent anti-HIV agent although it is the most toxic. The order of anti-HN potency was as follows: cytosine (&isomer) > thymine > cytosine (a-isomer) > 5-chlorouracil > 5-bromouracil > 5-fluorouracil derivatives. Uracil, 5-methylcytosine, and 5-iodouracil derivatives were found to be inactive. Interestingly, a-isomer 20 showed good anti-HN activity without cytotoxicity. As expected, other a-isomers did not exhibit any significant antiviral activity. (-)-Dioxolane-T was 5-fold less effective against AZT-resistant virus than AZT-sensitive virus.

Synthesis and Antiviral Activity of Oxaselenolane Nucleosides

Journal of Medicinal Chemistry, 2000

As dioxolane and oxathiolane nucleosides have exhibited promising antiviral and anticancer activities, it was of interest to synthesize isoelectronically substituted oxaselenolane nucleosides, in which the 3′-CH 2 is replaced by a selenium atom. To study structure-activity relationships, various pyrimidine and purine oxaselenolane nucleosides were synthesized from the key intermediate, (()-2-benzoyloxymethyl-1,2-oxaselenolane 5-acetate (6). Among the synthesized racemic nucleosides, cytosine and 5-fluorocytosine analogues exhibited potent anti-HIV and anti-HBV activities. It was of interest to obtain the enantiomerically pure isomers to determine if they have differential antiviral activities. However, due to the difficult and time-consuming nature of enantiomeric synthesis, a chiral HPLC separation was performed to obtain optical isomers from the corresponding racemic mixtures. Each pair of enantiomers of Se-ddC and Se-FddC was separated by an amylose chiral column using a mobile phase of 100% 2-propanol. The results indicate that most of the anti-HIV activity of both cytosine and fluorocytosine nucleosides resides with the (-)-isomers.

Synthesis of [4,5Bis(hydroxymethyl)-1,3-dioxolan-2-yl]nucleosides as Potential Inhibitors of HIV

Journal of Organic Chemistry, 1996

The synthesis of 1,3-dioxolan-2-ylnucleosides and related chemistry is described. We have shown that 2-methoxy-1,3-dioxolane (6) reacts with silylated thymine and trimethylsilyl triflate to give the acyclic formate ester 1-[2-(formyloxy)ethyl]thymine (8) rather than 1-(1,3-dioxolan-2-yl)thymine (7). A tentative mechanism which could explain this result is discussed. On the other hand, 2-methoxy-1,3-dioxolane 13c reacts with silylated bases to give [4,5-bis(hydroxymethyl)-1,3-dioxolan-2-yl]nucleosides, thus representing the first examples of this novel class of compounds. The nature of the nucleobase and the hydroxyl protecting groups was found to have great influence on the reaction and on the stability of the nucleosides. Compounds 16 and 18 were found to be inactive when tested for anti HIV-1 activity in vitro.

Structure−Activity Relationships of 2‘-Fluoro-2‘,3‘-unsaturated d-Nucleosides as Anti-HIV-1 Agents

Journal of Medicinal Chemistry, 2002

We studied the structure-activity relationships of a series of 2′-fluoro-2′,3′-unsaturated D-nucleosides against HIV-1 in human peripheral blood mononuclear (PBM) cells. The target compounds 10-21 and 28-33 were prepared by N-glycosylation of the acetate 4, which was readily prepared from 2,3-O-isopropylidene-D-glyceraldehyde in five steps. Among the newly synthesized nucleosides, 2-amino-6-chloropurine (11), adenine (14), inosine (16), guanine (18), 2,6-diaminopurine (20), and 5-fluorocytosine (30) derivatives were found to exhibit interesting anti-HIV activities with EC 50 values of 4.3, 0.44, 1.0, 2.6, 3.0, and 0.82 µM, respectively. The implications for drug resistance of the titled nucleosides with respect to lamivudine-resistant variants (M184V) were also examined, and no significant cross-resistance with the variants was observed with the D-series.

Antiviral optically pure dioxolane purine nucleosides analogues

Bioorganic & Medicinal Chemistry Letters, 1993

Selective deamination of (k) cis 2,6-diaminopurine dioxolane nucleoside produces the (-) guanine analogue having the 2R,4R absolute stereochemistry. The (zb) cis-adenine analogue generates the 2R,4R hypoxanthinyl derivative. Asymmetric synthesis of purine dioxolanes have been developed. The (-) adenine and (-) guanine compounds 6 and 7 emerged as potent inhibitors of the HIV-1 replication in vitro.

Synthesis and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-methyl-7-deazapurine nucleosides, their phosphoramidate prodrugs and 5′-triphosphates

Bioorganic & Medicinal Chemistry Letters, 2011

Thirty novel αand β-D-2′-deoxy-2′-fluoro-2′-C-methyl-7-deazapurine nucleoside analogs were synthesized and evaluated for in vitro antiviral activity. Several αand β-7-deazapurine nucleoside analogs exhibited modest anti-HCV activity and cytotoxicity. Four synthesized 7-deazapurine nucleoside phosphoramidate prodrugs (18-21) showed no anti-HCV activity, whereas the nucleoside triphosphates (22-24) demonstrated potent inhibitory effects against both wild-type and S282T mutant HCV polymerases. Cellular pharmacology studies in Huh-7 cells revealed that the 5′-triphosphates were not formed at significant levels from either the nucleoside or the phosphoramidate prodrugs, indicating that insufficient phosphorylation was responsible for the lack of anti-HCV activity. Evaluation of anti-HIV-1 activity revealed that an unusual α-form of 7carbomethoxyvinyl substituted nucleoside (10) had good anti-HIV-1 activity (EC 50 = 0.71 ± 0.25 μM; EC 90 = 9.5 ± 3.3 μM) with no observed cytotoxicity up to 100 μM in four different cell lines.

Inhibition of HIV-1 by Octadecyloxyethyl Esters of (S)-[3-Hydroxy-2-(Phosphonomethoxy)Propyl] Nucleosides and Evaluation of Their Mechanism of Action

Antimicrobial Agents and Chemotherapy, 2011

To investigate the mechanism of the antiviral activity, the active metabolites of HPMPC and HPMPA were studied for their effects on reactions catalyzed by HIV-1 RT. Incorporation of HPMPC and HPMPA into a DNA primer strand resulted in multiple inhibitory effects exerted on the enzyme and showed that neither compound acts as an absolute chain terminator. Further, inhibition of HIV-1 RT also occurred when these drugs were located in the template strand. These results indicate that HPMPC and HPMPA inhibit HIV-1 by a complex mechanism and suggest that this class of drugs has a broader spectrum of activity than previously shown.

Synthesis of [4,5Bis(hydroxymethyl)-1,3-dithiolan-2-yl]nucleosides as Potential Inhibitors of HIV 1

Journal of Organic Chemistry, 1996

The synthesis of [4,5-bis(hydroxymethyl)-1,3-dithiolan-2-yl]nucleosides is described. (2S,3S)-1,2: 3,4-Diepoxybutane (13) was reacted with potassium thiocyanate to give (2R,3R)-1,2:3,4-diepithiobutane (14). Thiiranering opening with acetate followed by deacetylation gave (2R,3R)-2,3dithiothreitol (19) which was silylated and treated with trimethyl orthoformate to give the 2-methoxy-1,3-dithiolane 20. Condensation of 20 with silylated thymine, uracil, N 4 -benzoylcytosine and 6-chloropurine using a modified Vorbrü ggen procedure, followed by deprotection, gave the nucleoside analogues. Compounds 26, 28, and 30 were found to be inactive when tested for anti-HIV activity in vitro.