Publications

Bicyclic Nucleoside Inhibitors of Varicella—Zoster Virus: The Effect of Branching in the p‐Alkylphenyl Side Chain.

Abstract For Abstract see ChemInform Abstract in Full Text.

Generierende, schichtweise Herstellung von Werkstücken und Werkzeugen aus Metallen 3D-Erfahrungsforum Werkzeug- und Formenbau

HIV‐1‐specific RT inhibitors: Highly selective inhibitors of human immunodeficiency virus type 1 that are specifically targeted at the viral reverse transcriptase

The TIBO, HEPT, nevirapine, pyridinone, BHAP, TSAO, and alpha-APA derivatives, although belonging to structurally diverging classes of molecules, share remarkable common features. They are specifically active against the reverse transcriptase of HIV-1 (TIBO and HEPT also, to a certain extent, against the reverse transcriptase of SIVagm strains), but not against the reverse transcriptases of HIV-2 or any other retroviruses. Nor are they active against any of the cellular DNA polymerases. These HIV-1-specific RT inhibitors seem to interact with a specific target site (YQYMDDLY) at positions 181-188, which is distinct from, but functionally and spatially related to, the substrate (dNTP) binding site. The tyrosine residues Y181 and Y188 play a crucial role in the interaction of TIBO and its congeners with their target site. The HIV-1-specific RT inhibitors have proven to inhibit the replication of various HIV-1 strains, including AZT-resistant HIV-1 strains, in different cell culture systems, including peripheral blood lymphocytes and monocyte/macrophages. In vitro they exhibit selectivity indexes of up to 5 orders of magnitude, which means that they are inhibitory to virus replication in cell culture at concentrations that are up to 100,000 times lower than the concentrations at which they are toxic to the host cells. As a rule, the HIV-1-specific RT inhibitors are orally bioavailable, as has been demonstrated with the TIBO and HEPT derivatives, nevirapine, pyridinones, and the alpha-APA derivatives in rats, dogs, monkeys, and humans. They sustain plasma drug levels that are well above the concentration required to inhibit virus replication in cell culture. Clinical studies have been undertaken with TIBO R82913, nevirapine, and pyridinones, and others (i.e., alpha-APA R89439) will soon follow. The problem of virus-drug resistance, which seems to readily emerge in vitro, will have to be addressed in the in vivo studies.

Synthesis, anti-HIV-1 activity, and modeling studies of N-3 Boc TSAO compound

Sulphated and Sulphonated Polymers Inhibit the Initial Interaction of Hepatitis B Virus with Hepatocytes

The initial step during hepatitis B virus (HBV) infection is the specific attachment of the virus to the hepatocyte. Here we studied whether the binding of HBV to hepatocytes can, as is the case with most other enveloped viruses, be blocked by polyanionic compounds. Viral particles produced by HepAD38 cells were used as inoculum and HBV-negative HepG2 cells, as well as primary human hepatocytes, as target cells. Three sulphated polymers, that is, PAVAS (a co-polymer of acrylic acid with vinyl alcohol sulphate), heparin and dextran sulphate (DS) (MW 5000), and the sulphonated polymer PAMPS [poly(2-acryl-amido-2-methyl-1-propanesulfonic acid] (MW approximately 7000-12000), proved strong inhibitors of the binding of HBV to HepG2 cells and primary hepatocytes. The 50% effective concentration (EC50) for inhibition of HBV binding to HepG2 cells by PAVAS, heparin, DS and PAMPS was 1.3 microg/ml, 1.6 microg/ml, 1.8 microg/ml and 3.3 microg/ml, respectively, and to primary hepatocytes 1.6 microg/ml (PAVAS), 1.6 microg/ml (heparin), 2.6 microg/ml (DS) and 4.1 microg/ml (PAMPS). These values are in the same range as the concentrations required for these compounds to prevent such viruses as herpesviruses and HIV from binding to cells. These findings may be helpful in elucidating the mechanism of the initial interaction of HBV with hepatocytes.

2‐(2,6‐Dihalo‐phenyl)‐3‐heteroaryl‐2‐ylmethyl‐1, 3‐thiazolidin‐4‐ones: Anti‐HIV agents

A diversity of novel 2-aryl-3-heteroaryl-2-ylmethyl-1,3-thiazolidin-4-ones were designed and synthesized by reacting heteroaryl-2-ylmethyl amine with various 2,6-dihalosubstituted benzaldehydes and mercaptoacetic acid. The title compounds were evaluated for human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) inhibitory activity. The results of in vitro assays showed that some of the compounds were effective inhibitors of HIV-1 reverse transcriptase enzyme at micromolar concentrations with less cytotoxicity in both MT-4 cells as well as acutely infected human T-lymphoid CEM cells. Compounds 4h and 4k emerged as moderately more potent with EC(50) are at 0.20 and 0.21 microM as compared to reference parent compound thiazolobenzimidazoles EC(50) 0.35 microM in MT-4 cells.

Interferon Induction by Two 2′‐Modified Double‐Helical RNAs, Poly(2′‐nuoro‐2′‐deoxymosimc acid) · poly(cytidylic acid) and Poly(2′‐chloro‐2′‐deoxyinosinic acid) · poly(cytidylic acid)

In addition to the 2'-azido analogue of (I)n x (C)n, (dIn3)n x (C)n, we have found two other (I)n x (C)n analogues, (dIfl)n x (C)n and (dIcl)n x (C)n, in which the 2'-hydroxyls of the (I)n strand are replaced by either fluorine or chlorine, to be highly effective in inducing interferon. This contrasted with the lack of interferon-inducing activity noted for various other 2'-halogeno analogues of (I)n x (C)n and (A)n x (U)n, i.e. (I)n x (dCcl)n, (dAfl)n x (U)n, (dAcl)n x (U)n, (A)n x (dUfl)n and (A)n x (dUcl)n. In most assay systems, viz. primary rabbit kidney cells, human diploid fibroblasts, HeLa cells, interferon-primed mouse L-929 cells, and intact rabbits, (dIfl)n x (C)n and (dIcl)n x (C)n induced interferon levels that were comparable to those induced by (I)n x (C)n. There was one particular system (L-929 cells treated with DEAE-dextran), however, in which (dIfl)n x (C)n and (dIcl)n x (C)n, unlike (I)n x (C)n, failed to stimulate interferon production. As monitored by both radiochemical and biological means, (dIfl)n x (C)n and, to a lesser extent, (dIcl)n x (C)n were more resistant to degradation by ribonuclease A, T1 and human serum nucleases than was (I)n x (C)n. In their reactivity towards antibodies to double-stranded RNA (dIfl)n x (C)n and (dIcl)n x (C)n conformed more closely to (I)n x (C)n than did other 2'-substituted (e.g. 2'-O-methyl or 2'-O-ethyl) analogues of (I)n x (C)n. The high interferon-inducing potency of (dIfl)n x (C)n and (dIcl)n x (C)n has both theoretical and practical implications. While our findings suggest that (dIfl)n x (C)n and (dIcl)n x (C)n should be further explored for their therapeutic potentials, they also strengthen the notion that the interferon-inducing capacity, and possibly other biological functions of double-stranded RNAs is dependent on the recognition of the overall conformation of the polynucleotide rather than on the binding of specific functional groups such as the 2'-hydroxyl group.

Structure−Antiviral Activity Relationship in the Series of Pyrimidine and Purine <i>N</i>-[2-(2-Phosphonomethoxy)ethyl] Nucleotide Analogues. 1. Derivatives Substituted at the Carbon Atoms of the Base

A series of dialkyl esters of purine and pyrimidine N-[2-(phosphonomethoxy)ethyl] derivatives substituted at position 2, 6, or 8 of the purine base or position 2, 4, or 5 of the pyrimidine base were prepared by alkylation of the appropriate heterocyclic base with 2-chloroethoxymethylphosphonate diester in the presence of sodium hydride, cesium carbonate, or 1,8-diazabicyclo[5,4, 0]undec-7-ene (DBU) in dimethylformamide. Additional derivatives were obtained by the transformations of the bases in the suitably modified intermediates bearing reactive functions at the base moiety. The diesters were converted to the corresponding monoesters by sodium azide treatment, while the free acids were obtained from the diester by successive treatment with bromotrimethylsilane and hydrolysis. None of the PME derivatives in the pyrimidine series, their 6-aza or 3-deaza analogues, exhibited any activity against DNA viruses or retroviruses tested, except for the 5-bromocytosine derivative. Substitution of the adenine ring in PMEA at position 2 by Cl, F, or OH group decreased the activity against all DNA viruses tested. PMEDAP was highly active against HSV-1, HSV-2, and VZV in the concentration range (EC50) of 0.07-2 microg/mL. Also the 2-amino-6-chloropurine derivative was strongly active (EC50 = 0.1-0. 4 microg/mL) against herpes simplex viruses and (EC50 = 0.006-0.3 microg/mL) against CMV and VZV. PMEG was the most active compound of the whole series against DNA viruses (EC50 approximately 0.01-0.02 microg/mL), though it exhibited significant toxicity against the host cells. The base-modified compounds did not show any appreciable activity against DNA viruses except for 7-deazaPMEA (IC50 approximately 7.5 microg/mL) against HIV-1 and MSV. The neutral (diisopropyl, diisooctyl) diesters of PMEA were active against CMV and VZV, while the corresponding monoesters were inactive. The diisopropyl ester of the 2-chloroadenine analogue of PMEA showed substantially (10-100x) higher activity against CMV and VZV than the parent phosphonate. Also, the diisopropyl and diisooctyl ester of PMEDAP inhibited CMV and VZV, but esterification of the phosphonate residue did not improve the activity against either MSV or HIV.

Retinoic Acid Conjugates as Potential Antitumor Agents:  Synthesis and Biological Activity of Conjugates with Ara-A, Ara-C, 3(2<i>H</i>)-Furanone, and Aniline Mustard Moieties

In a dual targeting approach, to explore the ability of tretinoin (all-trans-retinoic acid) to behave as a covalent carrier for cytotoxic entities, conjugates of retinoic acid with a few representative molecules, being important examples of antitumor pharmacophores (i.e., nucleoside analogues and alkylating agents), have been synthesized and tested for their cytostatic and differentiating activity. All compounds were stable to in vitro hydrolysis in human plasma and more lipophilic than the parent compounds, thus consenting enhanced uptake into the cells. Among the nucleoside analogues the Ara-C derivatives 3 and 6 and the Ara-A derivative 7 proved the most cytostatic (IC50 < 0.32 microgram/mL) resulting from 25- to > 144-fold more active (Ara-A derivatives) or at least as equally active (Ara-C derivatives) as compared to the parent nucleosides. Compound 3, endowed with a highly lipophilic silyl moiety at the 3' and 5' positions, showed the highest differentiating activity (54% and 44% differentiated HL-60 cells at 0.2 and 0.05 microgram/mL respectively). With regard to the retinoic acid conjugates of alkylating agents, compound 10 was the most cytostatic agent (IC50 < 0.32 microgram/mL) and the most potent differentiating agent (33-34% at 0.32 and 0.08 microgram/mL). These structures may also be regarded as analogs of either retinoic acid or the cytotoxic compound.

Structures et activités des inhibiteurs non-nucléosidiques de la transcriptase inverse du VIH (INNTI)

ChemInform Abstract: Palladium‐Catalyzed Aryl Amination Reactions of 6‐Bromo‐ and 6‐Chloropurine Nucleosides.

Abstract Amination of bromo‐ (I) and chloropurine derivatives (IV) with aromatic amines is smoothly achieved in the presence of Pd(O‐Ac) 2 —Xantphos catalytic system.

A design support system using high level mould objects

No abstract is provided for this article.

Triple or quadruple drug therapy in naive HIV-1 seropositives does not prevent the selection of resistant virus in a subset of patients

Generalisation of the Dick effect to continuous beam frequency standards

In atomic frequency standard operating in pulsed mode, the frequency noise of the interrogating oscillator is not completely seen by the atoms (ions) and thereby the long term stability of such standards is limited by the "Dick effect" which is formulated using the sensitivity function of the standard. Here, we introduce the sensitivity function for continuous frequency standards in a way similar to that of pulsed standards. We compute it in some typical cases for a monokinetic and for a weighted maxwellian velocity distribution. We find that Dick effect is present in this kind of standards and that it is due essentially to the modulation-demodulation operation.

Synthesis, antiviral activity, and cytotoxicity of some novel quinazolin-4 (3h)-one derivatives

Ribavirin therapy for SSPE virus infection in hamster

ChemInform Abstract: Cytotoxic and Anticancer Properties of Some 4‐Aryl‐3‐arylcarbonyl‐1‐ethyl‐4‐piperidinols and Related Compounds.

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.

2',3'-Dideoxynucleoside analogues as inhibitors of human immunodeficiency virus

status: Published