Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines

Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines

Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemothe...

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Main Authors: Susanna Nencetti, Doretta Cuffaro, Elisa Nuti, Lidia Ciccone, Armando Rossello, Marina Fabbi, Flavio Ballante, Gabriella Ortore, Grazia Carbotti, Francesco Campelli, Irene Banti, Rosaria Gangemi, Garland R. Marshall, Elisabetta Orlandini
Format: Article
Language:English
Published: Taylor & Francis Group 2021-01-01
Series:Journal of Enzyme Inhibition and Medicinal Chemistry
Subjects:
uveal melanoma
hdac inhibitors
hdac6
saha
(arylidene)aminoxy-based hydroxamates
Online Access:http://dx.doi.org/10.1080/14756366.2020.1835883
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spelling doaj-dd29395ad7324c7e95f604e5f4b25f962020-11-25T03:37:07ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742021-01-01361344710.1080/14756366.2020.18358831835883Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell linesSusanna Nencetti0Doretta Cuffaro1Elisa Nuti2Lidia Ciccone3Armando Rossello4Marina Fabbi5Flavio Ballante6Gabriella Ortore7Grazia Carbotti8Francesco Campelli9Irene Banti10Rosaria Gangemi11Garland R. Marshall12Elisabetta Orlandini13Dipartimento di Farmacia, Università di PisaDipartimento di Farmacia, Università di PisaDipartimento di Farmacia, Università di PisaDipartimento di Farmacia, Università di PisaDipartimento di Farmacia, Università di PisaIRCCS Ospedale Policlinico San MartinoDepartment of Biochemistry and Molecular Biophysics, Washington University School of MedicineDipartimento di Farmacia, Università di PisaIRCCS Ospedale Policlinico San MartinoIRCCS Ospedale Policlinico San MartinoDipartimento di Farmacia, Università di PisaIRCCS Ospedale Policlinico San MartinoDepartment of Biochemistry and Molecular Biophysics, Washington University School of MedicineResearch Center “E. Piaggio”, Università di PisaUveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA.http://dx.doi.org/10.1080/14756366.2020.1835883uveal melanomahdac inhibitorshdac6saha(arylidene)aminoxy-based hydroxamates
collection DOAJ
language English
format Article
sources DOAJ
author Susanna Nencetti
Doretta Cuffaro
Elisa Nuti
Lidia Ciccone
Armando Rossello
Marina Fabbi
Flavio Ballante
Gabriella Ortore
Grazia Carbotti
Francesco Campelli
Irene Banti
Rosaria Gangemi
Garland R. Marshall
Elisabetta Orlandini
spellingShingle Susanna Nencetti
Doretta Cuffaro
Elisa Nuti
Lidia Ciccone
Armando Rossello
Marina Fabbi
Flavio Ballante
Gabriella Ortore
Grazia Carbotti
Francesco Campelli
Irene Banti
Rosaria Gangemi
Garland R. Marshall
Elisabetta Orlandini
Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines
Journal of Enzyme Inhibition and Medicinal Chemistry
uveal melanoma
hdac inhibitors
hdac6
saha
(arylidene)aminoxy-based hydroxamates
author_facet Susanna Nencetti
Doretta Cuffaro
Elisa Nuti
Lidia Ciccone
Armando Rossello
Marina Fabbi
Flavio Ballante
Gabriella Ortore
Grazia Carbotti
Francesco Campelli
Irene Banti
Rosaria Gangemi
Garland R. Marshall
Elisabetta Orlandini
author_sort Susanna Nencetti
title Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines
title_short Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines
title_full Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines
title_fullStr Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines
title_full_unstemmed Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines
title_sort identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines
publisher Taylor & Francis Group
series Journal of Enzyme Inhibition and Medicinal Chemistry
issn 1475-6366
1475-6374
publishDate 2021-01-01
description Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA.
topic uveal melanoma
hdac inhibitors
hdac6
saha
(arylidene)aminoxy-based hydroxamates
url http://dx.doi.org/10.1080/14756366.2020.1835883
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