Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells
Bis-(3-bromo-4-hydroxy)benzylidene cyclic compounds have been reported by us as epigenetic multiple ligands, but different substitutions at the two wings provided analogues with selective inhibition. Since the 1-benzyl-3,5-bis((<i>E</i>)-3-bromobenzylidene)piperidin-4-one <b>3</...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/14/3122 |
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| author | Rossella Fioravanti Stefano Tomassi Elisabetta Di Bello Annalisa Romanelli Andrea Maria Plateroti Rosaria Benedetti Mariarosaria Conte Ettore Novellino Lucia Altucci Sergio Valente Antonello Mai |
| author_facet | Rossella Fioravanti Stefano Tomassi Elisabetta Di Bello Annalisa Romanelli Andrea Maria Plateroti Rosaria Benedetti Mariarosaria Conte Ettore Novellino Lucia Altucci Sergio Valente Antonello Mai |
| author_sort | Rossella Fioravanti |
| collection | DOAJ |
| description | Bis-(3-bromo-4-hydroxy)benzylidene cyclic compounds have been reported by us as epigenetic multiple ligands, but different substitutions at the two wings provided analogues with selective inhibition. Since the 1-benzyl-3,5-bis((<i>E</i>)-3-bromobenzylidene)piperidin-4-one <b>3</b> displayed dual p300/EZH2 inhibition joined to cancer-selective cell death in a panel of tumor cells and in in vivo xenograft models, we prepared a series of bis((<i>E</i>)-2-bromobenzylidene) cyclic compounds <b>4a</b>–<b>n</b> to test in biochemical (p300, PCAF, SIRT1/2, EZH2, and CARM1) and cellular (NB4, U937, MCF-7, SH-SY5Y) assays. The majority of <b>4a</b>–<b>n</b> exhibited potent dual p300 and CARM1 inhibition, sometimes reaching the submicromolar level, and induction of apoptosis mainly in the tested leukemia cell lines. The most effective compounds in both enzyme and cellular assays carried a 4-piperidone moiety and a methyl (<b>4d</b>), benzyl (<b>4e</b>), or acyl (<b>4k</b>–<b>m</b>) substituent at N1 position. Elongation of the benzyl portion to 2-phenylethyl (<b>4f</b>) and 3-phenylpropyl (<b>4g</b>) decreased the potency of compounds at both the enzymatic and cellular levels, but the activity was promptly restored by introduction of a ketone group into the phenylalkyl substituent (<b>4h</b>–<b>j</b>). Western blot analyses performed in NB4 and MCF-7 cells on selected compounds confirmed their inhibition of p300 and CARM1 through decrease of the levels of acetyl-H3 and acetyl-H4, marks for p300 inhibition, and of H3R17me2, mark for CARM1 inhibition. |
| first_indexed | 2024-03-10T18:37:01Z |
| format | Article |
| id | doaj.art-e229a14799334f0dab48062741b9823c |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T18:37:01Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-e229a14799334f0dab48062741b9823c2023-11-20T06:13:25ZengMDPI AGMolecules1420-30492020-07-012514312210.3390/molecules25143122Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer CellsRossella Fioravanti0Stefano Tomassi1Elisabetta Di Bello2Annalisa Romanelli3Andrea Maria Plateroti4Rosaria Benedetti5Mariarosaria Conte6Ettore Novellino7Lucia Altucci8Sergio Valente9Antonello Mai10Dipartimento di Chimica e Tecnologie del Farmaco, ‘Sapienza’ Università di Roma, 00185 Roma, ItalyDipartimento di Farmacia, Università di Napoli ‘Federico II’, 80131 Napoli, ItalyDipartimento di Chimica e Tecnologie del Farmaco, ‘Sapienza’ Università di Roma, 00185 Roma, ItalyDipartimento di Chimica e Tecnologie del Farmaco, ‘Sapienza’ Università di Roma, 00185 Roma, ItalyDipartimento di Neuroscienze, Salute Mentale e Organi di Senso–Nesmos, ‘Sapienza’ Università di Roma, 00185 Roma, ItalyDipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, 80138 Napoli, ItalyDipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, 80138 Napoli, ItalyDipartimento di Farmacia, Università di Napoli ‘Federico II’, 80131 Napoli, ItalyDipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, 80138 Napoli, ItalyDipartimento di Chimica e Tecnologie del Farmaco, ‘Sapienza’ Università di Roma, 00185 Roma, ItalyDipartimento di Chimica e Tecnologie del Farmaco, ‘Sapienza’ Università di Roma, 00185 Roma, ItalyBis-(3-bromo-4-hydroxy)benzylidene cyclic compounds have been reported by us as epigenetic multiple ligands, but different substitutions at the two wings provided analogues with selective inhibition. Since the 1-benzyl-3,5-bis((<i>E</i>)-3-bromobenzylidene)piperidin-4-one <b>3</b> displayed dual p300/EZH2 inhibition joined to cancer-selective cell death in a panel of tumor cells and in in vivo xenograft models, we prepared a series of bis((<i>E</i>)-2-bromobenzylidene) cyclic compounds <b>4a</b>–<b>n</b> to test in biochemical (p300, PCAF, SIRT1/2, EZH2, and CARM1) and cellular (NB4, U937, MCF-7, SH-SY5Y) assays. The majority of <b>4a</b>–<b>n</b> exhibited potent dual p300 and CARM1 inhibition, sometimes reaching the submicromolar level, and induction of apoptosis mainly in the tested leukemia cell lines. The most effective compounds in both enzyme and cellular assays carried a 4-piperidone moiety and a methyl (<b>4d</b>), benzyl (<b>4e</b>), or acyl (<b>4k</b>–<b>m</b>) substituent at N1 position. Elongation of the benzyl portion to 2-phenylethyl (<b>4f</b>) and 3-phenylpropyl (<b>4g</b>) decreased the potency of compounds at both the enzymatic and cellular levels, but the activity was promptly restored by introduction of a ketone group into the phenylalkyl substituent (<b>4h</b>–<b>j</b>). Western blot analyses performed in NB4 and MCF-7 cells on selected compounds confirmed their inhibition of p300 and CARM1 through decrease of the levels of acetyl-H3 and acetyl-H4, marks for p300 inhibition, and of H3R17me2, mark for CARM1 inhibition.https://www.mdpi.com/1420-3049/25/14/3122epigeneticshistone acetylationhistone methylationdrug discoverymulti-target agents |
| spellingShingle | Rossella Fioravanti Stefano Tomassi Elisabetta Di Bello Annalisa Romanelli Andrea Maria Plateroti Rosaria Benedetti Mariarosaria Conte Ettore Novellino Lucia Altucci Sergio Valente Antonello Mai Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells Molecules epigenetics histone acetylation histone methylation drug discovery multi-target agents |
| title | Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells |
| title_full | Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells |
| title_fullStr | Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells |
| title_full_unstemmed | Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells |
| title_short | Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells |
| title_sort | properly substituted cyclic bis 2 bromobenzylidene compounds behaved as dual p300 carm1 inhibitors and induced apoptosis in cancer cells |
| topic | epigenetics histone acetylation histone methylation drug discovery multi-target agents |
| url | https://www.mdpi.com/1420-3049/25/14/3122 |
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