Publications

CCDC 192233: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Synthesis and Antiviral Activity of 1,2-Carbonucleosides

Abstract Members of a new class of carbonucleoside analogues (OTC, o ne t wo substituted c arbonucleosides) were synthesized and evaluated against HIV.

Een computer-ondersteunde methode voor het ontwerpen van smeedmatrijzen (en de integratie in een CAD/CAM systeem)

No abstract is provided for this article.

On the mechanism of selective inhibition of herpesvirus replication by (E)-5-(2-bromovinyl)-2'-deoxyuridine.

Bromovinyldeoxyuridine (BVdUrd) is a potent antiherpesvirus compound with low cytotoxicity. To gain an insight into its selectivity and mechanism of inhibition, we chemically synthesized the 5'-triphosphate of BVdUrd, BVdUTP, and tested its effect on the activities of DNA polymerases [DNA nucleotidyltransferase (DNA directed), EC 2.7.7.7] of two herpesviruses--i.e., herpes simplex virus type 1 (HSV-1) and Epstein-Barr virus (EBV)--as well as cellular DNA polymerases alpha, beta, and gamma. The effects on the DNA polymerases were determined under assay conditions optimal for the individual polymerases. We found that the BVdUTP was considerably more inhibityory to the utilization of dTTP by the HSV-1 DNA polymerase then by the cellular DNA polymerases. For instance, as little as 1 microM BVdUTP inhibited the utilization of dTTP by HSV-1 DNA polymerase 50%, whereas the same concentration inhibited the DNA polymerase alpha and the DNA polymerase beta activities only 9% and 3%, respectively. The BVdUTP inhibited DNA synthesis by competing with the natural substrate, dTTP. The Km for dTTP and the Ki for the BVdUTP of the HSV-1 DNA polymerase were 0.66 and 0.25 microM, respectively. Kinetic analyses with the DNA polymerases alpha and beta and the EBV DNA polymerase also reflected a similar difference in sensitivity between the HSV-1 enzyme and other enzymes. Increasing the concentration of either the DNA template or the enzyme in the reaction mixture did not bring about a significant change in the extent of inhibition. Preincubation of the inhibitor with the enzyme was not necessary for inhibition. Studies on time course of inhibition revealed that the compound is inhibitory even after the initiation of DNA synthesis. These studies indicate that the ability of BVdUTP to preferentially inhibit the HSV-1 DNA polymerase may contribute towards its selective inhibition of the viral DNA replication in infected cells.

Molecular modifications of 2-arylidene-1-indanones leading to increased cytotoxic potencies

A series of 2-arylidene-1-indanones, 1, had been shown previously to display cytotoxic properties towards Molt 4/C8, CEM and L1210 cells. In the present study, two series of analogues of 1 were prepared namely various 2-arylidene-1,3-indandiones, 2, and chalcones, 3. In general, the potencies of compounds 2 and 3 were greater than the analogues bearing the same aryl substituents in series 1. Molecular modeling was undertaken in order to seek explanations for the variation in bioactivities.

Simple quantitative radioiodination of (E)-5-(2-iodovinyl)-2′-deoxyuridine (IVDU) by exchange labelling

CCDC 789968: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Structure-activity studies on open-chain analogues of nucleosides: Inhibition of S-adenosyl-L-homocysteine hydrolase and antiviral activity 1. Neutral open-chain analogues

Over 70 alkyl derivatives of purine bases were examined for their inhibitory effects toward rat liver S-adenosyl-L-homocysteine hydrolase and their antiviral activity. The following structural features must be fulfilled by an inhibitor of SAH-hydrolase: an intact adenine moiety, an alkyl chain bound at the 9-position and bearing a vicinal diol at the 2',3'-position, with 2 S configuration. An additional substitution at the 3-position lowers or annihilates the inhibitory activity. The enzyme inhibition is reversible. Some of the compounds are substrates of adenosine aminohydrolase. All inhibitors of SAH-hydrolase exhibit antiviral activity, e.g. against vesicular stomatitis virus and vaccinia virus in cell culture, and this antiviral correlates with the inhibition of SAH-hydrolase.

Mouse Adenovirus Type 1 Infection in SCID Mice: an Experimental Model for Antiviral Therapy of Systemic Adenovirus Infections

The importance of human adenovirus infections in immunocompromised patients urges for new and adequate antiadenovirus compounds. Since human adenoviruses are species specific, animal models for systemic adenovirus infections rely on a nonhuman adenovirus. We established mouse adenovirus type 1 (MAV-1) infection of BALB/c SCID mice as a model for the evaluation of antiadenovirus therapy. In vitro studies with mouse embryonic fibroblasts pointed to the acyclic nucleoside phosphonate cidofovir and the N-7-substituted acyclic derivative 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine (S-2242) as markedly active compounds against MAV-1. SCID mice, infected intranasally with MAV-1, developed a fatal disseminated infection after approximately 19 days, characterized by hemorrhagic enteritis. Several techniques were optimized to monitor viral, immunological, and pathological aspects of MAV-1 infection. Real-time PCR quantification of viral DNA revealed that after replication in the lungs, virus disseminated to several organs, including the brain, liver, spleen, intestine, heart, and kidneys (resulting in viruria). Immunohistochemical staining showed that MAV-1 was localized in the endothelial cells of the affected organs. Using reverse transcription-PCR, tissue levels of proinflammatory cytokines (i.e., interleukin-1beta and tumor necrosis factor alpha) were found to be markedly increased. The MAV-1/SCID model appears to be an appropriate model for in vivo evaluation of antiadenovirus agents. Treatment with cidofovir or S-2242 at a dose of 100 mg per kg of body weight resulted in a significant delay in MAV-1-related death, although these antivirals were unable to completely suppress virus replication despite continued drug treatment. These findings suggest that complete virus clearance during antiviral therapy for disseminated adenovirus infection may require an efficient adaptive immune response from the host.

ChemInform Abstract: Antiviral Activity of 3‐(3,5‐Dimethylbenzyl)uracil Derivatives Against HIV‐1 and HCMV

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Differential Activity of Polyanionic Compounds and Castanospermine against HIV Replication and HIV-Induced Syncytium Formation Depending on Virus Strain and Cell Type

Polyanionic compounds [i.e. pentosan polysulphate, dextran sulphate, heparin, suramin, and aurintricarboxylic acid (ATA)] and castanospermine were examined for their inhibitory effect on human immunodeficiency virus (HIV) strains (HIV-1 IIIB , HIV-1 RF , HIV-2 ROD and HIV-2 EHO ) in two different assays (HIV cytopathicity in MT-4 cells and HIV antigen expression in CEM cells). In the MT-4 assay dextran sulphate and pentosan polysulphate were more active against HIV-2 ROD , suramin was more active against HIV-1 RF , and ATA more active against HIV-2 EHO -Heparin was less, but castanospermine was more, active against the two HIV-2 strains. In the CEM assay dextran sulphate and suramin were equally active against all HIV strains, pentosan polysulphate was more active against both HIV-2 strains, whereas heparin was less active against HIV-2 ROD and ATA again was more active against HIV-2 EHO . The compounds and soluble CD4 (sCD4) were also tested in the HIV-induced syncytium formation assay, where chronically infected HUT-78 cells were mixed with uninfected MOLT-4 or CEM cells. The inhibitory effect of suramin and ATA on syncytium formation was independent of the virus strain or cell type. For dextran sulphate and pentosan polysulphate, it was dependent on virus strain, and for heparin, castanospermine, and sCD4, it was dependent on both the virus strain and cell type.

Comparative Efficacy of Antiherpes Drugs against Different Strains of Herpes Simplex Virus

A large variety of antiherpes compounds was compared for their inhibitory activity against laboratory strains and clinical isolates of herpes simplex virus (HSV) type 1 and type 2. From studies performed in primary rabbit kidney cell cultures, six, E-5-(2-bromovinyl)-2'-deoxyuridine, E-5-(2-iodovinyl)-2'-deoxyuridine, 5-vinyl-2'-deoxyuridine, 2'-fluoro-5-iodoaracytosine, acycloguanosine, and 5-iodo-2'-deoxycytidine, emerged as the most potent and selective antiherpes agents. For HSV type 1, the 50% inhibitory doses (ID50) were 0.008, 0.012, 0.018, 0.017, 0.04, and 0.06 micrograms/ml, respectively; those for HSV type 2 were 1, 2, 0.1, 0.05, 0.04, and 0.3 microgram/ml, respectively. These compounds did not inhibit host-cell metabolism or replication of vaccinia virus except at concentrations 100--10,000 times greater than the ID50 for any HSV. All were significantly less inhibitory for a thymidine kinase (TK)-deficient mutant of HSV type 1 than for normal strains, suggesting that phosphorylation by virus-induced TK was required to produce specific inhibition of HSV replication.

Synthesis and Comparative Cytostatic Activity of the New N-7 Acyclic Purine Nucleoside Analogues with Natural N-9 Regioisomers

The synthesis of the purine derivatives alkylated at N-7 (2a) and N-9 (2b) with 2-acetoxyethoxymethyl side chain, and chemical transformations of keto to chloro (5a), chloro to thio (6a) at C-6, and amino to fluoro (7a) at C-2 position of the purine ring were described.Structures of compounds were elucidated by analysis of their 1 H and 13 C NMR spectra, MS spectra and elemental analyses.N-7 Regioisomers (2a-7a) were evaluated for their cytostatic activities and their inhibitory effects were compared with those of the corresponding N-9 isomers.The 2-aminopurin-6-thione derivative (6a) showed the highest cytostatic activity, particularly against murine leukemia (L1210).

Recent Progress in Small Molecule CCR5 Antagonists as Potential HIV-1 Entry Inhibitors

Currently the long-term usage of traditional anti-HIV drugs, such as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), eventually leads to the emergence of drug resistance and severe side effects. Thus it is imperative to design and develop more promising HIV-1 inhibitors to overcome these drawbacks. Fortunately, with the identification of some fascinating targets in the entry process of viral life cycle, HIV-1 entry inhibitors (EIs) with low cytotoxicity and mild side effects turned out as novel and effective anti-HIV agents. Especially, of these potent EIs, small molecule CCR5 antagonist maraviroc was approved by US FDA in 2007, which significantly increased the therapeutic options for the clinical treatment of HIV-infected patients. Subsequently, as promising anti-HIV drug candidates, kinds of small molecule CCR5 antagonists have been synthesized and evaluated in clinical trials. In this article, current progress in the development of novel small molecule CCR5 antagonists will be reviewed on the basis of their chemical structures with a special attention to their discovery stories. Simultaneously, binding mode analysis based on molecular modeling studies will also be introduced.

ChemInform Abstract: Synthesis, Antiviral and Cytostatic Activities, of Carbocyclic Nucleosides Incorporating a Modified Cyclopentane Ring. Part 4. Adenosine and Uridine Analogues.

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Protective effects of anionic detergents on interferons: Reversible denaturation

Discovery, optimization, and target identification of novel coumarin derivatives as HIV-1 reverse transcriptase-associated ribonuclease H inhibitors

E-5-(2-Bromovinyl)-2'-Deoxyuridine vs. Interferon in the Systemic Treatment of Infection with Herpes Simplex Virus of Athymic Nude Mice

The effects of systemic administration of E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and interferon (IFN)--mouse IFN type I (MuIFN-alpha plus -beta), mouse IFN type II (MuIFN-gamma), and polyriboinosinic-polyribocytidylic acid (an IFN inducer)--on the development of herpetic skin lesions and associated mortality were studied in athymic nude (nu/nu) mice inoculated intracutaneously with herpes simplex virus (HSV) type 1 (strain KOS). BVDU was given intraperitoneally or orally at dosages of up to 5 mg per mouse per day; IFN and polyriboinosinic-polyribocytidylic acid were given intraperitoneally at dosages of up to 10(6) units per mouse per day and 100 microgram per mouse per day, respectively. Under conditions in which BVDU effectively suppressed the progression of the disease, IFN and polyriboinosinic-polyribocytidylic acid failed to suppress the disease. Thus, BVDU was superior to IFN in the treatment of HSV infection in immunologically compromised mice.