P. Claes

Sulphated Cyclodextrins are Potent anti-HIV Agents Acting Synergistically with 2′,3′-dideoxynucleoside Analogues

Sulphated cyclodextrins proved to be potent inhibitors of human immunodeficiency virus (HIV), cytomegalovirus (CMV) and herpes simplex virus (HSV) but not other enveloped viruses (i.e. Sindbis virus, respiratory syncytial virus, Tacaribe virus, vesicular stomatitis virus or vaccinia virus). Their mechanism of action against HIV can be attributed to an inhibition of the binding of HIV-1 virions to the cells, as demonstrated by flow cytometric analysis. The sulphated cyclodextrins enhanced the anti-HIV-1 activity of pyrimidine 2′,3′-dideoxyribosides (i.e. azidothymidine, dideoxycytidine, didehydro-dideoxythymidine, fluorodide-oxychlorouridine), in a subsynergistic manner, and the anti-HIV-1 activity of purine 2′,3′-dideoxyribosides (dideoxyadenosine, dideoxyinosine, 2,6-diaminopurine dideoxyriboside) and 9-(2-phosphonylmethoxyethyl)adenine in a synergistic manner. Following intravenous administration of the sulphated cyclodextrins to rabbits, drug serum concentrations were obtained that were 100- to 1000-fold above the minimum inhibitory concentration for HIV or CMV.

Synthesis of 2′-Deoxy-2′ -Fluoro-D-Arabinopyranopyranosyl Nucleosides and Their 3′,4′-Seco analogues

Abstract 2′-Deoxy-2′-fluoro-D-arabinopyranosyl nucleosides were synthesized by condensation of 1,3,4-tri-O-benzoyl-2-deoxy-2-fluoro-D-arabinopyranose with the appropriate silylated bases in the presence of trimethylsilyl triflate. Scission of the 3′,4′-bond by periodate oxidation followed by sodium borohydride reduction resulted in the formation of the 3′,4′-seco analogues of the 2′-deoxy-2′-fluoro-D-arabinofuranosyl nucleosides.

New Polyacetal Polysulphate Active against Human Immunodeficiency Virus and other Enveloped Viruses

A new polyacetal polysulphate, termed PAPS, was synthesized starting from dextran through oxidation, reduction, and subsequent sulphation. PAPS inhibited HIV-1- and HIV-2-induced cytopathicity in MT-4 cells at concentrations comparable to those required for dextran sulphate (MW5000) to inhibit the cytopathicity of these viruses (50% inhibitory concentration: 0.4–0.04 μg ml−1). At these concentrations PAPS had no anticoagulant activity. PAPS suppressed syncytium formation between MOLT-4 cells and persistently HIV-1- or HIV-2-infected HUT-78 cells at a concentration of 1 μg ml−1, that is 25- to 30-fold lower than that required for dextran sulphate to inhibit syncytium formation. Like dextran sulphate, PAPS inhibited HIV-1 binding to the cells and anti-gp120 mAb binding to HIV-1 gp120. Also, PAPS proved equally active as dextran sulphate against herpes simplex virus, cytomegalovirus and the arenaviruses Junin and Tacaribe, and 10-fold more active than dextran sulphate against vaccinia, Sindbis, influenza A, and vesicular stomatitis virus. Neither PAPS nor dextran sulphate proved inhibitory to the non-enveloped viruses polio, Coxsackie and reovirus. Pharmacokinetic studies in rabbits revealed that after intravenous bolus injection the serum concentrations of PAPS decayed biphasically, with an initial half-life of approximately 45–60 min. Twenty-four hours following their intraperitoneal administration to mice, PAPS as well as dextran sulphate generated low titres of an antiviral principle that was at least partially interferon-like.

Synthesis, enzymatic stability and physicochemical properties of oligonucleotides containing a N-cyanoguanidine linkage.

Abstract Nucleoside dimers with a N-cyanoguanidine linkage were synthesized and used as building blocks for oligonucleotide synthesis. Oligonucleotides composed of alternating phosphodiester and cyanoguanidine functions are still able to hybridize with a complementary natural oligodeoxynucleotide.

A more sensitive assay system for the detection of RNA-dependent DNA polymerase in oncogenic RNA viruses

Abstract Addition of Carbopol 934 (carboxypolymethylene, carboxyvinyl polymer) to an in vitro RNA-dependent DNA polymerase assay system resulted in a significant increase in the rate and extent of DNA synthesis. Carbopol may be a valuable tool for increasing the sensitivity of detection of reverse transcriptase activity in oncogenic RNA viruses and malignant tissues.

Synthesis of Thymidine Analogues with a Cyanoimido Substituent

Abstract The synthesis of thymidine analogues with a N-cyanoimido substituent in the 3′- or 5′-position is described.

2-Hydroxyethoxyethylated Bases as Acyclic Analogues of 1,5-Anhydrohexitol Nucleoside Derivatives

Abstract The synthesis and antiviral activity of a new series of acyclic nucleoside analogues containing a (2-hydroxyethoxy)ethyl moiety is discussed.

Mixed oligonucleotide analogues with an acyclic carbohydrate moiety and a N-cyanoguanidine functionality

Abstract Mixed aligonucleotide analogues having a backbone structure with a N-cyanoguanidine functionality and an acyclic sugar moiety were synthesized. This combination, however, has a detrimental effect on duplex stability of DNA-DNA hybrids.

Synthesis and antiviral evaluation of 3′-substituted thymidine analogues derived from 3′-amino-3′-deoxythymidine

Abstract Based on the structure-activity relationship for antiviral activity, a series of 3′-deoxy-3′- N -functionalized thymidine analogues derived from 3′-amino-3′-deoxythymidine was synthesized. These compounds were evaluated for their antiviral activity. Three of the prepared molecules namely 3′-(1,2,4-triazol-1-yl)carbimidoylamino-3′-deoxythymidine 6 , 3′-(3-amino-1-methyl-1,2,4-triazol-5-yl)amino-3′-deoxythymidine 8b and 3′- N -cyano- O -phenylisourea-3′-deoxythymidine 7 show moderate but selective in vitro activity against HIV-1 and HIV-2. These data demonstrate that some steric bulk in the 3′-position is compatible with anti-HIV activity

Synthesis and Antiviral Evaluation of 3′-Substituted Thymidine Analogues Derived from 3′-Amino-3′-deoxythymidine

Abstract To assess the structure-activity relationship for antiviral activity, a series of 3′-deoxy-3′-N-functionalized thymidine analogues were synthesized. Several of these thymidine analogues show moderate in vitro activity against HIV-1 and HIV-2.