Perfluorinated HDAC inhibitors as selective anticancer agents

Abstract

A series of potent histone deacetylase inhibitors is presented that incorporate alkyl or perfluorinated alkyl chains. Several new compounds show greater in vitro antiproliferative activity than the clinically approved inhibitor, SAHA. Furthermore, the new compounds show up to 5-fold greater activity against cancer cells than healthy cells. This selectivity is in contrast to SAHA, which is more active against the healthy cell line than the cancer cell line tested. Finally, we report an increase in activity for SAHA under mild hyperthermia, indicating that it could be an interesting candidate to use in combination with thermal therapy.

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

“… 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. 74 Several of the compounds containing the 1,2-difluoroethylene unit showed greater in vitro potency than the clinically approved drug itself against HDAC1.…”

α,ß-Didehydrosuberoylanilide hydroxamic acid (DDSAHA) as precursor and possible analogue of the anticancer drug SAHA

“…On the other hand, trichostatin A ( 3 ), containing an α,ß-unsaturated hydroxamic acid unit is the best known HDAC inhibitor which shows antifungal activities [10–11]. Because of the impressive level of biological activity, SAHA has received considerable attention in terms of SAR studies in the quest for a selective inhibitor and/or improved/altered biological activity [12–13]. Many of these studies have shown that minor variations in the structure of SAHA have sometimes led to significant changes in biological activity [14].…”

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

“…18,19 An elegant study by Dyson and coworkers reported a series of analogues containing perfluorinated alkyl chains attached to the aromatic headgroup (Figure 1, center). 20 This structural motif was introduced to induce thermoresponsiveness as a means to obtain more selective HDACi through activation by localized heating. Although only vorinostat itself was found to be responsive toward heat stimuli, the authors reported that several derivatives showed enhanced selectivity toward cancer cells over healthy cells.…”

“…Building block 1 was synthesized from 4-aminophenylacetic acid following the procedure described by Dyson and coworkers. 20 The fluorinated alkyl chains were prepared from the corresponding terminal alkenes via direct, catalytic vicinal difluorination. For this purpose, p-iodotoluene was employed as an inexpensive organo catalyst, Selectfluor as the terminal oxidant, and an amine:HF (1:5) solution mixture, comprised of Et 3 N•3HF and Olah's reagent, as the fluoride source and Brønsted acid activator (Scheme 1, please also see the Supporting Information for full details).…”

“…Nonfluorinated compounds 4e, 4g, 5e, and 5g were previously reported by Dyson and coworkers. 20 Installation of the aliphatic chains was achieved via facile displacement (K 2 CO 3 , DMF, 70 °C) to afford ethyl esters 2a− h and 4a−h (Scheme 1). Finally, the benzyl protecting group in intermediates 2a−h and 4a−h was cleaved using boron trichloride based on a previously reported procedure 41 to obtain the free hydroxamic acid.…”