Curcumin Conjugates of Non-steroidal Anti-Inflammatory Drugs : Synthesis, Structures, Anti-proliferative Assays, Computational Docking, and Inflammatory Response
© 2020 The Authors. Published by Wiley-VCH GmbH..
In an effort to combine the anti-proliferative effect of CUR-BF2 and CUR compounds with anti-inflammatory benefits of non-steroidal anti-inflammatory drugs (NSAIDs), a library of the bis- and mono-NSAID/CUR-BF2 and NSAID/CUR conjugates were synthesized by coupling flufenamic acid, flurbiprofen, naproxen, indomethacin, and ibuprofen to diversely substituted hydroxy-benzaldehydes via an ester linkage, and by subsequent reaction with acetylacetone-BF2 to form the bis- and the mono-NSAID/CUR-BF2 adducts. Since conversion to NSAID/CUR by the previously developed decomplexation protocol showed limited success, a set of NSAID/CUR conjugates were independently prepared by directly coupling the NSAIDs with parent curcumin. The bis-NSAID/CUR-BF2 and bis-NSAID-CUR hybrids exhibited low cytotoxicity in NCI-60 assay, and in independent cell viability assay on colorectal cancer (CRC) cells (HCT116, HT29, DLD-1, RKO, SW837, CaCo2) and in normal CR cells (CCD841CoN). By contrast, the mono-naproxin and mono-flurbiprofen CUR-BF2 adducts exhibited remarkable anti-proliferative and apoptopic activity in NCI-60 assay most notably against HCT-116 (colon), OVCAR-3 (ovarian), and ACHN (renal) cells. Computational molecular docking calculations showed favorable binding energies to HER2, VEGFR2, BRAF, and Bcl-2 as well as to COX-1 and COX-2, which in several cases exceeded known inhibitors. The main interactions between the ligands and the proteins were hydrophobic, although several hydrogen bonds were also observed. A sub-set of six compounds that had exhibited little or no cytotoxicity were tested for their anti-inflammatory response with THP-1 human macrophages in comparison to parent NSAIDs or parent curcumin.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
ChemistryOpen - 9(2020), 8 vom: 16. Aug., Seite 822-834 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Laali, Kenneth K [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.08.2021 Date Revised 29.03.2024 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.1002/open.202000173 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM313773351 |
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| 100 | 1 | |a Laali, Kenneth K |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Curcumin Conjugates of Non-steroidal Anti-Inflammatory Drugs |b Synthesis, Structures, Anti-proliferative Assays, Computational Docking, and Inflammatory Response |
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| 520 | |a © 2020 The Authors. Published by Wiley-VCH GmbH. | ||
| 520 | |a In an effort to combine the anti-proliferative effect of CUR-BF2 and CUR compounds with anti-inflammatory benefits of non-steroidal anti-inflammatory drugs (NSAIDs), a library of the bis- and mono-NSAID/CUR-BF2 and NSAID/CUR conjugates were synthesized by coupling flufenamic acid, flurbiprofen, naproxen, indomethacin, and ibuprofen to diversely substituted hydroxy-benzaldehydes via an ester linkage, and by subsequent reaction with acetylacetone-BF2 to form the bis- and the mono-NSAID/CUR-BF2 adducts. Since conversion to NSAID/CUR by the previously developed decomplexation protocol showed limited success, a set of NSAID/CUR conjugates were independently prepared by directly coupling the NSAIDs with parent curcumin. The bis-NSAID/CUR-BF2 and bis-NSAID-CUR hybrids exhibited low cytotoxicity in NCI-60 assay, and in independent cell viability assay on colorectal cancer (CRC) cells (HCT116, HT29, DLD-1, RKO, SW837, CaCo2) and in normal CR cells (CCD841CoN). By contrast, the mono-naproxin and mono-flurbiprofen CUR-BF2 adducts exhibited remarkable anti-proliferative and apoptopic activity in NCI-60 assay most notably against HCT-116 (colon), OVCAR-3 (ovarian), and ACHN (renal) cells. Computational molecular docking calculations showed favorable binding energies to HER2, VEGFR2, BRAF, and Bcl-2 as well as to COX-1 and COX-2, which in several cases exceeded known inhibitors. The main interactions between the ligands and the proteins were hydrophobic, although several hydrogen bonds were also observed. A sub-set of six compounds that had exhibited little or no cytotoxicity were tested for their anti-inflammatory response with THP-1 human macrophages in comparison to parent NSAIDs or parent curcumin | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a NSAID/CUR-BF2 and NSAID/CUR conjugates | |
| 650 | 4 | |a anti-inflammatory assays | |
| 650 | 4 | |a anti-proliferative activity | |
| 650 | 4 | |a antiproliferative assays | |
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| 650 | 4 | |a inflammation response | |
| 650 | 4 | |a synthesis | |
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| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
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| 650 | 7 | |a Curcumin |2 NLM | |
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| 700 | 1 | |a Zwarycz, Angela T |e verfasserin |4 aut | |
| 700 | 1 | |a Beck, Nicholas |e verfasserin |4 aut | |
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| 700 | 1 | |a Nukaya, Manabu |e verfasserin |4 aut | |
| 700 | 1 | |a Kennedy, Gregory D |e verfasserin |4 aut | |
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