Mannich bases of 1,2,4-triazole-3-thione containing adamantane moiety: Synthesis, preliminary anticancer evaluation, and molecular modeling studies

Milošev, Milorad Z.; Jakovljević, Katarina; Joksović, Milan D.; Stanojković, Tatjana; Matić, Ivana Z.; Perović, Milka; Tešić, Vesna; Kanazir, Selma; Mladenović, Milan; Rodić, Marko; Leovac, Vukadin M.; Trifunović, Snežana S.; Marković, Violeta

doi:10.1111/cbdd.12920

Abstract

A series of 18 novel N-Mannich bases derived from 5-adamantyl-1,2,4-triazole-3-th ione was synthesized and characterized using NMR spectroscopy and X-ray diffraction technique. All derivatives were evaluated for their anticancer potential against four human cancer cell lines. Several tested compounds exerted good cytotoxic activities on K562 and HL-60 cell lines, along with pronounced selectivity, showing lower cytotoxicity against normal fibroblasts MRC-5 compared to cancer cells. The effects of compounds 5b,5e, and 5j on the cell cycle were investigated by flow cytometric analysis. It was found that these compounds cause the accumulation of cells in the subG1 and G1 phases of the cell cycle and induce caspase-dependent apoptosis, while the anti-angiogenic effects of 5b, 5e, and 5j have been confirmed in EA. hy926 cells using a tube formation assay. Further, the interaction of Bax protein with compound 5b was investigated by means of molecular modeling, applying the combined molecular...

Keywords:

adamantane / anticancer activity / Mannich bases / molecular modeling / triazoles

Source:
Chemical Biology and Drug Design, 2017, 89, 6, 943-952

Publisher:

Wiley, Hoboken

Funding / projects:

Note:

This is the peer-reviewed version of the following article: Milošev, M. Z.; Jakovljević, K.; Joksović, M. D.; Stanojković, T.; Matić, I. Z.; Perović, M.; Tešić, V.; Kanazir, S.; Mladenović, M.; Rodić, M. V.; et al. Mannich Bases of 1,2,4-Triazole3-Thione Containing Adamantane Moiety: Synthesis, Preliminary Anticancer Evaluation, and Molecular Modeling Studies. Chemical Biology and Drug Design 2017, 89 (6), 943–952. https://doi.org/10.1111/cbdd.12920
Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/3222

DOI: 10.1111/cbdd.12920

ISSN: 1747-0277

WoS: 000405100700012

Scopus: 2-s2.0-85019213707

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TY - JOUR
AU - Milošev, Milorad Z.
AU - Jakovljević, Katarina
AU - Joksović, Milan D.
AU - Stanojković, Tatjana
AU - Matić, Ivana Z.
AU - Perović, Milka
AU - Tešić, Vesna
AU - Kanazir, Selma
AU - Mladenović, Milan
AU - Rodić, Marko
AU - Leovac, Vukadin M.
AU - Trifunović, Snežana S.
AU - Marković, Violeta
PY - 2017
UR - https://cherry.chem.bg.ac.rs/handle/123456789/3221
AB - A series of 18 novel N-Mannich bases derived from 5-adamantyl-1,2,4-triazole-3-th ione was synthesized and characterized using NMR spectroscopy and X-ray diffraction technique. All derivatives were evaluated for their anticancer potential against four human cancer cell lines. Several tested compounds exerted good cytotoxic activities on K562 and HL-60 cell lines, along with pronounced selectivity, showing lower cytotoxicity against normal fibroblasts MRC-5 compared to cancer cells. The effects of compounds 5b,5e, and 5j on the cell cycle were investigated by flow cytometric analysis. It was found that these compounds cause the accumulation of cells in the subG1 and G1 phases of the cell cycle and induce caspase-dependent apoptosis, while the anti-angiogenic effects of 5b, 5e, and 5j have been confirmed in EA. hy926 cells using a tube formation assay. Further, the interaction of Bax protein with compound 5b was investigated by means of molecular modeling, applying the combined molecular docking/molecular dynamics approach.
PB - Wiley, Hoboken
T2 - Chemical Biology and Drug Design
T1 - Mannich bases of 1,2,4-triazole-3-thione containing adamantane moiety: Synthesis, preliminary anticancer evaluation, and molecular modeling studies
VL - 89
IS - 6
SP - 943
EP - 952
DO - 10.1111/cbdd.12920
ER -

@article{
author = "Milošev, Milorad Z. and Jakovljević, Katarina and Joksović, Milan D. and Stanojković, Tatjana and Matić, Ivana Z. and Perović, Milka and Tešić, Vesna and Kanazir, Selma and Mladenović, Milan and Rodić, Marko and Leovac, Vukadin M. and Trifunović, Snežana S. and Marković, Violeta",
year = "2017",
abstract = "A series of 18 novel N-Mannich bases derived from 5-adamantyl-1,2,4-triazole-3-th ione was synthesized and characterized using NMR spectroscopy and X-ray diffraction technique. All derivatives were evaluated for their anticancer potential against four human cancer cell lines. Several tested compounds exerted good cytotoxic activities on K562 and HL-60 cell lines, along with pronounced selectivity, showing lower cytotoxicity against normal fibroblasts MRC-5 compared to cancer cells. The effects of compounds 5b,5e, and 5j on the cell cycle were investigated by flow cytometric analysis. It was found that these compounds cause the accumulation of cells in the subG1 and G1 phases of the cell cycle and induce caspase-dependent apoptosis, while the anti-angiogenic effects of 5b, 5e, and 5j have been confirmed in EA. hy926 cells using a tube formation assay. Further, the interaction of Bax protein with compound 5b was investigated by means of molecular modeling, applying the combined molecular docking/molecular dynamics approach.",
publisher = "Wiley, Hoboken",
journal = "Chemical Biology and Drug Design",
title = "Mannich bases of 1,2,4-triazole-3-thione containing adamantane moiety: Synthesis, preliminary anticancer evaluation, and molecular modeling studies",
volume = "89",
number = "6",
pages = "943-952",
doi = "10.1111/cbdd.12920"
}

Milošev, M. Z., Jakovljević, K., Joksović, M. D., Stanojković, T., Matić, I. Z., Perović, M., Tešić, V., Kanazir, S., Mladenović, M., Rodić, M., Leovac, V. M., Trifunović, S. S.,& Marković, V.. (2017). Mannich bases of 1,2,4-triazole-3-thione containing adamantane moiety: Synthesis, preliminary anticancer evaluation, and molecular modeling studies. in Chemical Biology and Drug Design
Wiley, Hoboken., 89(6), 943-952.
https://doi.org/10.1111/cbdd.12920

Milošev MZ, Jakovljević K, Joksović MD, Stanojković T, Matić IZ, Perović M, Tešić V, Kanazir S, Mladenović M, Rodić M, Leovac VM, Trifunović SS, Marković V. Mannich bases of 1,2,4-triazole-3-thione containing adamantane moiety: Synthesis, preliminary anticancer evaluation, and molecular modeling studies. in Chemical Biology and Drug Design. 2017;89(6):943-952.
doi:10.1111/cbdd.12920 .

Milošev, Milorad Z., Jakovljević, Katarina, Joksović, Milan D., Stanojković, Tatjana, Matić, Ivana Z., Perović, Milka, Tešić, Vesna, Kanazir, Selma, Mladenović, Milan, Rodić, Marko, Leovac, Vukadin M., Trifunović, Snežana S., Marković, Violeta, "Mannich bases of 1,2,4-triazole-3-thione containing adamantane moiety: Synthesis, preliminary anticancer evaluation, and molecular modeling studies" in Chemical Biology and Drug Design, 89, no. 6 (2017):943-952,
https://doi.org/10.1111/cbdd.12920 . .