Exploring hydroxamic acid inhibitors of HDAC1 and HDAC2 using small molecule tools and molecular or homology modelling. Issue 18 (15th September 2019)

• Record Type: Journal Article
• Authors: Daniel, Lydia; Gotsbacher, Michael P.; Richardson-Sanchez, Tomas; Tieu, William; Codd, Rachel
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 18(2019)
• Page Start: 2581
• Page End: 2586
• Publication Date: 2019-09-15
• Subjects: Histone deacetylases (HDACs) -- Hydroxamic acids -- N-Hydroxycinnamamide -- Molecular modelling -- Homology modelling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.08.002
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Hydroxamic acid compounds 1 –10 containing a N -hydroxycinnamamide scaffold and a 4-(benzylamino)methyl cap group that was either unsubstituted (1 ) or substituted with one (2 –4 ) or two (5 –10 ) methoxy groups in variable positions were prepared as inhibitors of Zn(II)-containing histone deacetylases (HDACs). The 3, 4- (9 ) and 3, 5- (10 ) bis-methoxy-substituted compounds were the least potent against HeLa nuclear extract, HDAC1 and HDAC2. Molecular modelling showed methoxy groups in the 3-, 4- and 5-position, but not the 2-position, had unfavourable steric interactions with the G32-H33-P34 triad on a loop at the surface of the HDAC2 active site cavity. An HDAC1 homology model showed potential ionic (E243..K288) and cation-pi (K247..F292) interactions between helix 10 and helix 11 that were absent in HDAC2 ((G243..K288) and (K247..V292)). This surface-located interhelical constraint could inform the design of bitopic HDAC1 and HDAC2 selective ligands using an allosteric approach, and/or protein-protein interaction (PPI) inhibitors.