Fluorinated Analogues of the Histone Deacetylase Inhibitor Vorinostat (Zolinza): Validation of a Chiral Hybrid Bioisostere, BITE

Abstract

A chiral, hybrid bioisostere of the CF3 and Et groups (BITE) was installed in a series of vorinostat (Zolinza) analogues, and their histone deacetylase (HDAC) inhibitory behavior was studied relative to that of their nonfluorinated counterparts. Several of these compounds containing the 1,2-difluoroethylene unit showed in vitro potency greater than that of the clinically approved drug itself against HDAC1. This trend was found to be general with the BITE-modified HDAC inhibitors performing significantly better than the ethyl derivatives. Installed by the direct, catalytic vicinal difluorination of terminal alkenes using an I­(I)/I­(III) manifold, this underexplored chiral bioisostere shows potential in drug discovery.

Borinostats: solid-phase synthesis of carborane-capped histone deacetylase inhibitors with a tailor-made selectivity profile

“…44b With the eight hydroxamates 8a-d and 9a-d in hand, we set out to explore their inhibitory activity against HDAC1 and HDAC6 in a fluorogenic assay using ZMAL (Z-Lys(Ac)-AMC) as substrate and vorinostat (suberoylanilide hydroxamic acid, SAHA) as a control (Table 1) following our previously published protocol. 45 To our delight, all new compounds showed IC 50 values for HDAC6 in the double-or even single-digit nanomolar range comparable to those of SAHA (IC 50 : 0.031 μM). Two of the compounds (9a and 9d) showed improved HDAC6 inhibition Please do not adjust margins Please do not adjust margins compared to the control.…”

“…To evaluate the anticancer properties of the carborane-capped HDACis, compounds 8a–d and 9a–d , as well as their phenyl analogues 10 and 11 were tested in MTT assays in the ovarian cancer cell line A2780, again using the FDA-approved HDACi vorinostat ( SAHA ) as positive control. 45 The results are summarized in Table 1 . All compounds demonstrated antiproliferative effects in the single-digit micromolar concentration range.…”

Synthesis, Antiplasmodial, and Antileukemia Activity of Dihydroartemisinin–HDAC Inhibitor Hybrids as Multitarget Drugs

“…The inhibition of human HDAC1 and 6 was determined as previously described [ 35 ]. OptiPlate-96 black microplates (Perkin Elmer Inc., Waltham, MA, USA) were used with an assay volume of 50 µL.…”

Expanding organofluorine chemical space: the design of chiral fluorinated isosteres enabled by I(i)/I(iii) catalysis

“…Examples from this laboratory include the synthesis of a series of Vorinostat (Zolinza®) derivatives ( 45 ) containing a pendant chain capped with a vicinal difluoro motif. 72 The HDAC inhibitory behaviour of this compound set was evaluated relative to the non-fluorinated systems. 73 In all cases, the FDA approved Vorinostat (Zolinza®) was used as a control.…”