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Cytotoxic Potential of a-Azepano- and 3-Amino-3,4-SeCo-Triterpenoids

Semi-synthetic triterpenoids, holding an amino substituted seven-membered A-ring (azepano-ring), which could be synthesized from triterpenic oximes through a Beckmann type rearrangement followed by a reduction of lactame fragment, are considered to be novel promising agents exhibiting anti-microbial...

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Autores principales: Kazakova, Oxana, Smirnova, Irina, Tret’yakova, Elena, Csuk, René, Hoenke, Sophie, Fischer, Lucie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914897/
https://www.ncbi.nlm.nih.gov/pubmed/33567783
http://dx.doi.org/10.3390/ijms22041714
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author Kazakova, Oxana
Smirnova, Irina
Tret’yakova, Elena
Csuk, René
Hoenke, Sophie
Fischer, Lucie
author_facet Kazakova, Oxana
Smirnova, Irina
Tret’yakova, Elena
Csuk, René
Hoenke, Sophie
Fischer, Lucie
author_sort Kazakova, Oxana
collection PubMed
description Semi-synthetic triterpenoids, holding an amino substituted seven-membered A-ring (azepano-ring), which could be synthesized from triterpenic oximes through a Beckmann type rearrangement followed by a reduction of lactame fragment, are considered to be novel promising agents exhibiting anti-microbial, alpha-glucosidase, and butyrylcholinesterase inhibitory activities. In this study, in an attempt to develop new antitumor candidates, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives of betulin, oleanolic, ursolic, and glycyrrhetinic acids were evaluated for their cytotoxic activity against five human cancer cell lines and non-malignant mouse fibroblasts by means of a colorimetric sulforhodamine assay. Azepanoallobetulinic acid amide derivative 11 was the most cytotoxic compound of this series but showed little selectivity between the different human tumor cell lines. Flow cytometry experiments showed compound 11 to act mainly by apoptosis (44.3%) and late apoptosis (21.4%). The compounds were further screened at the National Cancer Institute towards a panel of 60 cancer cell lines. It was found that compounds 3, 4, 7, 8, 9, 11, 15, 16, 19, and 20 showed growth inhibitory (GI(50)) against the most sensitive cell lines at submicromolar concentrations (0.20–0.94 μM), and their cytotoxic activity (LC(50)) was also high (1–6 μM). Derivatives 3, 8, 11, 15, and 16 demonstrated a certain selectivity profile at GI(50) level from 5.16 to 9.56 towards K-562, CCRF-CEM, HL-60(TB), and RPMI-8226 (Leukemia), HT29 (Colon cancer), and OVCAR-4 (Ovarian cancer) cell lines. Selectivity indexes of azepanoerythrodiol 3 at TGI level ranged from 5.93 (CNS cancer cell lines SF-539, SNB-19 and SNB-75) to 14.89 for HCT-116 (colon cancer) with SI 9.56 at GI(50) level for the leukemia cell line K-562. The present study highlighted the importance of A-azepano-ring in the triterpenic core for the development of novel antitumor agents, and a future aim to increase the selectivity profile will thus lie in the area of modifications of azepano-triterpenic acids at their carboxyl group.
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spelling pubmed-79148972021-03-01 Cytotoxic Potential of a-Azepano- and 3-Amino-3,4-SeCo-Triterpenoids Kazakova, Oxana Smirnova, Irina Tret’yakova, Elena Csuk, René Hoenke, Sophie Fischer, Lucie Int J Mol Sci Article Semi-synthetic triterpenoids, holding an amino substituted seven-membered A-ring (azepano-ring), which could be synthesized from triterpenic oximes through a Beckmann type rearrangement followed by a reduction of lactame fragment, are considered to be novel promising agents exhibiting anti-microbial, alpha-glucosidase, and butyrylcholinesterase inhibitory activities. In this study, in an attempt to develop new antitumor candidates, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives of betulin, oleanolic, ursolic, and glycyrrhetinic acids were evaluated for their cytotoxic activity against five human cancer cell lines and non-malignant mouse fibroblasts by means of a colorimetric sulforhodamine assay. Azepanoallobetulinic acid amide derivative 11 was the most cytotoxic compound of this series but showed little selectivity between the different human tumor cell lines. Flow cytometry experiments showed compound 11 to act mainly by apoptosis (44.3%) and late apoptosis (21.4%). The compounds were further screened at the National Cancer Institute towards a panel of 60 cancer cell lines. It was found that compounds 3, 4, 7, 8, 9, 11, 15, 16, 19, and 20 showed growth inhibitory (GI(50)) against the most sensitive cell lines at submicromolar concentrations (0.20–0.94 μM), and their cytotoxic activity (LC(50)) was also high (1–6 μM). Derivatives 3, 8, 11, 15, and 16 demonstrated a certain selectivity profile at GI(50) level from 5.16 to 9.56 towards K-562, CCRF-CEM, HL-60(TB), and RPMI-8226 (Leukemia), HT29 (Colon cancer), and OVCAR-4 (Ovarian cancer) cell lines. Selectivity indexes of azepanoerythrodiol 3 at TGI level ranged from 5.93 (CNS cancer cell lines SF-539, SNB-19 and SNB-75) to 14.89 for HCT-116 (colon cancer) with SI 9.56 at GI(50) level for the leukemia cell line K-562. The present study highlighted the importance of A-azepano-ring in the triterpenic core for the development of novel antitumor agents, and a future aim to increase the selectivity profile will thus lie in the area of modifications of azepano-triterpenic acids at their carboxyl group. MDPI 2021-02-08 /pmc/articles/PMC7914897/ /pubmed/33567783 http://dx.doi.org/10.3390/ijms22041714 Text en © 2021 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
Kazakova, Oxana
Smirnova, Irina
Tret’yakova, Elena
Csuk, René
Hoenke, Sophie
Fischer, Lucie
Cytotoxic Potential of a-Azepano- and 3-Amino-3,4-SeCo-Triterpenoids
title Cytotoxic Potential of a-Azepano- and 3-Amino-3,4-SeCo-Triterpenoids
title_full Cytotoxic Potential of a-Azepano- and 3-Amino-3,4-SeCo-Triterpenoids
title_fullStr Cytotoxic Potential of a-Azepano- and 3-Amino-3,4-SeCo-Triterpenoids
title_full_unstemmed Cytotoxic Potential of a-Azepano- and 3-Amino-3,4-SeCo-Triterpenoids
title_short Cytotoxic Potential of a-Azepano- and 3-Amino-3,4-SeCo-Triterpenoids
title_sort cytotoxic potential of a-azepano- and 3-amino-3,4-seco-triterpenoids
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914897/
https://www.ncbi.nlm.nih.gov/pubmed/33567783
http://dx.doi.org/10.3390/ijms22041714
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