Double-edged Swords : Diaryl pyrazoline thiazolidinediones synchronously targeting cancer epigenetics and angiogenesis
Copyright © 2021 Elsevier Inc. All rights reserved..
In the present study, two novel series of compounds incorporating naphthyl and pyridyl linker were synthesized and biological assays revealed 5-((6-(2-(5-(2-chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy) naphthalene-2-yl)methylene)thiazolidine-2,4-dione (14b) as the most potent dual inhibitors of vascular endothelial growth factors receptor-2 (VEGFR-2) and histone deacetylase 4 (HDAC4). Compounds 13b, 14b, 17f, and 21f were found to stabilize HDAC4; where, pyridyl linker swords were endowed with higher stabilization effects than naphthyl linker. Also, 13b and 14b showed best inhibitory activity on VEGFR-2 as compared to others. Compound 14b was most potent as evident by in-vitro and in-vivo biological assessments. It displayed anti-angiogenic potential by inhibiting endothelial cell proliferation, migration, tube formation and also suppressed new capillary formation in the growing chick chorioallantoic membranes (CAMs). It showed selectivity and potency towards HDAC4 as compared to other HDAC isoforms. Compound 14b (25 mg/kg, i.p.) also indicated exceptional antitumor efficacy on in-vivo animal xenograft model of human colorectal adenocarcinoma (HT-29). The mechanism of action of 14b was also confirmed by western blot.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:116 |
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| Enthalten in: |
Bioorganic chemistry - 116(2021) vom: 12. Nov., Seite 105350 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Upadhyay, Neha [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.01.2022 Date Revised 04.01.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bioorg.2021.105350 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM330894579 |
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| 500 | |a Date Revised 04.01.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier Inc. All rights reserved. | ||
| 520 | |a In the present study, two novel series of compounds incorporating naphthyl and pyridyl linker were synthesized and biological assays revealed 5-((6-(2-(5-(2-chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy) naphthalene-2-yl)methylene)thiazolidine-2,4-dione (14b) as the most potent dual inhibitors of vascular endothelial growth factors receptor-2 (VEGFR-2) and histone deacetylase 4 (HDAC4). Compounds 13b, 14b, 17f, and 21f were found to stabilize HDAC4; where, pyridyl linker swords were endowed with higher stabilization effects than naphthyl linker. Also, 13b and 14b showed best inhibitory activity on VEGFR-2 as compared to others. Compound 14b was most potent as evident by in-vitro and in-vivo biological assessments. It displayed anti-angiogenic potential by inhibiting endothelial cell proliferation, migration, tube formation and also suppressed new capillary formation in the growing chick chorioallantoic membranes (CAMs). It showed selectivity and potency towards HDAC4 as compared to other HDAC isoforms. Compound 14b (25 mg/kg, i.p.) also indicated exceptional antitumor efficacy on in-vivo animal xenograft model of human colorectal adenocarcinoma (HT-29). The mechanism of action of 14b was also confirmed by western blot | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 7 | |a Repressor Proteins |2 NLM | |
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| 700 | 1 | |a Safuan, Sabreena |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Alan P |e verfasserin |4 aut | |
| 700 | 1 | |a Schweipert, Markus |e verfasserin |4 aut | |
| 700 | 1 | |a Meyer-Almes, Franz-Josef |e verfasserin |4 aut | |
| 700 | 1 | |a Ramaa, C S |e verfasserin |4 aut | |
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