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. 2019 Jul 19;10(9):1336–1340. doi: 10.1021/acsmedchemlett.9b00287

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

Nathalie Erdeljac †, Kathrin Bussmann †, Andrea Schöler ‡, Finn K Hansen ‡,*, Ryan Gilmour †,*
PMCID: PMC6745648  PMID: 31531206

Abstract

graphic file with name ml-2019-00287m_0005.jpg

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.

Keywords: Fluorine, bioisosteres, histone deacetylases, inhibitors, oncology

Small molecule therapeutics have a long and venerable history in clinical oncology, where persistently high cancer mortality rates continue to provide a powerful impetus for drug design and discovery.1 Therapeutic approaches based on nonselective DNA targeting cytotoxic agents have been complemented by a strategic shift toward more targeted molecular therapeutics.2−4 This paradigm change is exemplified by the success of low molecular weight histone deacetylase inhibitors (HDACi).5 Modulating histone deacetylase (HDAC) activity, and by extension that of histone acetyltransferase (HAT), has a direct impact on the degree of histone acetylation: this subsequently alters the structure of chromatin and allows gene transcription to be targeted.6 Specifically, hypoacetylation results in a compact chromatin structure (heterochromatin) that suppresses the expression of tumor-repressor genes.7 In contrast, hyperacetylated regions promote the expression of tumor-repressor genes because of an expanded, open chromatin structure (euchromatin) which is transcriptionally active. As targets for drug discovery, 18 human HDACs have been identified to date, and these can be subdivided into four groups: class I HDACs (HDACs 1, 2, 3, and 8), class II HDACs (further subdivided into class IIa HDACs 4, 5, 7, and 9 and the class IIb HDACs 6 and 10), class III (sirtuin family), and class IV (HDAC11).8 Enzymes from classes I, II, and IV share a catalytic mechanism that is zinc ion (Zn2+) dependent, whereas HDACs from class III require the cofactor nicotinamide adenine dinucleotide (NAD) for enzyme activity.9,10 Because the overexpression of HDACs is commonly associated with various cancer types, drugs that target HDACs have been intensively pursued.11−14 HDACs 1–3 and 6 are particularly noteworthy for cancer drug development due to their distinguished mechanisms of action.15,16 Currently, four HDACi drugs are FDA-approved for the treatment of multiple myeloma and T-cell lymphoma: vorinostat (Zolinza, Figure 1),17 belinostat (Beleodaq), romidepsin (Istodax), and panobinostat (Farydak).

Figure 1.

Figure 1

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Top: Vorinostat for the treatment of cutaneous T-cell lymphoma. Center: Vorinostat analogues with a pendant ester. Bottom: Target compounds of this study incorporating the BITE group.

With the exception of romidepsin (Istodax), these drugs contain a common hydroxamic acid zinc-binding group (ZBG) that is essential for Zn2+ chelation in the enzyme active site. In the case of vorinostat, a lipophilic chain connects the hydroxamic acid to an aromatic headgroup that occupies the entrance to this pocket. This ring lends itself to structural modifications and is a convenient platform from which to conduct structure–activity relationship studies.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. Interestingly, the best performing derivative was a nonfluorinated reference compound bearing a decyl ester functionality (Figure 1, center). Motivated by this study and our interest in the physicochemical properties of the vicinal difluoroethyl group, a study to explore the effect of the chiral hybrid bioisostere of the trifluoromethyl and ethyl groups (BITE group) on HDAC inhibition was initiated (Figure 1, lower).21−23

The conformation of the 1,2-difluoroethylene motif is characterized by the syn-clinal arrangement of the C–F bonds due to reinforcing hyperconjugative interactions (σC–H → σC–F*): this is commonly known as the gauche effect.24−30 In addition to restricting rotation about the C(sp3)–C(sp3) bond, the preferred gauche alignment (φFCCF = 60°) of the polarized carbon–fluorine bonds (Cδ+–Fδ−) gives rise to a large dipole moment that directly influences the compounds physicochemical and pharmacological properties: pertinent examples include lipophilicity, solubility, protein binding, and rate of metabolism (Figure 2).22,31 Moreover, the presence of a chiral center in this motif renders it a useful addition to the medicinal chemistry toolkit. Although the 1,2-difluoroethyl group has a unique shape, it is comparable in size to the trifluoromethyl and ethyl groups23 and thus may be considered as a hybrid, chiral bioisostere (BITE). Regrettably, exploring this motif in the context of drug discovery has been hampered by preparative difficulties. While an array of strategies has been developed that relies on oxidation/displacement sequences,32−35 the direct vicinal difluorination of alkenes has only recently been achieved.36−40 As validated in our recent study of fluorinated fingolimod (Gilenya) analogues,22 I(I)/(III) catalysis enables the direct installation of this group without substrate prefunctionalization. By extension, the preparation of fluorinated vorinostat analogues containing the BITE group is disclosed, and their HDAC inhibitory activity is compared to their nonfluorinated congeners.

Figure 2.

Figure 2

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The gauche effect and dipole moment in 1,2-difluoroethylene.

Preparation of the two test series (BITE versus Et) from the common precursor 1 is described in Scheme 1. 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 Et3N·3HF and Olah’s reagent, as the fluoride source and Brønsted acid activator (Scheme 1, please also see the Supporting Information for full details). The corresponding nonfluorinated hydrocarbon chains were obtained from commercial sources or prepared from readily available starting materials (Supporting Information). 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 (K2CO3, 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 procedure41 to obtain the free hydroxamic acid.

Scheme 1. Synthesis of Fluorinated and Nonfluorinated Target Compounds.

Scheme 1

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Reagents and conditions: (a) K2CO3, DMF, RT; (b) BCl3 in DCM (1 M), THF, 0 °C to ambient temperature.

The fluorinated and nonfluorinated target compounds (3a–h and 5a–h) were initially tested for their in vitro inhibitory activity toward HDAC1 and HDAC6 (Figure 3, A and B) using a previously published biochemical assay.42 In all cases, vorinostat (Zolinza) was used as a reference compound. The IC50 values and standard deviations are summarized in Table S1. Compounds 5g and 5h did not reach 100% inhibition against HDAC1 and are therefore reported as percent inhibition at 1 μM (see Table S1 in the Supporting Information). In the majority of cases, the fluorinated compounds containing the BITE group (CHFCH2F) outperformed their nonfluorinated (Et) equivalents. This distinction was particularly evident for the longer alkyl esters (i.e., heptyl and above). Notably, all the BITE containing compounds exceeded the activities of their ethyl bearing analogues toward HDAC1. Solely the nonfluorinated butyl and pentyl esters 5a and 5b had a potency slightly higher than those of their BITE fluorinated derivatives with regards to HDAC6 inhibition. Furthermore, the potencies of compounds 5e and 5g were both lower than that of vorinostat, which is consistent with previously reported data.20

Figure 3.

Figure 3

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In vitro inhibitory activity of the two compound series as a function of methylene spacer length is shown toward: HDAC1 (A), HDAC6 (B), HDAC2 (C), and HDAC3 (D) (for more details, see Table S1 in the Supporting Information). The drug vorinostat (Zolinza) was used as a reference compound (gray).

Several of the target compounds performed better than vorinostat (HDAC1 IC50: 102 nM and HDAC6 IC50: 47 nM) against both HDAC1 (3a–d) and HDAC6 (3a–f and 5a–c). Furthermore, an apparent relationship was observed between the length of the alkyl ester and inhibitory activity: potency gradually decreased with increasing alkyl chain length. This effect is much more prominent in the nonfluorinated compound series, particularly in the inhibition of HDAC1. Most of the target compounds possess a slightly higher selectivity index (SI: 3–7, Table S1) to that found in vorinostat (SI: 2) and therefore a slight preference for the class IIb enzyme HDAC6. This partiality becomes more evident with increasing size of the alkyl esters and particularly reduced potencies toward HDAC1. Subsequently, the compounds that displayed more promising potency against HDAC1 and HDAC6 (3a–c and 5a–c) were screened against HDAC2 and HDAC3 (Figure 3, C and D) due to their particular interest as cancer targets.43 The results did not, however, show any specific trend, and the majority of compounds showed an inhibitory activity comparable to that of vorinostat. The only exception proved to be the nonfluorinated hexyl ester 5c, whose potency was significantly lower than those of the remaining compounds, particularly toward HDAC2.

In summary, a novel series of vorinostat analogues bearing a chiral, hybrid bioisostere of the trifluoromethyl and ethyl groups (BITE group) was prepared. This was achieved by the direct vicinal difluorination of alkenes via I(I)/I(III) catalysis. Evaluation as potential HDAC inhibitors was conducted simultaneously with the nonfluorinated (Et) equivalents using vorinostat as the control. Several of these new fluorinated compounds exceed the inhibition activities of the FDA approved drug vorinostat (eight toward HDAC6 and four against HDAC1). In the majority of cases, the BITE fluorinated compounds significantly outperformed their nonfluorinated analogues. In addition, a clear correlation between the inhibitory potency and the size of the alkyl ester was observed, where the inhibitory activity is gradually reduced with increasing alkyl chain length in both compound series. Interestingly, this effect is more pronounced in the nonfluorinated series. Furthermore, most of the compounds in this study showed an increased activity toward HDAC6 in comparison to HDAC1–3. A slightly increased preference for HDAC6 over HDAC1 was observed for a majority of compounds (SI: 3–7) when compared to that of vorinostat (SI: 2). Enabled by advances in catalysis, it is envisaged that the underexplored 1,2-difluoroethylene unit (BITE) will find further application as a useful fluorine-containing bioisostere44 for small molecule drug discovery. Because the BITE group is chiral, exploring the behavior of each enantiomer will be the subject of future research in our laboratory.

Acknowledgments

We thank the analytical departments of the Institute for Organic Chemistry at the WWU Münster for technical support.

Glossary

Abbreviations

HATs

histone acetyltransferases

HDACs

histone deacetylases

HDACi

histone deacetylase inhibitors

BITE

bioisostere of the trifluoromethyl and ethyl groups

Et

ethyl

DNA

deoxyribonucleic acid

FDA

U.S. Food and Drug Administration

DMF

dimethylformamide

DCM

dichloromethane

THF

tetrahydrofuran

SI

selectivity index

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.9b00287.

  • Experimental and analytical data and assay protocols (PDF)

We acknowledge generous financial support from the WWU Münster, the DFG (SFB 858), and the European Research Council for an ERC Consolidator Grant (RG, 818949 RECON ERC-2018-CoG).

The authors declare no competing financial interest.

Supplementary Material

ml9b00287_si_001.pdf (6.4MB, pdf)

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Supplementary Materials

ml9b00287_si_001.pdf (6.4MB, pdf)

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