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Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition
Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the pheny...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Beilstein-Institut
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155894/ https://www.ncbi.nlm.nih.gov/pubmed/32318119 http://dx.doi.org/10.3762/bjoc.16.59 |
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author | Balasubramaniam, Sivaraman Vijayan, Sajith Goldman, Liam V May, Xavier A Dodson, Kyra Adhikari, Sweta Rivas, Fatima Watkins, Davita L Stoddard, Shana V |
author_facet | Balasubramaniam, Sivaraman Vijayan, Sajith Goldman, Liam V May, Xavier A Dodson, Kyra Adhikari, Sweta Rivas, Fatima Watkins, Davita L Stoddard, Shana V |
author_sort | Balasubramaniam, Sivaraman |
collection | PubMed |
description | Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative, docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets TOI1, TOI2, TOI3-rev and TOI4 whose biological evaluation confirmed the strength of HDAC8 inhibition with TOI4 displaying the greatest efficacy at varying concentrations. The results of this study lay the foundation for future design strategies toward more potent HDACis for HDAC8 isozymes and further therapeutic applications for neuroblastoma. |
format | Online Article Text |
id | pubmed-7155894 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Beilstein-Institut |
record_format | MEDLINE/PubMed |
spelling | pubmed-71558942020-04-21 Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition Balasubramaniam, Sivaraman Vijayan, Sajith Goldman, Liam V May, Xavier A Dodson, Kyra Adhikari, Sweta Rivas, Fatima Watkins, Davita L Stoddard, Shana V Beilstein J Org Chem Full Research Paper Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative, docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets TOI1, TOI2, TOI3-rev and TOI4 whose biological evaluation confirmed the strength of HDAC8 inhibition with TOI4 displaying the greatest efficacy at varying concentrations. The results of this study lay the foundation for future design strategies toward more potent HDACis for HDAC8 isozymes and further therapeutic applications for neuroblastoma. Beilstein-Institut 2020-04-07 /pmc/articles/PMC7155894/ /pubmed/32318119 http://dx.doi.org/10.3762/bjoc.16.59 Text en Copyright © 2020, Balasubramaniam et al. https://creativecommons.org/licenses/by/4.0https://www.beilstein-journals.org/bjoc/termsThis is an Open Access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0). Please note that the reuse, redistribution and reproduction in particular requires that the authors and source are credited. The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (https://www.beilstein-journals.org/bjoc/terms) |
spellingShingle | Full Research Paper Balasubramaniam, Sivaraman Vijayan, Sajith Goldman, Liam V May, Xavier A Dodson, Kyra Adhikari, Sweta Rivas, Fatima Watkins, Davita L Stoddard, Shana V Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition |
title | Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition |
title_full | Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition |
title_fullStr | Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition |
title_full_unstemmed | Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition |
title_short | Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition |
title_sort | design and synthesis of diazine-based panobinostat analogues for hdac8 inhibition |
topic | Full Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155894/ https://www.ncbi.nlm.nih.gov/pubmed/32318119 http://dx.doi.org/10.3762/bjoc.16.59 |
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