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Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan
Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane–monoterpene conjuga...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9182348/ https://www.ncbi.nlm.nih.gov/pubmed/35684313 http://dx.doi.org/10.3390/molecules27113374 |
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author | Munkuev, Aldar A. Dyrkheeva, Nadezhda S. Kornienko, Tatyana E. Ilina, Ekaterina S. Ivankin, Dmitry I. Suslov, Evgeniy V. Korchagina, Dina V. Gatilov, Yuriy V. Zakharenko, Alexandra L. Malakhova, Anastasia A. Reynisson, Jóhannes Volcho, Konstantin P. Salakhutdinov, Nariman F. Lavrik, Olga I. |
author_facet | Munkuev, Aldar A. Dyrkheeva, Nadezhda S. Kornienko, Tatyana E. Ilina, Ekaterina S. Ivankin, Dmitry I. Suslov, Evgeniy V. Korchagina, Dina V. Gatilov, Yuriy V. Zakharenko, Alexandra L. Malakhova, Anastasia A. Reynisson, Jóhannes Volcho, Konstantin P. Salakhutdinov, Nariman F. Lavrik, Olga I. |
author_sort | Munkuev, Aldar A. |
collection | PubMed |
description | Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane–monoterpene conjugates with a 1,2,4-triazole or 1,3,4-thiadiazole linker core were synthesized, where (+)-and (−)-campholenic and (+)-camphor derivatives were used as monoterpene fragments. The campholenic derivatives 14a–14b and 15a–b showed activity against TDP1 at a low micromolar range with IC(50) ~5–6 μM, whereas camphor-containing compounds 16 and 17 were ineffective. Surprisingly, all the compounds synthesized demonstrated a clear synergy with topotecan, a TOP1 poison, regardless of their ability to inhibit TDP1. These findings imply that different pathways of enhancing topotecan toxicity other than the inhibition of TDP1 can be realized. |
format | Online Article Text |
id | pubmed-9182348 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-91823482022-06-10 Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan Munkuev, Aldar A. Dyrkheeva, Nadezhda S. Kornienko, Tatyana E. Ilina, Ekaterina S. Ivankin, Dmitry I. Suslov, Evgeniy V. Korchagina, Dina V. Gatilov, Yuriy V. Zakharenko, Alexandra L. Malakhova, Anastasia A. Reynisson, Jóhannes Volcho, Konstantin P. Salakhutdinov, Nariman F. Lavrik, Olga I. Molecules Article Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane–monoterpene conjugates with a 1,2,4-triazole or 1,3,4-thiadiazole linker core were synthesized, where (+)-and (−)-campholenic and (+)-camphor derivatives were used as monoterpene fragments. The campholenic derivatives 14a–14b and 15a–b showed activity against TDP1 at a low micromolar range with IC(50) ~5–6 μM, whereas camphor-containing compounds 16 and 17 were ineffective. Surprisingly, all the compounds synthesized demonstrated a clear synergy with topotecan, a TOP1 poison, regardless of their ability to inhibit TDP1. These findings imply that different pathways of enhancing topotecan toxicity other than the inhibition of TDP1 can be realized. MDPI 2022-05-24 /pmc/articles/PMC9182348/ /pubmed/35684313 http://dx.doi.org/10.3390/molecules27113374 Text en © 2022 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 Munkuev, Aldar A. Dyrkheeva, Nadezhda S. Kornienko, Tatyana E. Ilina, Ekaterina S. Ivankin, Dmitry I. Suslov, Evgeniy V. Korchagina, Dina V. Gatilov, Yuriy V. Zakharenko, Alexandra L. Malakhova, Anastasia A. Reynisson, Jóhannes Volcho, Konstantin P. Salakhutdinov, Nariman F. Lavrik, Olga I. Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan |
title | Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan |
title_full | Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan |
title_fullStr | Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan |
title_full_unstemmed | Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan |
title_short | Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan |
title_sort | adamantane-monoterpenoid conjugates linked via heterocyclic linkers enhance the cytotoxic effect of topotecan |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9182348/ https://www.ncbi.nlm.nih.gov/pubmed/35684313 http://dx.doi.org/10.3390/molecules27113374 |
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