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

Sivaraman Balasubramaniam; Sajith Vijayan; Liam V Goldman; Xavier A May; Kyra Dodson; Sweta Adhikari; Fatima Rivas; Davita L Watkins; Shana V Stoddard

doi:10.3762/bjoc.16.59

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

Beilstein J Org Chem. 2020 Apr 7:16:628-637. doi: 10.3762/bjoc.16.59. eCollection 2020.

Authors

Sivaraman Balasubramaniam¹, Sajith Vijayan¹, Liam V Goldman², Xavier A May², Kyra Dodson¹, Sweta Adhikari¹, Fatima Rivas³, Davita L Watkins¹, Shana V Stoddard²

Affiliations

¹ Department of Chemistry and Biochemistry, University of Mississippi, University, MS 38677-1848, USA.
² Department of Chemistry, Rhodes College, Memphis, TN 38112, USA.
³ Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.

Abstract

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.

Keywords: diazine; histone deacetylase; inhibitors; isozymes; panobinostat.

Grants and funding

For the synthesis of the nitrogen containing heterocyclic cores, S.B., S.V., K.D. S.A. and D. L. W. appreciate financial support from the National Science Foundation under Grant Numbers CHE-1652094. X. A. M., L. V. G. and S. V. S. would like to thank the William Randolph Hearst Fellowship for the funding.