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Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies

A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) c...

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Autores principales: Piechowska, Katarzyna, Mizerska-Kowalska, Magdalena, Zdzisińska, Barbara, Cytarska, Joanna, Baranowska-Łączkowska, Angelika, Jaroch, Karol, Łuczykowski, Kamil, Płaziński, Wojciech, Bojko, Barbara, Kruszewski, Stefan, Misiura, Konrad, Łączkowski, Krzysztof Z.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731314/
https://www.ncbi.nlm.nih.gov/pubmed/33260768
http://dx.doi.org/10.3390/ijms21239050
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author Piechowska, Katarzyna
Mizerska-Kowalska, Magdalena
Zdzisińska, Barbara
Cytarska, Joanna
Baranowska-Łączkowska, Angelika
Jaroch, Karol
Łuczykowski, Kamil
Płaziński, Wojciech
Bojko, Barbara
Kruszewski, Stefan
Misiura, Konrad
Łączkowski, Krzysztof Z.
author_facet Piechowska, Katarzyna
Mizerska-Kowalska, Magdalena
Zdzisińska, Barbara
Cytarska, Joanna
Baranowska-Łączkowska, Angelika
Jaroch, Karol
Łuczykowski, Kamil
Płaziński, Wojciech
Bojko, Barbara
Kruszewski, Stefan
Misiura, Konrad
Łączkowski, Krzysztof Z.
author_sort Piechowska, Katarzyna
collection PubMed
description A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) cell lines. Toxicity was tested on human normal skin fibroblasts (HSF) and normal colon fibroblasts (CCD-18Co). The growth inhibition mechanism of the most active derivative was analyzed through investigation of its effect on the distribution of cell cycle phases and ability to induce apoptosis and necrosis in RPMI 8226 and A549 cancer cells. The tyrosinase inhibitory potential was assessed, followed by molecular docking studies. Compounds 3a–3h show high anticancer activity against MDA-MB-231 and B16-F10 cell lines with IC(50) values of 1.51–3.03 µM. Moreover, the cytotoxic activity of the investigated compounds against HSF and CCD-18Co cells was 8–70 times lower than against the cancer cells or no toxicity was shown in our tests, with derivative 3a being particularly successful. The mechanism of action of compound 3a in RPMI 8226 cell was shown to be through induction of cell death through apoptosis. The derivatives show ability to inhibit the tyrosinase activity with a mixed mechanism of inhibition. The final molecular docking results showed for IC(50) distinct correlation with experiment.
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spelling pubmed-77313142020-12-12 Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies Piechowska, Katarzyna Mizerska-Kowalska, Magdalena Zdzisińska, Barbara Cytarska, Joanna Baranowska-Łączkowska, Angelika Jaroch, Karol Łuczykowski, Kamil Płaziński, Wojciech Bojko, Barbara Kruszewski, Stefan Misiura, Konrad Łączkowski, Krzysztof Z. Int J Mol Sci Article A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) cell lines. Toxicity was tested on human normal skin fibroblasts (HSF) and normal colon fibroblasts (CCD-18Co). The growth inhibition mechanism of the most active derivative was analyzed through investigation of its effect on the distribution of cell cycle phases and ability to induce apoptosis and necrosis in RPMI 8226 and A549 cancer cells. The tyrosinase inhibitory potential was assessed, followed by molecular docking studies. Compounds 3a–3h show high anticancer activity against MDA-MB-231 and B16-F10 cell lines with IC(50) values of 1.51–3.03 µM. Moreover, the cytotoxic activity of the investigated compounds against HSF and CCD-18Co cells was 8–70 times lower than against the cancer cells or no toxicity was shown in our tests, with derivative 3a being particularly successful. The mechanism of action of compound 3a in RPMI 8226 cell was shown to be through induction of cell death through apoptosis. The derivatives show ability to inhibit the tyrosinase activity with a mixed mechanism of inhibition. The final molecular docking results showed for IC(50) distinct correlation with experiment. MDPI 2020-11-28 /pmc/articles/PMC7731314/ /pubmed/33260768 http://dx.doi.org/10.3390/ijms21239050 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Piechowska, Katarzyna
Mizerska-Kowalska, Magdalena
Zdzisińska, Barbara
Cytarska, Joanna
Baranowska-Łączkowska, Angelika
Jaroch, Karol
Łuczykowski, Kamil
Płaziński, Wojciech
Bojko, Barbara
Kruszewski, Stefan
Misiura, Konrad
Łączkowski, Krzysztof Z.
Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies
title Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies
title_full Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies
title_fullStr Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies
title_full_unstemmed Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies
title_short Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies
title_sort tropinone-derived alkaloids as potent anticancer agents: synthesis, tyrosinase inhibition, mechanism of action, dft calculation, and molecular docking studies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731314/
https://www.ncbi.nlm.nih.gov/pubmed/33260768
http://dx.doi.org/10.3390/ijms21239050
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