Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

Authors

Sivaraman Balasubramaniam, University of Mississippi
Sajith Vijayan, University of Mississippi
Liam V. Goldman, Rhodes College
Xavier A. May, Rhodes College
Kyra Dodson, University of Mississippi
Sweta Adhikari, University of Mississippi
Fatima Rivas, St. Jude Children's Research Hospital
Davita L. Watkins, University of Mississippi
Shana V. Stoddard, Rhodes College

Document Type

Article

Publication Date

4-7-2020

Abstract

© 2020 Balasubramaniam et al. 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.

Relational Format

journal article

Recommended Citation

Balasubramaniam, Sivaraman, et al. “Design and Synthesis of Diazine-Based Panobinostat Analogues for HDAC8 Inhibition.” Beilstein Journal of Organic Chemistry, vol. 16, Apr. 2020, pp. 628–37, doi:10.3762/bjoc.16.59.

DOI

10.3762/bjoc.16.59

Accessibility Status

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