Discovery of the Biginelli hybrids as novel caspase-9 activators in apoptotic machines: Lipophilicity, molecular docking study, influence on angiogenesis gene and miR-21 expression levels

Janković, Nenad; Ristovski, Jovana Trifunović; Tot, Aleksandar; Petronijević, Jelena; Joksimović, Nenad; Stanojković, Tatjana; Crnogorac, Marija Đorđić; Petrović, Nina; Boljević, Ivana; Matić, Ivana Z.; Bogdanović, Goran A.; Mikov, Momir; Bugarčić, Živadin D.

doi:10.1016/j.bioorg.2019.02.026

Cited by 27 publications

(10 citation statements)

References 63 publications

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“…MiR-21 is considered an oncogenic molecular due to inhibiting the expression of phosphatases, which regulate the signaling pathways such as AKT and MAPK in cells [27,28]. In non-cancer cells, miR-21 usually acts as a protector [29,30,31]. Although microRNA-21 (miR-21) is believed to be related to the regulation of mitochondrial energy metabolism [32,33,34,35], the effect of TiO 2 NPs on miR-21 has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Titanium Dioxide Nanoparticles Induce Cognitive Dysfunction of Rats with Endogenous Protective Mechanism of Increased miR-21-5p

Li¹,

Wei

Shen

et al. 2021

Preprint

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BackgroundTitanium dioxide nanoparticles (TiO2 NPs) cause nerve cell damage and central nervous system dysfunction has been well known. However, most of the cognitive deficits occurs before the observable damage to nerve cells and the regulatory mechanism is largely unknown. Mitochondria and energy metabolism are the targets of many neurotoxic substances. ResultsHere, we showed that TiO2 NPs exposure reduced the mitochondrial membrane potential (ΔΨm) and ATP content, which is the important cause of cognitive deficits, and upregulated microRNA-21-5p (miR-21-5p) levels in rat neuron cells. Upregulated miR-21-5p promoted phosphorylation of c-Jun, consequently promoting transcription of VDAC1 (encoding voltage-dependent anion channel 1), which in turn preserved the ΔΨm and ATP content of neuron cells. ConclusionsMechanistically, upregulated VDAC1 was attributed to TiO2 NPs-induced phosphorylation of c-Jun (Ser73), which is predicted to be a transcription factor of VDAC1, while upregulation of the ΔΨm and ATP content was caused by the increased oxygen consumption rate induced by VDAC1. The results of our present study revealed an endogenous self-protection mechanism in the process of TiO2 NPs-induced cognitive deficits.

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Section: Discussionmentioning

confidence: 99%

Titanium Dioxide Nanoparticles Induce Cognitive Dysfunction of Rats with Endogenous Protective Mechanism of Increased miR-21-5p

Li¹,

Wei

Shen

et al. 2021

Preprint

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“…At the same time, one of the pharmaceutical industry's mainstream trends is developing dual-active (multitarget) drugs to treat complex associated diseases [ 18 , 19 ]. Besides anticancer activities [ [20] , [21] , [22] ], these days the most crucial target of THPMs could be a SARS-CoV-2 M pro , the protein responsible for COVID-19 disease. A decade ago, Ramajayam et al synthesized a series of the thiourea-based Biginelli hybrids that are showed significant inhibitory activity (2–10 μM) against SARS-CoV 3CL pro [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…There is an burning need to design and synthesis of novel prospective dual-active compounds, especially anticancer-antiviral [ [32] , [33] , [34] ]. Our interest is the design, synthesis, and pharmacological evaluation of the heterocyclic compounds, especially those derived from the Biginelli reaction [ [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] ]. Selected molecules have proven to be excellent ligands for the synthesis of copper and palladium complexes with significant anticancer and antimicrobial activity [ [44] , [45] , [46] , [47] ].…”

Section: Introductionmentioning

confidence: 99%

A new class of half-sandwich ruthenium complexes containing Biginelli hybrids: anticancer and anti-SARS-CoV-2 activities

Janković

Milović

Jovanović

et al. 2022

Chemico-Biological Interactions

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“…Considering the significance of THPMs and our previous activity in Biginelli chemistry, [13][14][15][16][17][18] twenty-four compounds were investigated ( Table 1 ) in terms of their anticancer activity and pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

The evaluation of the anticancer activity of the Biginelli hybrids and pharmacokinetic profiling based on their retention parameters

Ristovski

Minorics

Bartha

et al. 2022

Journal of Molecular Structure

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The present investigation gives an insight into the evaluation and analysis of the anticancer activity of the library of the Biginelli hybrids using the appropriate QSRR approach. Using the RP TLC method retention parameters of tested compounds were obtained and examined to measure of lipophilicity of investigated molecules. The compounds were examined in seven different cancer cell lines and their IC 50 and% of inhibition of cell proliferation at 100 μM were established. These experimental values as well as appropriate molecular descriptors are included in QSRR analysis. For this purpose, the variable selection was made, PCA and HCA were carried out, nine MR models were developed and ranked. The quality of the established models was confirmed through internal and external statistical validation. The goal was to define the main differences and similarities between three groups of the tested Biginelli hybrids to -find out which molecular features affect lipophilicity the most and which are crucial for the development of high-quality QSRR models. Tetrahydropyrimidines with butyl (11) and benzyl fragment (19) possess the best anticancer activity and selectivity. Nowadays modern design of an active pharmaceutical ingredient includes specific requirements of rationalization to adapt physicochemical characteristics, pharmacological activity, and safety through structural changes of the molecule. We believe that the developed profile is a step forward in Biginelli chemistry and could be useful in the future synthesis of novel Biginelli-based compounds with significantly improved activities.

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Discovery of the Biginelli hybrids as novel caspase-9 activators in apoptotic machines: Lipophilicity, molecular docking study, influence on angiogenesis gene and miR-21 expression levels

Cited by 27 publications

References 63 publications

Titanium Dioxide Nanoparticles Induce Cognitive Dysfunction of Rats with Endogenous Protective Mechanism of Increased miR-21-5p

Titanium Dioxide Nanoparticles Induce Cognitive Dysfunction of Rats with Endogenous Protective Mechanism of Increased miR-21-5p

A new class of half-sandwich ruthenium complexes containing Biginelli hybrids: anticancer and anti-SARS-CoV-2 activities

The evaluation of the anticancer activity of the Biginelli hybrids and pharmacokinetic profiling based on their retention parameters

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