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Indolo[2,3-e]benzazocines and indolo[2,3-f]benzazonines and their copper(ii) complexes as microtubule destabilizing agents
A series of four indolo[2,3-e]benzazocines HL(1)–HL(4) and two indolo[2,3-f]benzazonines HL(5) and HL(6), as well as their respective copper(ii) complexes 1–6, were synthesized and characterized by (1)H and (13)C NMR spectroscopy, ESI mass spectrometry, single crystal X-ray diffraction (SC-XRD) and...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10368209/ https://www.ncbi.nlm.nih.gov/pubmed/37431840 http://dx.doi.org/10.1039/d3dt01632c |
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author | Wittmann, Christopher Dömötör, Orsolya Kuznetcova, Irina Spengler, Gabriella Reynisson, Jóhannes Holder, Lauren Miller, Gavin J. Enyedy, Eva A. Bai, Ruoli Hamel, Ernest Arion, Vladimir B. |
author_facet | Wittmann, Christopher Dömötör, Orsolya Kuznetcova, Irina Spengler, Gabriella Reynisson, Jóhannes Holder, Lauren Miller, Gavin J. Enyedy, Eva A. Bai, Ruoli Hamel, Ernest Arion, Vladimir B. |
author_sort | Wittmann, Christopher |
collection | PubMed |
description | A series of four indolo[2,3-e]benzazocines HL(1)–HL(4) and two indolo[2,3-f]benzazonines HL(5) and HL(6), as well as their respective copper(ii) complexes 1–6, were synthesized and characterized by (1)H and (13)C NMR spectroscopy, ESI mass spectrometry, single crystal X-ray diffraction (SC-XRD) and combustion analysis (C, H, N). SC-XRD studies of precursors Vd, VIa·0.5MeOH, of ligands HL(4) and HL(6)·DCM, and complexes 2·2DMF, 5·2DMF, 5′·(i)PrOH·MeOH provided insights into the energetically favored conformations of eight- and nine-membered heterocycles in the four-ring systems. In addition, proton dissociation constants (pK(a)) of HL(1), HL(2) and HL(5), complexes 1, 2 and 5, overall stability constants (log β) of 1, 2 and 5 in 30% (v/v) DMSO/H(2)O at 298 K, as well as thermodynamic solubility of HL(1)–HL(6) and 1–6 in aqueous solution at pH 7.4 were determined by UV–vis spectroscopy. All compounds were tested for antiproliferative activity against Colo320, Colo205 and MCF-7 cell lines and showed IC(50) values in the low micromolar to sub-micromolar concentration range, while some of them (HL(1), HL(5) and HL(6), 1, 2 and 6) showed remarkable selectivity towards malignant cell lines. Ethidium bromide displacement studies provided evidence that DNA is not the primary target for these drugs. Rather, inhibition of tubulin assembly is likely the underlying mechanism responsible for their antiproliferative activity. Tubulin disassembly experiments showed that HL(1) and 1 are effective microtubule destabilizing agents binding to the colchicine site. This was also confirmed by molecular modelling investigations. To the best of our knowledge, complex 1 is the first reported transition metal complex to effectively bind to the tubulin-colchicine pocket. |
format | Online Article Text |
id | pubmed-10368209 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-103682092023-07-26 Indolo[2,3-e]benzazocines and indolo[2,3-f]benzazonines and their copper(ii) complexes as microtubule destabilizing agents Wittmann, Christopher Dömötör, Orsolya Kuznetcova, Irina Spengler, Gabriella Reynisson, Jóhannes Holder, Lauren Miller, Gavin J. Enyedy, Eva A. Bai, Ruoli Hamel, Ernest Arion, Vladimir B. Dalton Trans Chemistry A series of four indolo[2,3-e]benzazocines HL(1)–HL(4) and two indolo[2,3-f]benzazonines HL(5) and HL(6), as well as their respective copper(ii) complexes 1–6, were synthesized and characterized by (1)H and (13)C NMR spectroscopy, ESI mass spectrometry, single crystal X-ray diffraction (SC-XRD) and combustion analysis (C, H, N). SC-XRD studies of precursors Vd, VIa·0.5MeOH, of ligands HL(4) and HL(6)·DCM, and complexes 2·2DMF, 5·2DMF, 5′·(i)PrOH·MeOH provided insights into the energetically favored conformations of eight- and nine-membered heterocycles in the four-ring systems. In addition, proton dissociation constants (pK(a)) of HL(1), HL(2) and HL(5), complexes 1, 2 and 5, overall stability constants (log β) of 1, 2 and 5 in 30% (v/v) DMSO/H(2)O at 298 K, as well as thermodynamic solubility of HL(1)–HL(6) and 1–6 in aqueous solution at pH 7.4 were determined by UV–vis spectroscopy. All compounds were tested for antiproliferative activity against Colo320, Colo205 and MCF-7 cell lines and showed IC(50) values in the low micromolar to sub-micromolar concentration range, while some of them (HL(1), HL(5) and HL(6), 1, 2 and 6) showed remarkable selectivity towards malignant cell lines. Ethidium bromide displacement studies provided evidence that DNA is not the primary target for these drugs. Rather, inhibition of tubulin assembly is likely the underlying mechanism responsible for their antiproliferative activity. Tubulin disassembly experiments showed that HL(1) and 1 are effective microtubule destabilizing agents binding to the colchicine site. This was also confirmed by molecular modelling investigations. To the best of our knowledge, complex 1 is the first reported transition metal complex to effectively bind to the tubulin-colchicine pocket. The Royal Society of Chemistry 2023-07-04 /pmc/articles/PMC10368209/ /pubmed/37431840 http://dx.doi.org/10.1039/d3dt01632c Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/ |
spellingShingle | Chemistry Wittmann, Christopher Dömötör, Orsolya Kuznetcova, Irina Spengler, Gabriella Reynisson, Jóhannes Holder, Lauren Miller, Gavin J. Enyedy, Eva A. Bai, Ruoli Hamel, Ernest Arion, Vladimir B. Indolo[2,3-e]benzazocines and indolo[2,3-f]benzazonines and their copper(ii) complexes as microtubule destabilizing agents |
title | Indolo[2,3-e]benzazocines and indolo[2,3-f]benzazonines and their copper(ii) complexes as microtubule destabilizing agents |
title_full | Indolo[2,3-e]benzazocines and indolo[2,3-f]benzazonines and their copper(ii) complexes as microtubule destabilizing agents |
title_fullStr | Indolo[2,3-e]benzazocines and indolo[2,3-f]benzazonines and their copper(ii) complexes as microtubule destabilizing agents |
title_full_unstemmed | Indolo[2,3-e]benzazocines and indolo[2,3-f]benzazonines and their copper(ii) complexes as microtubule destabilizing agents |
title_short | Indolo[2,3-e]benzazocines and indolo[2,3-f]benzazonines and their copper(ii) complexes as microtubule destabilizing agents |
title_sort | indolo[2,3-e]benzazocines and indolo[2,3-f]benzazonines and their copper(ii) complexes as microtubule destabilizing agents |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10368209/ https://www.ncbi.nlm.nih.gov/pubmed/37431840 http://dx.doi.org/10.1039/d3dt01632c |
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