Publications

5-Alkynyl Analogs of Arabinouridine and 2‘-Deoxyuridine:  Cytostatic Activity against Herpes Simplex Virus and Varicella-Zoster Thymidine Kinase Gene-Transfected Cells

A group of arabinouridines (TMSEAU, EAU, IEAU-TA) and 2'-deoxyuridines (TMSEDU, EDU, IEDU) having a variety of substituents at the uracil C-5 position (trimethylsilylethynyl, TMSE; ethynyl, E; or iodoethynyl, IE), and the sugar C-2' position (2'-arabino OH in arabinouridine, AU; or 2'-deoxyribo H in 2'-deoxyuridine, DU) were prepared to acquire antiviral structure-activity relationships. A broad-spectrum viral panel screen showed that these 5-alkynylarabino/deoxy-uridines exhibit moderate anti-HSV-1 activity, with no difference in potency between arabinouridines and 2'-deoxyuridines. The 2'-deoxyuridines TMSEDU, EDU, and IEDU, unlike the arabinouridines, exhibited potent antiviral activity against cytomegalovirus, but they were also highly cytostatic. The abilities of the 5-alkynylarabino/deoxy-uridines to inhibit nontransfected (wild-type or thymidine kinase-deficient, tk-) and viral gene transfected (HSV-1, HSV-2, or VZV thymidine kinase-positive, tk+) FM3A and OST (osteosarcoma) cells were determined. This group of 5-alkynylarabino/deoxy-uridines showed an enhanced ability to inhibit cells transfected with a viral thymidine kinase gene (HSV-1tk+, HSV-2tk+, VZVtk+) relative to wild-type or thymidine kinase-deficient (tk-) cells.

6‐[2‐Phosphonomethoxy)Alkoxy]‐2,4‐Diaminopyrimidines: A New Class of Acyclic Pyrimidine Nucleoside Phosphonates with Antiviral Activity

Acyclic nucleoside phosphonate derivatives containing a pyrimidine base preferably bearing amino groups at C-2 and C-4 (DAPym), and linked at the C-6 position to (S)-[3-hydroxy-2-(phosphonomethoxy)propoxy] (HPMPO), 2-(phosphonomethoxy) ethoxy (PMEO) or (R)-[2-(phosphonomethoxy)propoxy] (PMPO), display an antiviral sensitivity spectrum that closely mimic that of the parental (S)-HPMP-, PME- and (R)-PMP-purine derivatives. Several PMEO-DAPym derivatives proved as potent as PMEA (adefovir) and (R)-PMPA (tenofovir) in inhibiting Moloney murine sarcoma virus (MSV)-induced tumor formation in newborn NMRI mice. The HPMPO-, PMEO- and PMPO-DAPym derivatives represent a novel well-defined subclass among the acyclic nucleoside phosphonates endowed with potent and selective antiviral activity.

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

Measurements of Cs-buffer gas collisional frequency shift using CPT interrogation

International audience

Inhibitory Effects ofAcyclic Nucleoside Phosphonates on HumanHepatitis BVirus andDuckHepatitis BVirus Infections inTissue Culture

and(S)-1-(3-hydroxy-2phosphonylmethoxypropyl)cytosine onhumanhepatitis Bvirus replication inthehumanhepatoma cell line HepG22.2.15 andduckhepatitis Bvirus infection inprimary duckhepatocytes wereinvestigated. (R)-9-(2phosphonylmethoxypropyl-2,6-diaminopurine hadthelowest 50%o inhibitory concentrations against hepatitis B virus andduckhepatitis Bvirus, 0.22 and0.06,iM, respectively, i.e., two-tofivefold lower concentrations than required for(R)-9-(2-phosphonylmethoxypropyl)adenine and9-(2-phosphonylmethoxyethyl)adenine. Allcompounds werenottoxic invitro ataconcentration of100,uM. Inchronic hepatitis Bvirus (HBV)infection thebasic therapy istheadministration ofinterferon, although complete disappearanceofvirus markers isseldom observed. Hepatitis Beantigen seroconversion, reflecting adrastic decline ofviral replication, isseeninonly 20to40%ofpatients withHBV infections. Morepotent antiviral drugs areeagerly awaited, andinlight ofthis, theacyclic nucleoside phosphonates described earlier (3,4)wereconsidered adequate candidates tobefurther pursued forthetreatment ofHBV infections. Inanearlier study (6) weinvestigated theacyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA) intwohepatoma cell lines andprimary duckhepatocytes. The 50%inhibitory concentrations (IC50) forhumanHBV and duckHBV (DHBV)werefoundtobe1.2and0.2,uMas measured inHepG22.2.15 cells andprimary duckhepatocytes, respectively. Amongtheacyclic nucleoside phosphonates several other

Pharmacokinetics of intravenous pentosan polysulphate (HOE/BAY 946) in HIV-positive patients

Department of Internal Medicine, Division of Infectious Diseases, Rudolf Virchow University Hospital, Free University of Berlin, D-100 Berlin 65, Germany * Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

A test object for calibration and accuracy assessment in X-ray CT metrology

No abstract is provided for this article.

Melt pool feature analysis using a high-speed coaxial monitoring system for laser powder bed fusion of Ti-6Al-4 V grade 23

In laser powder bed fusion (LPBF), defects such as pores or cracks can seriously affect the final part quality and lifetime. Keyhole porosity, being one ty

ChemInform Abstract: Synthesis and Biological Evaluation of 1,2‐Disubstituted Carbonucleosides of 2‐Amino‐6‐substituted Purine and 8‐Azapurine.

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.

1,2,4-Triazole Derivatives Inhibiting the Human Immunodeficiency Virus Type 1 (HIV-1) in vitro

A novel series of selective 1,2,4-triazole nonnucleoside reverse transcriptase inhibitors (NNRTIs) is described. In MT-4 cells compound, 4f inhibited human immunodeficiency virus type 1 (HIV-1) induced cytopathology at an IC50 of 9.98 μM with a selectivity index of 18.6. The hypothetical docking model of RT/4f derived from X-ray crystallographic structure of capravirine complex with HIV-1 RT links the activity profile to the H-bonding network.

Therapeutic strategies for COVID-19: progress and lessons learned

HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation

HIV type 1 (HIV-1) uses the chemokine receptors CCR5 and CXCR4 as coreceptors for entry into target cells. Here we show that the HIV-1 envelope gp120 (Env) activates multiple ionic signaling responses in primary human macrophages, which are important targets for HIV-1 in vivo. Env from both CCR5-dependent JRFL (R5) and CXCR4-dependent IIIB (X4) HIV-1 opened calcium-activated potassium (K(Ca)), chloride, and calcium-permeant nonselective cation channels in macrophages. These signals were mediated by CCR5 and CXCR4 because macrophages lacking CCR5 failed to respond to JRFL and an inhibitor of CXCR4 blocked ion current activation by IIIB. MIP-1beta and SDF-1alpha, chemokine ligands for CCR5 and CXCR4, respectively, also activated K(Ca) and Cl(-) currents in macrophages, but nonselective cation channel activation was unique to gp120. Intracellular Ca(2+) levels were also elevated by gp120. The patterns of activation mediated by CCR5 and CXCR4 were qualitatively similar but quantitatively distinct, as R5 Env activated the K(Ca) current more frequently, elicited Cl(-) currents that were approximately 2-fold greater in amplitude, and elevated intracellular Ca(+2) to higher peak and steady-state levels. Env from R5 and X4 primary isolates evoked similar current responses as the corresponding prototype strains. Thus, the interaction of HIV-1 gp120 with CCR5 or CXCR4 evokes complex and distinct signaling responses in primary macrophages, and gp120-evoked signals differ from those activated by the coreceptors' chemokine ligands. Intracellular signaling responses of macrophages to HIV-1 may modulate postentry steps of infection and cell functions apart from infection.

Activity of the (R)-Enantiomers of 9-(2-Phosphonylmethoxypropyl)-Adenine and 9-(2-Phosphonylmethoxypropyl)-2,6-diaminopurine against Human Immunodeficiency Virus in Different Human Cell Systems

Rapid manufacturing of dental prostheses by means of selective laser sintering/melting

Selective laser sintering of hard metal powders

5'-O-Phosphonomethyl-2',3'-dideoxynucleosides: synthesis and anti-HIV activity

5'-O-Phosphonomethylation of different pyrimidine 2',3'-dideoxynucleosides was accomplished by reaction of the latter with diethyl [(p-toylsulfonyl)oxy]methanephosphonate (1) in the presence of sodium hydride. The base-phosphonomethylated (15-19) and sugar-phosphonomethylated (8-12) derivatives could be readily distinguished by 1H and 13C NMR and MS analysis. Protection of the uracil or thymine residue with a N3-benzoyl group failed to prevent base modification. However, O4-methyl-protected 2',3'-dideoxyuridine readily afforded the 5'-O-phosphonomethylated derivative 12, which was converted to both the 2',3'-didoxyuridine analogue 27 and the 2',3'-dideoxycytidine counterpart 29. The 5'-O-phosphonomethyl derivatives of 3'-deoxythymidine (23), 2',3'-dideoxyuridine, (27), 2',3'-dideoxycytidine (29), 3'-O-methylthymidine (26), and 3'-amino-3'-deoxythymidine (28) did not show an appreciable anti-HIV activity in MT-4 cells. In contrast, the 5'-O-phosphonomethyl derivatives of 3'-deoxy-3'-fluorothymidine (24) and 3'-azido-3'-deoxythymidine (25) inhibited HIV-1 cytopathogenicity by 50% at a concentration of approximately 1 microM.

Structural optimization of pyridine-type DAPY derivatives to exploit the tolerant regions of the NNRTI binding pocket

Inactivity of the bicyclic pyrimidine nucleoside analogues against simian varicella virus (SVV) does not correlate with their substrate activity for SVV-encoded thymidine kinase