Structure-activity studies on open-chain analogues of nucleosides: Inhibition of S-adenosyl-L-homocysteine hydrolase and antiviral activity 2. Acid open-chain analogues

1985 ◽  
Vol 50 (1) ◽  
pp. 262-279 ◽  
Author(s):  
Antonín Holý ◽  
Ivan Votruba ◽  
Erik De Clercq
Keyword(s):  
Antiviral Activity ◽  
Antiviral Agents ◽  
Inhibitory Effects ◽  
Open Chain ◽  
Reovirus Type ◽  
Vesicular Stomatitis ◽  
Hydroxybutanoic Acid ◽  
Type 3 ◽  
Derivatives Of

Over 50 ω-carboxyalkyl derivatives of adenine and other purine bases were examined for their inhibitory effects on rat liver S-adenosyl-L-homocysteine hydrolase and their antiviral activity. To be an inhibitor of SAH-hydrolase the analogue must contain an adenine base substituted at the position 9 by an ω-carboxyalkyl (C3-C5) chain bearing at least one hydroxyl function. The absolute configuration at the side-chain is decisive for the dihydroxy and trihydroxy compounds, but less important for the monohydroxyalkanoic acids. D-Eritadenine (1a) and 3-(adenin-9-yl)-2-hydroxypropanoic acids (12a) are the most potent SAH-hydrolase inhibitors and the only compounds possessing an antiviral activity (against vesicular stomatitis, parainfluenza type 3, reovirus type 1, and vaccinia virus). All these compounds effect a rapid irreversible inactivation of SAH-hydrolase. The esters of 1a and 12a exhibit little, if any inhibitory activity toward the enzyme; they are, however, much more potent antiviral agents than the parent compounds 1a and 12a, most probably acting as prodrugs of the latter. 2-Amino-D-eritadenine, (2R,3R)-5-(adenin-9-yl)-2,3-dihydroxypentanoic acid, 9-(dicarboxymethyl)adenine, 4-(adenin-9-yl)-2-hydroxybutanoic acid, 3-(8-bromoadenin-9-yl)-2-hydroxypropanoic acid and O-carboxymethyl derivatives of 9-(2,3-dihydroxypropyl)- and 9-(2,3,4-trihydroxybutyl)adenine are described as novel compounds.

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

1985 ◽  
Vol 50 (1) ◽  
pp. 245-261 ◽  
Author(s):  
Antonín Holý ◽  
Ivan Votruba ◽  
Erik De Clercq
Keyword(s):  
Antiviral Activity ◽  
Alkyl Chain ◽  
Structural Features ◽  
Inhibitory Effects ◽  
Open Chain ◽  
Structure Activity ◽  
Vicinal Diol ◽  
Alkyl Derivatives ◽  
Vesicular Stomatitis ◽  
Derivatives Of

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 2S 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.

scholarly journals Highly Oxygenated Triterpenoids and Diterpenoids from Fructus Rubi (Rubus Chingii Hu) and Their NF-kappa B Inhibitory Effects

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1911
Author(s):  
Jiang Wan ◽  
Xiao-Juan Wang ◽  
Nan Guo ◽  
Xi-Ying Wu ◽  
Juan Xiong ◽  
...  
Keyword(s):  
Inhibitory Effects ◽  
Nf Kappa B ◽  
Pentacyclic Triterpenoids ◽  
Chemical Structures ◽  
Phytochemical Investigation ◽  
Ic50 Values ◽  
Rubus Chingii ◽  
Rubus Chingii Hu ◽  
Type 3

During a phytochemical investigation of the unripe fruits of Rubus chingii Hu (i.e., Fructus Rubi, a traditional Chinese medicine named “Fu-Pen-Zi”), a number of highly oxygenated terpenoids were isolated and characterized. These included nine ursane-type (1, 2, and 4–10), five oleanane-type (3, 11–14), and six cucurbitane-type (15–20) triterpenoids, together with five ent-kaurane-type diterpenoids (21–25). Among them, (4R,5R,8R,9R,10R,14S,17S,18S,19R,20R)-2,19α,23-trihydroxy-3-oxo-urs-1,12-dien-28-oic acid (rubusacid A, 1), (2R*,4S*,5R*,8R*,9R*,10R*,14S*,17S*, 18S*,19R*,20R*)-2α,19α,24-trihydroxy-3-oxo-urs-12-en-28-oic acid (rubusacid B, 2), (5R,8R,9R,10R, 14S,17R,18S,19S)-2,19α-dihydroxy-olean-1,12-dien-28-oic acid (rubusacid C, 3), and (3S,5S,8S,9R, 10S,13R,16R)-3α,16α,17-trihydroxy-ent-kaur-2-one (rubusone, 21) were previously undescribed. Their chemical structures and absolute configurations were elucidated on the basis of spectroscopic data and electronic circular dichroism (ECD) analyses. Compounds 1 and 3 are rare naturally occurring pentacyclic triterpenoids featuring a special α,β-unsaturated keto-enol (diosphenol) unit in ring A. Cucurbitacin B (15), cucurbitacin D (16), and 3α,16α,20(R),25-tetrahydroxy-cucurbita-5,23- dien-2,11,22-trione (17) were found to have remarkable inhibitory effects against NF-κB, with IC50 values of 0.08, 0.61, and 1.60 μM, respectively.

scholarly journals Activity of Penciclovir in Combination with Azido-Thymidine, Ganciclovir, Acyclovir, Foscarnet and Human Interferons against Herpes Simplex Virus Replication in Cell Culture

1992 ◽  
Vol 3 (2) ◽  
pp. 85-94 ◽  
Author(s):  
D. Sutton ◽  
J. Taylor ◽  
T. H. Bacon ◽  
M. R. Boyd
Keyword(s):  
Cell Culture ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Antiviral Agents ◽  
High Concentrations ◽  
Simplex Virus ◽  
Hsv 1

Combinations of penciclovir (PCV) with other antiviral agents (acyclovir, ACV; ganciclovir, GCV; foscarnet, PFA; azido-thymidine, AZT) or with human interferons (HulFN-α,β,γ) were tested for inhibitory activity against herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) in cell culture. The antiviral interactions observed between combinations of PCV with ACV or GCV were purely additive. Combinations of PCV with HulFNs demonstrated highly synergistic anti-herpesvirus activity; some synergy was also detected between PCV and PFA against HSV-1. High concentrations of AZT inhibited the antiviral activity of PCV; this antagonism was competitive. In more detailed studies it was demonstrated that high concentrations of AZT also inhibited the antiviral activity of ACV, and that ACV was more sensitive to this antagonism than PCV. It was concluded that the antagonism was unlikely to have clinical significance.

Reovirus type 1 and type 3 differ in their binding to isolated intestinal epithelial cells

1988 ◽  
Vol 5 (1) ◽  
pp. 29-40 ◽  
Author(s):  
David B. Weiner ◽  
Karen Girard ◽  
William V. Williams ◽  
Thomas McPhillips ◽  
Donald H. Rubin
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Reovirus Type ◽  
Type 3

scholarly journals A novel role for calmodulin: Ca2+-independent inhibition of type-1 inositol trisphosphate receptors

1998 ◽  
Vol 334 (2) ◽  
pp. 447-455 ◽  
Author(s):  
Thomas J. A. CARDY ◽  
Colin W. TAYLOR
Keyword(s):  
Spodoptera Frugiperda ◽  
Inhibitory Effect ◽  
Ip3 Receptors ◽  
Inhibitory Effects ◽  
Independent Manner ◽  
S 100 ◽  
High Concentrations ◽  
Type 3 ◽  
Stimulation Of

Calmodulin inhibits both inositol 1,4,5-trisphosphate (IP3) binding to, and IP3-evoked Ca2+ release by, cerebellar IP3 receptors [Patel, Morris, Adkins, O'Beirne and Taylor (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 11627–11632]. In the present study, full-length rat type-1 and -3 IP3 receptors were expressed at high levels in insect Spodoptera frugiperda 9 cells and the effects of calmodulin were examined. In the absence of Ca2+, calmodulin caused a concentration-dependent and reversible inhibition of [3H]IP3 binding to type-1 IP3 receptors by decreasing their apparent affinity for IP3. The effect was not reproduced by high concentrations of troponin C, parvalbumin or S-100. Increasing the medium free [Ca2+] ([Ca2+]m) inhibited [3H]IP3 binding to type-1 receptors, but the further inhibition caused by a submaximal concentration of calmodulin was similar at each [Ca2+]m. In the absence of Ca2+, 125I-calmodulin bound to a single site on each type-1 receptor subunit and to an additional site in the presence of Ca2+. There was no detectable binding of 125I-calmodulin to type-3 receptors and binding of [3H]IP3 was insensitive to calmodulin at all [Ca2+]m. Both peptide and conventional Ca2+–calmodulin antagonists affected neither [3H]IP3 binding directly nor the inhibitory effect of calmodulin in the absence of Ca2+, but each caused a [Ca2+]m-dependent reversal of the inhibition of [3H]IP3 binding caused by calmodulin. Camstatin, a peptide that binds to calmodulin equally well in the presence or absence of Ca2+, reversed the inhibitory effects of calmodulin on [3H]IP3 binding at all [Ca2+]m. We conclude that calmodulin specifically inhibits [3H]IP3 binding to type-1 IP3 receptors: the first example of a protein regulated by calmodulin in an entirely Ca2+-independent manner. Inhibition of type-1 IP3 receptors by calmodulin may dynamically regulate their sensitivity to IP3 in response to the changes in cytosolic free calmodulin concentration thought to accompany stimulation of neurones.

scholarly journals Virus-induced diabetes mellitus. XX. Polyendocrinopathy and autoimmunity.

1981 ◽  
Vol 153 (6) ◽  
pp. 1457-1473 ◽  
Author(s):  
T Onodera ◽  
A Toniolo ◽  
U R Ray ◽  
A B Jenson ◽  
R A Knazek ◽  
...  
Keyword(s):  
Anterior Pituitary ◽  
Gene Segment ◽  
Inflammatory Cells ◽  
S1 Gene ◽  
Virus Particles ◽  
Viral Antigens ◽  
Reovirus Type ◽  
Type 3 ◽  
Runting Syndrome

Mice infected with reovirus type 1 developed transient diabetes and a runting syndrome. The diabetes was characterized by hyperglycemia, abnormal glucose tolerance tests, and hypoinsulinemia. Inflammatory cells and viral antigens were found in the islets of Langerhans, and virus particles were seen in alpha, beta, and delta cells. The runting syndrome consisted of retarded growth, oily hair, alopecia, and steatorrhea. Inflammatory cells and viral antigens were found in the anterior, but not posterior pituitary. Electron microscopy revealed virus particles in growth hormone (GH)-producing cells and radioimmunoassay showed that the concentration of GH in the blood was decreased. Examination of sera from infected mice revealed autoantibodies that, by immunofluorescence, reacted with cytoplasmic antigens in the islets of Langerhans, anterior pituitary, and gastric mucosa of uninfected mice. Absorption studies and enzyme-linked immunosorbent assays designed to identify the reactive antigens showed that some of the autoantibodies were directed against insulin and others against GH. Reovirus type 3, in contrast to reovirus type 1, did not induce autoantibodies to GH. By use of recombinant viruses, the segment of the reovirus genome responsible for the induction of autoantibodies to GH was identified. Virus containing the S1 gene segment from reovirus type 1, which codes for the sigma 1 polypeptide (i.e., hemagglutinin), infected cells in the anterior pituitary and induced autoantibodies to GH, whereas virus containing the S1 gene segment from reovirus type 3 failed to infect cells in the anterior pituitary and did not induce autoantibodies to GH. We conclude that reovirus type 1 infection can lead to polyendocrinopathy and autoimmunity and that the S1 gene segment is required for the induction of autoantibodies to GH.

Triazene derivatives of (1,x)-diazacycloalkanes — Part IX. Synthesis and characterization of a series of 1,4-di[2-aryl-1-diazenyl]-2,6-dimethylpiperazines

2010 ◽  
Vol 88 (4) ◽  
pp. 344-351 ◽  
Author(s):  
Naomi Hunter ◽  
Keith Vaughan
Keyword(s):  
Diazonium Salt ◽  
Mass Measurement ◽  
2D Nmr ◽  
Piperazine Ring ◽  
Ir And Nmr Spectroscopy ◽  
Methylene Groups ◽  
Type 3 ◽  
Derivatives Of

A series of 1,4-di-[2-aryl-1-diazenyl]-2,6-dimethylpiperazines (5a–5l), have been synthesized by the reaction of 2,6-dimethylpiperazine with 2 equiv. of the appropriate diazonium salt. The products have been characterized by IR and NMR spectroscopy, and the molecular composition has been verified by high-resolution EI mass spectrometry with accurate mass measurement of the molecular ion. The presence of stereocenters at C2 and C6 of the piperazine ring in the bis-triazene 5 creates two unique pairs of diastereotopic protons in the methylene groups at positions 3 and 5 of the piperazine ring, as evidenced by the complexity of the NMR spectra, which nevertheless can be fully assigned in most cases. The assignment of the proton and carbon signals in the 1,4-di-[2-aryl-1-diazenyl]-2,6-dimethylpiperazines has been aided by the use of 2D NMR HSQC spectroscopy. These results compare favorably with assignments of proton and carbon signals reported previously for triazenes of type 1 and bis-triazenes of type 3.

scholarly journals Synthesis and antiviral activity of 4,6-bis-ethylamino[1,3,5]triazine derivatives for Flu A (H1N1) virus California/07/2009

2020 ◽  
Vol 14 (2) ◽  
Author(s):  
A. M. Demchenko ◽  
O. V. Moskalenko ◽  
V. V. Sukhoveev ◽  
O. I. Barchyna ◽  
Yu. A. Fedchenkova
Keyword(s):  
Antiviral Activity ◽  
Influenza A ◽  
H1n1 Virus ◽  
Antiviral Agents ◽  
Pharmaceutical Chemistry ◽  
Test Substance ◽  
Triazine Derivatives ◽  
Pharmacological Screening ◽  
Derivatives Of

Nowadays, control of viral diseases becomes especially relevant, considering spreading of influenza A (subtype H1N1) in this season and appearance of new coronavirus SARS-CoV-2, which caused their epidemic spreading in the world. This is why development and introduction of new highly effective antiviral drugs are a relevant direction of pharmaceutical chemistry. The aim of research is to synthesize the derivatives of (4,6-bis-amino[1,3,5]triazin-2-yl-sulphanyl)-Naryl-acetamide and to study the antiviral activity for FluA (H1N1) virus California/07/2009 at primary pharmacological screening stage. The investigated compounds – (4,6-bis-amino[1,3,5]triazin-2-yl-sulphanyl)-N-aryl-acetamide derivatives, were synthesized on the basis of 4,6-bis-ethylamino[1, 3,5]triazin-2-tiol. The antiviral activity of (4,6-bis-amino[1,3,5]triazin-2-yl-sulphanyl)-N-(2,4,6-trichlorphenyl)-acetamide against the virus FluA (H1N1) California/07/2009 was evaluated on MDCK cell culture test in vitro. It has been shown that the test substance exhibits high antiviral activity against the influenza A virus H1N1 California/ 07/2009 with effective concentration of EC50 0,6 μg/ml and the selectivity index SI > 170 (for Ribavirin SI > 160 and Amizona SI > 2,1). The data obtained substantiate the expediency of further study of derivatives of (4,6-diamino[1,3,5] triazine-2-yl-sulphanyl)-N-aryl-acetamide as potential antiviral agents.

scholarly journals Synthesis and Screening of Anti-HSV-1 Activity of Thioglucoside Derivatives of Natural Polyhydroxy-1,4-Naphthoquinones

2019 ◽  
Vol 14 (6) ◽  
pp. 1934578X1986067 ◽  
Author(s):  
Sergey G. Polonik ◽  
Natalia V. Krylova ◽  
Galina G. Kompanets ◽  
Olga V. Iunikhina ◽  
Yuri E. Sabutski
Keyword(s):  
Antiviral Activity ◽  
Radical Scavenging ◽  
Effective Inhibition ◽  
Infected Cells ◽  
Virucidal Effect ◽  
Simplex Virus ◽  
Derivatives Of ◽  
Hsv 1

Four 1,4-naphthoquinone dithioglucoside derivatives based on natural polyhydroxy-1,4-naphthoquinones were synthesized. These thioglucosides were screened for their antiradical and antiviral activity in vitro. Antiradical activity of tested compounds was determined by the 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay. The anti-herpes simplex virus type 1 (anti-HSV-1) activity of thioglucosides was analyzed by the cytopathic effect inhibition assay and mode of antiviral action was determined by the addition of the tested compounds to uninfected cells, to the virus prior to infection, or to herpes-infected cells. Most effective inhibition of HSV-1 replication was observed at pretreatment of virus by the compounds (direct virucidal effect). The dithioglucoside conjugate with the single β-OH group and lipophilic ethyl substituent in naphthoquinone core showed the greatest antiviral activity.

Sign in / Sign up

Export Citation Format

Share Document