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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...

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Autores principales: Balasubramaniam, Sivaraman, Vijayan, Sajith, Goldman, Liam V, May, Xavier A, Dodson, Kyra, Adhikari, Sweta, Rivas, Fatima, Watkins, Davita L, Stoddard, Shana V
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Beilstein-Institut 2020
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.
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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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