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Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin

Multidrug resistance (MDR) is a common phenomenon in clinical oncology, whereby cancer cells become resistant to chemotherapeutic drugs. A common MDR mechanism is the overexpression of ATP-binding cassette efflux transporters in cancer cells, with P-glycoprotein (P-gp) being one of them. New 3,4-sec...

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Autores principales: Tolmacheva, Irina, Beloglazova, Yulia, Nazarov, Mikhail, Gagarskikh, Olga, Grishko, Victoria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10298530/
https://www.ncbi.nlm.nih.gov/pubmed/37373011
http://dx.doi.org/10.3390/ijms24129863
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author Tolmacheva, Irina
Beloglazova, Yulia
Nazarov, Mikhail
Gagarskikh, Olga
Grishko, Victoria
author_facet Tolmacheva, Irina
Beloglazova, Yulia
Nazarov, Mikhail
Gagarskikh, Olga
Grishko, Victoria
author_sort Tolmacheva, Irina
collection PubMed
description Multidrug resistance (MDR) is a common phenomenon in clinical oncology, whereby cancer cells become resistant to chemotherapeutic drugs. A common MDR mechanism is the overexpression of ATP-binding cassette efflux transporters in cancer cells, with P-glycoprotein (P-gp) being one of them. New 3,4-seco-lupane triterpenoids, and the products of their intramolecular cyclization with the removed 4,4-gem-dimethyl group, were synthesized by the selective transformations of the A-ring of dihydrobetulin. Among the semi-synthetic derivatives, the MT-assay-enabled methyl ketone 31 (MK), exhibiting the highest cytotoxicity (0.7–16.6 µM) against nine human cancer cell lines, including P-gp overexpressing subclone HBL-100/Dox, is identified. In silico, MK has been classified as a potential P-gp-inhibitor; however, the Rhodamine 123 efflux test, and the combined use of P-gp-inhibitor verapamil with MK in vitro, showed the latter to be neither an inhibitor nor a substrate of P-gp. As the studies have shown, the cytotoxic effect of MK against HBL-100/Dox cells is, arguably, induced through the activation of the ROS-mediated mitochondrial pathway, as evidenced by the positive Annexin V-FITC staining of apoptotic cells, the cell cycle arrest in the G0/G1 phase, mitochondrial dysfunction, cytochrome c release, and the activation of caspase-9 and -3.
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spelling pubmed-102985302023-06-28 Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin Tolmacheva, Irina Beloglazova, Yulia Nazarov, Mikhail Gagarskikh, Olga Grishko, Victoria Int J Mol Sci Article Multidrug resistance (MDR) is a common phenomenon in clinical oncology, whereby cancer cells become resistant to chemotherapeutic drugs. A common MDR mechanism is the overexpression of ATP-binding cassette efflux transporters in cancer cells, with P-glycoprotein (P-gp) being one of them. New 3,4-seco-lupane triterpenoids, and the products of their intramolecular cyclization with the removed 4,4-gem-dimethyl group, were synthesized by the selective transformations of the A-ring of dihydrobetulin. Among the semi-synthetic derivatives, the MT-assay-enabled methyl ketone 31 (MK), exhibiting the highest cytotoxicity (0.7–16.6 µM) against nine human cancer cell lines, including P-gp overexpressing subclone HBL-100/Dox, is identified. In silico, MK has been classified as a potential P-gp-inhibitor; however, the Rhodamine 123 efflux test, and the combined use of P-gp-inhibitor verapamil with MK in vitro, showed the latter to be neither an inhibitor nor a substrate of P-gp. As the studies have shown, the cytotoxic effect of MK against HBL-100/Dox cells is, arguably, induced through the activation of the ROS-mediated mitochondrial pathway, as evidenced by the positive Annexin V-FITC staining of apoptotic cells, the cell cycle arrest in the G0/G1 phase, mitochondrial dysfunction, cytochrome c release, and the activation of caspase-9 and -3. MDPI 2023-06-07 /pmc/articles/PMC10298530/ /pubmed/37373011 http://dx.doi.org/10.3390/ijms24129863 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tolmacheva, Irina
Beloglazova, Yulia
Nazarov, Mikhail
Gagarskikh, Olga
Grishko, Victoria
Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin
title Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin
title_full Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin
title_fullStr Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin
title_full_unstemmed Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin
title_short Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin
title_sort synthesis and anticancer activity of a-ring-modified derivatives of dihydrobetulin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10298530/
https://www.ncbi.nlm.nih.gov/pubmed/37373011
http://dx.doi.org/10.3390/ijms24129863
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