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.

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.

scholarly journals Structure–Activity Relationship of Phytotoxic Natural 10-Membered Lactones and Their Semisynthetic Derivatives

2021 ◽  
Vol 7 (10) ◽  
pp. 829
Author(s):  
Anna Dalinova ◽  
Anatoly Fedorov ◽  
Vsevolod Dubovik ◽  
Olga Voitsekhovskaja ◽  
Elena Tyutereva ◽  
...  
Keyword(s):  
Rational Design ◽  
Fungicidal Activity ◽  
Structural Features ◽  
Hydroxyl Group ◽  
High Yield ◽  
Sf9 Cells ◽  
Structure Activity ◽  
Relationship Of ◽  
Derivatives Of ◽  
Target Activity

Ten-membered lactones (nonenolides) demonstrate phytotoxic, antimicrobial, and fungicidal activity promising for the development of natural product-derived pesticides. The fungus Stagonospora cirsii is able to produce phytotoxic stagonolides A (1), J (2), K (3) and herbarumin I (4) with high yield. The aim of this study was to create a set of structurally related nonenolides and to reveal the structural features that affect their biological activity. Stagonolide A (1) and C-7 oxidized stagonolide K (11) showed the highest phytotoxicity in leaf puncture assay and agar seedlings assay. The oxidation of C-7 hydroxyl group (as in 1, acetylstagonolide A (10) and (11) led to the manifestation of toxicity to microalgae, Bacillus subtilis and Sf9 cells regardless of the configuration of C-9 propyl chains (R in 1 and 10, S in 11). C-7 non-oxidized nonenolides displayed none or little non-target activity. Notably, 7S compounds were more phytotoxic than their 7R analogues. Due to the high inhibitory activity against seedling growth and the lack of side toxicity, mono- and bis(acetyl)- derivatives of herbarumin I were shown to be potent for the development of pre-emergent herbicides. The identified structural features can be used for the rational design of new herbicides.

scholarly journals N4-amino-acid derivatives of 6-azacytidine: structure-activity relationship.

2000 ◽  
Vol 47 (1) ◽  
pp. 95-101 ◽  
Author(s):  
I Alexeeva ◽  
L Palchikovskaya ◽  
A Shalamay ◽  
L Nosach ◽  
V Zhovnovataya ◽  
...  
Keyword(s):  
Amino Acid ◽  
Antiviral Activity ◽  
Chemical Structure ◽  
Specific Activity ◽  
Biological Properties ◽  
Activity Relationship ◽  
Amino Acid Derivatives ◽  
Condensation Method ◽  
Structure Activity ◽  
Derivatives Of

Several N4-derivatives of 6-azacytidine were synthesized using of Vorbrüggen's condensation method. Their antiviral activity with respect to the adenovirus serotypes 2 and 5 in Hep-2 cells culture was studied and primary specific activity was determined. Correlation between chemical structure of new 6-azacytidine derivatives and their biological properties is discussed.

scholarly journals Screening of Inhibitory Effects of Polyphenols on Akt-Phosphorylation in Endothelial Cells and Determination of Structure-Activity Features

Biomolecules ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 219 ◽  
Author(s):  
Stoyan Dirimanov ◽  
Petra Högger
Keyword(s):  
Endothelial Cells ◽  
Structural Characteristics ◽  
Structural Features ◽  
Cardiovascular Complications ◽  
Cellular Level ◽  
Inhibitory Effects ◽  
Akt Phosphorylation ◽  
Beneficial Effects ◽  
Structure Activity ◽  
Molecular Mode

Polyphenols exert beneficial effects in type 2 diabetes mellitus (T2DM). However, their mechanism of action remains largely unknown. Endothelial Akt-kinase plays a key role in the pathogenesis of cardiovascular complications in T2DM and therefore the modulation of its activity is of interest. This work aimed to characterize effects of structurally different polyphenols on Akt-phosphorylation (pAkt) in endothelial cells (Ea.hy926) and to describe structure-activity features. A comprehensive screening via ELISA quantified the effects of 44 polyphenols (10 µM) on pAkt Ser473. The most pronounced inhibitors were luteolin (44 ± 18%), quercetin (36 ± 8%), urolithin A (35 ± 12%), apigenin, fisetin, and resveratrol; (p < 0.01). The results were confirmed by Western blotting and complemented with corresponding experiments in HUVEC cells. A strong positive and statistically significant correlation between the mean inhibitory effects of the tested polyphenols on both Akt-residues Ser473 and Thr308 (r = 0.9478, p = 0.0003) was determined by immunoblotting. Interestingly, the structural characteristics favoring pAkt inhibition partially differed from structural features enhancing the compounds’ antioxidant activity. The present study is the first to quantitatively compare the influence of polyphenols from nine different structural subclasses on pAkt in endothelial cells. These effects might be advantageous in certain T2DM-complications involving over-activation of the Akt-pathway. The suggested molecular mode of action of polyphenols involving Akt-inhibition contributes to understanding their effects on the cellular level.

Heterocyclization of Thiophenes Derived from Estrone Followed by Cytotoxic, HTRF Kinase and Pim-1 Kinase Evaluations

2019 ◽  
Vol 18 (12) ◽  
pp. 1711-1728 ◽  
Author(s):  
Mahmoud A. Abdelaziz Mahmoud ◽  
Rafat M. Mohareb ◽  
Meshari. A. Al-Sharif
Keyword(s):  
Structural Features ◽  
Pharmacological Activities ◽  
Steroid Nucleus ◽  
Kinase C ◽  
Structure Activity ◽  
Wide Range ◽  
Thiophene Derivatives ◽  
Therapeutic Activities ◽  
Derivatives Of ◽  
Steroidal Derivatives

Background: A wide range of heterocyclic steroidal derivatives gained a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Many pharmacological drugs containing the steroid nucleus are known in the market. Objective: Our main aim of this work was to synthesise a series of heterocyclic compounds especially thiophene and thienopyridine derivatives containing the estrone nucleus. The synthesized compounds posses antitumor and kinases inhibitions. Method: Thiophene derivatives of estrone were synthesized and used for further heterocyclization reactions through the reaction with the different reagent. Results: Antiproliferative evaluations and c-Met kinase, Pim-1 kinase inhibitions were performed where some compounds revealed high activities. Conclusion: Compounds that showed high antiproliferative activity and c-Met- kinase inhibitions were tested for all compounds. The most promising compounds 3b, 5c, 6c, 8d, 8f, 13e, 13f, 18b and 20d were further investigated against tyrosine kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 6b, 13b, 16b and 16c were selected to examine their Pim-1 kinase inhibition activity where compounds 11c, 18b and 20f showed high activities. Structure-Activity Relationship (SAR) was rationalized by looking at the varying structural features of the molecules.

Synthesis and structure-activity relationships of new 9-N-alkyl derivatives of 9(S)-erythromycylamine

1990 ◽  
Vol 33 (11) ◽  
pp. 3086-3094 ◽  
Author(s):  
Herbert A. Kirst ◽  
Julie A. Wind ◽  
James P. Leeds ◽  
Kevin E. Willard ◽  
Manuel Debono ◽  
...  
Keyword(s):  
Structure Activity Relationships ◽  
Structure Activity ◽  
Alkyl Derivatives ◽  
Derivatives Of

scholarly journals Structural requirements of thiol compounds in the inhibition of human liver iodothyronine 5′-deiodinase

1984 ◽  
Vol 217 (2) ◽  
pp. 485-491 ◽  
Author(s):  
R Harbottle ◽  
S J Richardson
Keyword(s):  
Human Liver ◽  
Thiol Group ◽  
Structural Features ◽  
Inhibitory Potency ◽  
Structural Requirements ◽  
Thiol Compounds ◽  
Alkyl Derivatives ◽  
Free Thiol Group ◽  
Thiol Form ◽  
Derivatives Of

2-Thiouracil and a number of its alkyl derivatives are known to inhibit the enzymic 5′-deodination of thyroxine to 3,5,3′-tri-iodothyronine. The structural requirements for inhibition of iodothyronine 5′-deiodinase were investigated by using a washed postmitochondrial particulate fraction of human liver. A series of sulphur-containing derivatives of pyrimidine, pyridine, imidazole, benzene and urea, capable of existing in a thiol form, were incubated at several concentrations with the enzyme preparation in the presence of thyroxine and dithioerythritol (cofactor). The degree of inhibition by the respective compounds of the production of 3,5,3′-tri-iodothyronine was studied in relation to their structural features. The major observations were: (i) a free thiol group is essential; (ii) compounds that do not possess a polar hydrogen atom spatially configured so that it is proximal to the thiol group are poor inhibitors; (iii) aromatic characteristics in the presence of requirements (i) and (ii) lead to the expression of potent inhibitory properties; (iv) modification of potent inhibitors by the introduction of hydrophilic substituents reduces the inhibitory potency.

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