scholarly journals Betulinic Acid Decorated with Polar Groups and Blue Emitting BODIPY Dye: Synthesis, Cytotoxicity, Cell-Cycle Analysis and Anti-HIV Profiling

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1104
Author(s):  
David Kodr ◽  
Jarmila Stanková ◽  
Michaela Rumlová ◽  
Petr Džubák ◽  
Jiří Řehulka ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Betulinic Acid ◽  
Microscopy Study ◽  
Biological Evaluation ◽  
Cycle Arrest ◽  
Polar Groups ◽  
Mechanism Of Inhibition ◽  
New Compounds ◽  
Anti Hiv ◽  
Hiv 1

Betulinic acid (BA) is a potent triterpene, which has shown promising potential in cancer and HIV-1 treatment. Here, we report a synthesis and biological evaluation of 17 new compounds, including BODIPY labelled analogues derived from BA. The analogues terminated by amino moiety showed increased cytotoxicity (e.g., BA had on CCRF-CEM IC50 > 50 μM, amine 3 IC50 0.21 and amine 14 IC50 0.29). The cell-cycle arrest was evaluated and did not show general features for all the tested compounds. A fluorescence microscopy study of six derivatives revealed that only 4 and 6 were detected in living cells. These compounds were colocalized with the endoplasmic reticulum and mitochondria, indicating possible targets in these organelles. The study of anti-HIV-1 activity showed that 8, 10, 16, 17 and 18 have had IC50i > 10 μM. Only completely processed p24 CA was identified in the viruses formed in the presence of compounds 4 and 12. In the cases of 2, 8, 9, 10, 16, 17 and 18, we identified not fully processed p24 CA and p25 CA-SP1 protein. This observation suggests a similar mechanism of inhibition as described for bevirimat.

Piroxicam Analogs: Design, Synthesis, Docking Study and Biological Evaluation as Promising Anti-HIV-1 agents

2021 ◽  
Vol 17 ◽  
Author(s):  
Ali Imani ◽  
Sepehr Soleymani ◽  
Rouhollah Vahabpour ◽  
Zahra Hajimahdi ◽  
Afshin Zarghi
Keyword(s):  
Docking Study ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Hiv Integrase ◽  
Active Molecule ◽  
Design Synthesis ◽  
Molecule Docking ◽  
New Compounds ◽  
Anti Hiv ◽  
Hiv 1

Background: Taking the well-known drug, Piroxicam as a lead compound, we designed and synthesized two series of 1,2-benzothiazines 1,1-dioxide derivatives to assay their ability in inhibition of HIV-1 replication in cell culture. Objective: In this study, we describe the synthesis, docking study and biological evaluation of 1,2-benzothiazines 1,1- dioxide derivatives. Results: Most of the new compounds were active in the cell-based anti-HIV-1 assay with EC50 < 50 M. Among them, compounds 7g was found to be the most active molecule. Docking study using 3OYA pdb code on the most active molecule 7g with EC50 values of 10 M showed a similar binding mode to the HIV integrase inhibitors. Conclusion: Since all the compounds showed no remarkable cytotoxicity (CC50> 500 M), the designed scaffold is promising structure for development of new anti-HIV-1 agents.

Synthesis of Novel 8-Hydroxyquinoline Derivatives through Mannich Reaction and their Biological Evaluation as Potential Immunomodulatory Agents

2020 ◽  
Vol 16 (4) ◽  
pp. 531-543
Author(s):  
Shaheen Faizi ◽  
Tahira Sarfaraz ◽  
Saima Sumbul ◽  
Almas Jabeen ◽  
Sobia A. Halim ◽  
...  
Keyword(s):  
Mannich Reaction ◽  
Aromatic Aldehydes ◽  
Mannich Bases ◽  
Biological Evaluation ◽  
Mechanism Of Inhibition ◽  
Potent Inhibition ◽  
Tnf Α ◽  
Elisa Technique ◽  
Factor Α ◽  
New Compounds

Background: In continuation of our work on Mannich reaction on 8-hydroxyquinoline, fifteen different combinations of aromatic aldehydes and aniline were subjected to Mannich reaction from which twelve products (eight Mannich bases, two imines and two intramolecularly cyclized products with benzofuranone skeleton) were obtained. Among them six compounds (1, 2, 6, 8, 9 and 12) are the new compounds. The structures of the compounds were characterized by UV, IR, MS and 1H NMR. Method: The compounds were tested for the inhibition of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and Interleukin-1β (IL-1β) at a concentration of 25 µg/mL. The cytokines were produced by THP-1 cells differentiated with PMA for 24hrs and stimulated with LPS for 4 hrs and supernatant were analyzed through ELISA technique. Results and Discussion: Compounds 1-5, 8 and 9 inhibited the production of TNF-α and IL-1β. Compounds 1, 3, and 8 exerted potent inhibitions of TNF-α with 71%, 71%, and 83% inhibition, respectively. Compounds 1 and 8 significantly inhibited the production of IL-1β with 64% and 78% inhibition, respectively. Conclusion: Compounds 1 and 8 significantly inhibited the production of IL-1β with 64% and 78% inhibition, respectively. Notably compound 8 showed the most potent inhibition of these cytokines. Additionally, the effect of compounds on viability of THP-1 cells was also evaluated. Moreover, molecular docking was carried out to study the mechanism of inhibition of TNF-α production.

scholarly journals HIV-1 Vpr activates host CRL4-DCAF1 E3 ligase to degrade histone deacetylase SIRT7

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiaohong Zhou ◽  
Christina Monnie ◽  
Maria DeLucia ◽  
Jinwoo Ahn
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Cell Cycle Arrest ◽  
Histone Deacetylase ◽  
E3 Ligase ◽  
Cycle Arrest ◽  
Wide Range ◽  
In Vitro Reconstitution ◽  
Hiv 1

Abstract Background Vpr is a virion-associated protein that is encoded by lentiviruses and serves to counteract intrinsic immunity factors that restrict infection. HIV-1 Vpr mediates proteasome-dependent degradation of several DNA repair/modification proteins. Mechanistically, Vpr directly recruits cellular targets onto DCAF1, a substrate receptor of Cullin 4 RING E3 ubiquitin ligase (CRL4) for poly-ubiquitination. Further, Vpr can mediate poly-ubiquitination of DCAF1-interacting proteins by the CRL4. Because Vpr-mediated degradation of its known targets can not explain the primary cell-cycle arrest phenotype that Vpr expression induces, we surveyed the literature for DNA-repair-associated proteins that interact with the CRL4-DCAF1. One such protein is SIRT7, a deacetylase of histone 3 that belongs to the Sirtuin family and regulates a wide range of cellular processes. We wondered whether Vpr can mediate degradation of SIRT7 via the CRL4-DCAF1. Methods HEK293T cells were transfected with cocktails of plasmids expressing DCAF1, DDB1, SIRT7 and Vpr. Ectopic and endogeneous levels of SIRT7 were monitered by immunoblotting and protein–protein interactions were assessed by immunoprecipitation. For in vitro reconstitution assays, recombinant CRL4-DCAF1-Vpr complexes and SIRT7 were prepared and poly-ubiqutination of SIRT7 was monitored with immunoblotting. Results We demonstrate SIRT7 polyubiquitination and degradation upon Vpr expression. Specifically, SIRT7 is shown to interact with the CRL4-DCAF1 complex, and expression of Vpr in HEK293T cells results in SIRT7 degradation, which is partially rescued by CRL inhibitor MNL4924 and proteasome inhibitor MG132. Further, in vitro reconstitution assays show that Vpr induces poly-ubiquitination of SIRT7 by the CRL4-DCAF1. Importantly, we find that Vpr from several different HIV-1 strains, but not HIV-2 strains, mediates SIRT7 poly-ubiquitination in the reconstitution assay and degradation in cells. Finally, we show that SIRT7 degradation by Vpr is independent of the known, distinctive phenotype of Vpr-induced cell cycle arrest at the G2 phase, Conclusions Targeting histone deacetylase SIRT7 for degradation is a conserved feature of HIV-1 Vpr. Altogether, our findings reveal that HIV-1 Vpr mediates down-regulation of SIRT7 by a mechanism that does not involve novel target recruitment to the CRL4-DCAF1 but instead involves regulation of the E3 ligase activity.

Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel 4-[4-Arylpyridin-1(4H)-yl]benzoic Acid Derivatives as Anti-HIV-1 Agents

2017 ◽  
Vol 14 (12) ◽  
pp. e1700295 ◽  
Author(s):  
Saghi Sepehri ◽  
Sepehr Soleymani ◽  
Rezvan Zabihollahi ◽  
Mohammad R. Aghasadeghi ◽  
Mehdi Sadat ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Benzoic Acid ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Molecular Docking Studies ◽  
Benzoic Acid Derivatives ◽  
Anti Hiv ◽  
Hiv 1

Synthesis and Biological Evaluation of 8-Hydroxyquinoline-hydrazones for Anti-HIV-1 and Anticancer Potential

2018 ◽  
Vol 3 (38) ◽  
pp. 10727-10731 ◽  
Author(s):  
Purvi Shah ◽  
Leila F. Abadi ◽  
Shraddha Gaikwad ◽  
Dasharath Chaudhari ◽  
Varun Kushwah ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Synthesis And Biological Evaluation ◽  
Anti Hiv ◽  
Hiv 1

The HIV-1 Vif Protein Mediates Degradation of Vpr and Reduces Vpr-Induced Cell Cycle Arrest

2008 ◽  
Vol 27 (5) ◽  
pp. 267-277 ◽  
Author(s):  
Jiangfang Wang ◽  
Jason M. Shackelford ◽  
Nithianandan Selliah ◽  
Debra K. Shivers ◽  
Eduardo O’Neill ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cycle Arrest ◽  
Vif Protein ◽  
Hiv 1

scholarly journals Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors

Acta Naturae ◽  
2013 ◽  
Vol 5 (1) ◽  
pp. 63-72 ◽  
Author(s):  
S. P. Korolev ◽  
O. V. Kondrashina ◽  
D. S. Druzhilovsky ◽  
A. M. Starosotnikov ◽  
M. D. Dutov ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Integrase Inhibitors ◽  
Mechanism Of Inhibition ◽  
Immunodeficiency Virus ◽  
Pharmacokinetic Properties ◽  
Nitro Derivatives ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1

Human immunodeficiency virus type 1 integrase is one of the most attractive targets for the development of anti-HIV-1 inhibitors. The capacity of a series of 2,1,3-benzoxadiazoles (benzofurazans) and their N-oxides (benzofuroxans) selected using the PASS software to inhibit the catalytic activity of HIV-1 integrase was studied in the present work. Only the nitro-derivatives of these compounds were found to display inhibitory activity. The study of the mechanism of inhibition by nitro-benzofurazans/benzofuroxans showed that they impede the substrate DNA binding at the integrase active site. These inhibitors were also active against integrase mutants resistant to raltegravir, which is the first HIV-1 integrase inhibitor approved for clinical use. The comparison of computer-aided estimations of the pharmacodynamic and pharmacokinetic properties of the compounds studied and raltegravir led us to conclude that these compounds show promise and need to be further studied as potential HIV-1 integrase inhibitors.

Anti-inflammatory and Anti-HIV Compounds from Swertia bimaculata

Planta Medica ◽  
2017 ◽  
Vol 83 (17) ◽  
pp. 1368-1373 ◽  
Author(s):  
Miao Dong ◽  
Li-Qiu Quan ◽  
Wei-Feng Dai ◽  
Shi-Li Yan ◽  
Chin-Ho Chen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ethanol Extract ◽  
Moderate Activity ◽  
Nitric Oxide Production ◽  
X Ray Diffraction ◽  
Oxide Production ◽  
New Compounds ◽  
Anti Hiv ◽  
Hiv 1

AbstractThree new compounds (1 – 3), including a sesterterpenoid, aspterpenacid C (1), with an unusual 5/3/7/6/5 pentacyclic skeleton, together with seven known ones (4 – 10), were isolated from the ethanol extract of the traditional Chinese medicinal plant Swertia bimaculata. Their structures were elucidated on the basis of the methods of spectroscopic NMR, MS, and computational chemistry. The structure of 1 was further confirmed by single-crystal X-ray diffraction analysis. Compounds 1 – 10 were tested for activities on the inhibition of nitric oxide production and HIV-1 replication in vitro. Compound 1 exhibited moderate activity in inhibiting nitric oxide production (IC50 = 16.1 µM) and HIV-1 replication (EC50 = 1.35 µM).

scholarly journals Phosphate Derivatives of 3-Carboxyacylbetulin: SynThesis, In Vitro Anti-HIV and Molecular Docking Study

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1148
Author(s):  
Krzysztof Marciniec ◽  
Elwira Chrobak ◽  
Aleksandra Dąbrowska ◽  
Ewa Bębenek ◽  
Monika Kadela-Tomanek ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Betulinic Acid ◽  
Strong Interactions ◽  
Molecular Docking Study ◽  
Gag Protein ◽  
Terminal Domain ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1

Lupane-type pentacyclic triterpenes such as betulin and betulinic acid play an important role in the search for new therapies that would be effective in controlling viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3–5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid–spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3′,3′-dimethylsuccinyl)betulin (compound 3), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC50 (half maximal inhibitory concentration) equal to 0.02 μM. Compound 3 inhibits viral replication at a level comparable to bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1. Compared with interactions between bevirimat (BVM) and the protein, an increased number of strong interactions between ligand 3 and the protein, generated by the phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2 proteins, in as far as the intrinsically imprecise docking scores suggest.

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