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 Ž.; Trifunović Ristovski, Jovana; Vraneš, Milan; Tot, Aleksandar; Petronijević, Jelena; Joksimović, Nenad; Stanojković, Tatjana P.; Đorđić Crnogorac, Marija; Petrović, Nina; Boljević, Ivana; Matić, Ivana Z.; Bogdanović, Goran A.; Mikov, Momir; Bugarčić, Zorica M.

doi:10.1016/j.bioorg.2019.02.026

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2019

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Abstract

In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c, 4d, 4f, 4k and 4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound 4f has up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SI = 18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c, 4d, 4f, 4k and 4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of 4a-l was determinate by using reversed-phase high-performance liquid chroma...

Keywords:

Biginelli scaffold / Selectivity index / Apoptosis / Caspase-9 / Lipophilicity

Source:
Bioorganic Chemistry, 2019, 86, 569-582

Funding / projects:

DOI: 10.1016/j.bioorg.2019.02.026

ISSN: 0045-2068

WoS: 000464108100059

Scopus: 2-s2.0-85061741311

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TY  - JOUR
AU  - Janković, Nenad Ž.
AU  - Trifunović Ristovski, Jovana
AU  - Vraneš, Milan
AU  - Tot, Aleksandar
AU  - Petronijević, Jelena
AU  - Joksimović, Nenad
AU  - Stanojković, Tatjana P.
AU  - Đorđić Crnogorac, Marija
AU  - Petrović, Nina
AU  - Boljević, Ivana
AU  - Matić, Ivana Z.
AU  - Bogdanović, Goran A.
AU  - Mikov, Momir
AU  - Bugarčić, Zorica M.
PY  - 2019
UR  - https://linkinghub.elsevier.com/retrieve/pii/S0045206818312598
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8071
AB  - In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c, 4d, 4f, 4k and 4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound 4f has up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SI = 18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c, 4d, 4f, 4k and 4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of 4a-l was determinate by using reversed-phase high-performance liquid chromatography. © 2019 Elsevier Inc.
T2  - Bioorganic Chemistry
T1  - 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
VL  - 86
SP  - 569
EP  - 582
DO  - 10.1016/j.bioorg.2019.02.026
ER  -

@article{
author = "Janković, Nenad Ž. and Trifunović Ristovski, Jovana and Vraneš, Milan and Tot, Aleksandar and Petronijević, Jelena and Joksimović, Nenad and Stanojković, Tatjana P. and Đorđić Crnogorac, Marija and Petrović, Nina and Boljević, Ivana and Matić, Ivana Z. and Bogdanović, Goran A. and Mikov, Momir and Bugarčić, Zorica M.",
year = "2019",
abstract = "In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c, 4d, 4f, 4k and 4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound 4f has up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SI = 18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c, 4d, 4f, 4k and 4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of 4a-l was determinate by using reversed-phase high-performance liquid chromatography. © 2019 Elsevier Inc.",
journal = "Bioorganic Chemistry",
title = "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",
volume = "86",
pages = "569-582",
doi = "10.1016/j.bioorg.2019.02.026"
}

Janković, N. Ž., Trifunović Ristovski, J., Vraneš, M., Tot, A., Petronijević, J., Joksimović, N., Stanojković, T. P., Đorđić Crnogorac, M., Petrović, N., Boljević, I., Matić, I. Z., Bogdanović, G. A., Mikov, M.,& Bugarčić, Z. M.. (2019). 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. in Bioorganic Chemistry, 86, 569-582.
https://doi.org/10.1016/j.bioorg.2019.02.026

Janković NŽ, Trifunović Ristovski J, Vraneš M, Tot A, Petronijević J, Joksimović N, Stanojković TP, Đorđić Crnogorac M, Petrović N, Boljević I, Matić IZ, Bogdanović GA, Mikov M, Bugarčić ZM. 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. in Bioorganic Chemistry. 2019;86:569-582.
doi:10.1016/j.bioorg.2019.02.026 .

Janković, Nenad Ž., Trifunović Ristovski, Jovana, Vraneš, Milan, Tot, Aleksandar, Petronijević, Jelena, Joksimović, Nenad, Stanojković, Tatjana P., Đorđić Crnogorac, Marija, Petrović, Nina, Boljević, Ivana, Matić, Ivana Z., Bogdanović, Goran A., Mikov, Momir, Bugarčić, Zorica M., "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" in Bioorganic Chemistry, 86 (2019):569-582,
https://doi.org/10.1016/j.bioorg.2019.02.026 . .