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

Article abstract of DOI:10.1021/acsmedchemlett.9b00287

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.

Full text of DOI:10.1021/acsmedchemlett.9b00287

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Letter
Fluorinated Analogues of the HDAC Inhibitor Vorinostat
(Zolinza®): Validation of a Chiral Hybrid Bioisostere (BITE).
Nathalie Erdeljac, Kathrin Bussman, Andrea Schöller, Finn K. Hansen, and Ryan Gilmour
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00287 • Publication Date (Web): 19 Jul 2019
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Fluorinated Analogues of the HDAC Inhibitor Vorinostat (Zolinza®):
Validation of a Chiral Hybrid Bioisostere (BITE).
Nathalie Erdeljac,[a] Kathrin Bussman,[a] Andrea Schöler,[b] Finn K. Hansen§[b] and Ryan Gilmour*[a]
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[a] Institute for Organic Chemistry, WWU Münster, Correnstraße 40, 48149 Münster (Germany)
[b] Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Medical Faculty, Leipzig University, Brüderstraße 34, 04103
Leipzig (Germany)
KEYWORDS fluorine, bioisosteres, histone deacetylases, inhibitors, oncology.
ABSTRACT: A chiral, hybrid bioisostere of the CF3 and Et groups (BITE) has been installed in a series of vorinostat (Zolinza®)
analogues, and their HDAC inhibitory behavior studied relative to their non-fluorinated counterparts. Several of these compounds
containing the 1,2-difluoroethylene unit showed greater in vitro potency than 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 deriva-
tives. 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.
Small molecule therapeutics have a long and venerable his-
tory in clinical oncology, where persistently high cancer mor-
tality rates continue to provide a powerful impetus for drug
design and discovery.1 Therapeutic approaches based on non-
selective DNA targeting cytotoxic agents have been comple-
mented by a strategic shift towards 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), and by
extension histone acetyltransferase (HAT), activity 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 supresses
the expression of tumour-repressor genes.7 In contrast, hyper-
acetylated regions promote the expression of tumour-repressor
genes because of an expanded, open chromatin structure (eu-
chromatin), which is transcriptionally active. As targets for
drug discovery, 18 human HDACs have been identified to
date, and these can be sub-divided into four groups: class I
HDACs (HDACs 1, 2, 3 and 8), class II HDACs (further sub-
divided 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 class I, II and IV share a catalytic
mechanism that is zinc ion (Zn2+) dependent, whereas HDACs
from class III require the co-factor nicotinamide adenine dinu-
cleotide (NAD) for enzyme activity.9,10 Since the overexpres-
sion of HDACs is commonly associated with various cancer
types, drugs that target HDACs have been intensively pur-
sued.11-14 HDACs 1-3 and 6, are particularly noteworthy for
cancer drug development due to their distinguished mecha-
nisms 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 (Bele-
odaq®), romidepsin (Istodax®), and panobinostat (Farydak®).
Figure 1. Top: Vorinostat for the treatment of cutaneous T-cell lympho-
ma. Centre: Vorinostat analogues with a pendant ester. Bottom: Target
compounds of this study incorporating the BITE group.
With the exception of romidepsin (Istodax®) these drugs con-
tain 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 hydrox-
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amic acid to an aromatic head group that is occupies the en-
trance to this pocket. This ring lends itself to structural modi-
fications, and is a convenient platform from which to conduct
SAR studies.18,19
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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 fluoride source and Brønsted acid activator
[Scheme 1 (right), please also see the Supporting Information
for full details]. The corresponding non-fluorinated hydrocar-
bon chains were obtained from commercial sources, or pre-
pared from readily available starting materials (Supporting
Information). Non-fluorinated compounds 4e, 4g, 5e and 5g
were previously reported by Dyson and co-workers.20 Installa-
tion of the aliphatic chains was achieved via facile displace-
ment (K2CO3, DMF, 70 °C to afford ethyl esters 2a-h and 4a-
h (Scheme 1). Finally, the benzyl protecting group in interme-
diates 2a-h and 4a-h was cleaved using boron trichloride
based on a previously reported procedure41 to obtain the free
hydroxamic acid.
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An elegant study by Dyson and co-workers reported a series of
analogs containing perfluorinated alkyl chains attached to the
aromatic head group (Figure 1, center).20 This structural motif
was introduced to induce thermoresponsiveness as a means to
obtain more selective HDACi through activation by localised
heating. Although only vorinostat itself was found to be re-
sponsive towards heat stimuli, the authors reported that several
derivatives showed enhanced selectivity towards cancer cells
over healthy cells. Interestingly, the best performing derivative
was a non-fluorinated reference compound bearing a decyl
ester functionality (Figure 1, center). Motivated by this study
and our interest in the physicochemical properties of the vici-
nal 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 (Fig-
ure 1, lower).21-23
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The fluorinated and non-fluorinated target compounds (3a-h
and 5a-h) were initially tested for their in vitro inhibitory
activity towards 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 % inhibition at 1
µM (see Table S1 in Supporting Information). In the majority
of cases, the fluorinated compounds containing the BITE
group (CHFCH2F) outperformed their non-fluorinated (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 towards HDAC1. Solely the non-
fluorinated butyl and pentyl esters 5a and 5b had a slightly
higher potency than 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 2. The gauche effect and dipole moment in 1,2-difluoroethylene.
The conformation of the 1,2-difluoroethylene motif is charac-
terised 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 polarised carbon-
fluorine bonds (Cδ+-Fδ-) give rise to a large dipole moment that
directly influences the compounds physicochemical and phar-
macological properties: Pertinent examples include lipophilici-
ty, solubility, protein binding and rate of metabolism.22,31
Moreover, the presence of a chiral centre in this motif renders
it a useful addition to the medicinal chemistry toolkit. Alt-
hough the 1,2-difluoroethyl group has a unique shape, it is
comparable in size to the trifluoromethyl and ethyl groups,23
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.
Whilst an array of strategies have been developed that rely 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 pre-
functionalization. By extension, the preparation of fluorinated
vorinostat analogues containing the BITE group is disclosed,
and their HDAC inhibitory activity compared to their non-
fluorinated congeners.
Several of the target compounds performed better than vori-
nostat (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 non-fluorinated com-
pound 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 towards
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 major-
ity of compounds showed a comparable inhibitory activity to
that of vorinostat. The only exception proved to be the non-
fluorinated hexyl ester 5c, whose potency was significantly
lower than the remaining compounds, particularly towards
HDAC2.
Preparation of the two test series (BITE versus Et) from the
common precursor 1 is described in Scheme 1. Building block
1 was synthesised from 4-aminophenylacetic acid following
the procedure described by Dyson and co-workers.20 The
fluorinated alkyl chains were prepared from the corresponding
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Scheme 1. Synthesis of fluorinated and non-fluorinated target compounds. Reagents and conditions: (a) K2CO3, DMF, RT; (b) BCl3 in DCM (1 M), THF,
0 °C to ambient temperature.
B
HDAC6
A
HDAC1
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250
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150
100
50
1000
900
800
700
600
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400
300
200
100
0
1,2-Difluoro
Alkyl
1,2-Difluoro
Alkyl
Zolinza®
Zolinza®
0
Length of methylene spacer
Length of methylene spacer
D
HDAC3
C
HDAC2
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200
150
100
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500
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150
100
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1,2-Difluoro
Alkyl
1,2-Difluoro
Alkyl
Zolinza®
Zolinza®
0
0
Zolinza®
1
2
3
Zolinza®
1
2
3
Length of methylene spacer
Length of methylene spacer
Figure 3. In vitro inhibitory activity of the two compound series as a function of methylene spacer length is shown towards: HDAC1 (A), HDAC6 (B),
HDAC2 (C) and HDAC3 (D) (for more details see Table S1 in ESI). The drug vorinostat (Zolinza®) was used as a reference compound (grey).
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dimethylformamide; DCM, dichloromethane; THF, tetrahydrofu-
ran; SI, selectivity index.
In summary, a novel series of vorinostat analogues bearing a
chiral, hybrid, bioisostere of the trifluoromethyl and ethyl
groups (BITE group) has been prepared. This was achieved by
the direct vicinal difluorination of alkenes via I(I)/I(III) cataly-
sis. Evaluation as potential as HDAC inhibitors was conducted
simultaneously with the non-fluorinated (Et) equivalents using
vorinostat as the control. Several of these new, fluorinated
compounds exceed the inhibition activities of the FDA ap-
proved drug vorinostat (eight towards HDAC6 and four
against HDAC1). In the majority of cases, the BITE fluorinat-
ed compounds significantly outperformed their non-
fluorinated analogues. In addition, a clear correlation between
the inhibitory potency and the size of the alkyl ester was ob-
served, where the inhibitory activity is gradually reduced with
increasing alkyl chain length in both compound series. Inter-
estingly, this effect is more pronounced in the non-fluorinated
series. Furthermore, most of the compounds in this study
showed an increased activity towards 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 ad-
vances in catalysis, it is envisaged that the under-explored 1,2-
difluoroethylene unit (BITE) will find further application as a
useful fluorine-containing-bioisostere44,45 for small molecule
drug discovery. Since the BITE group is chiral, exploring the
behavior of each enantiomer will be the subject of future re-
search in our laboratory.
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Supporting Information
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AUTHOR INFORMATION
Corresponding Author
* ryan.gilmour@uni-muenster.de
§ finn.hansen@medizin.uni-leipzig.de
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script.
Funding Sources
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).
ACKNOWLEDGMENT
We thank the analytical departments of the Institute for Organic
Chemistry at the WWU Münster for technical support.
ABBREVIATIONS
HATs, histone acetyltransferases; HDACs, histone deacetylases;
HDACi, histone deacetylase inhibitors; BITE, bioisostere of the
trifluoromethyl and ethyl groups; Et, ethyl; DNA, deoxyribonu-
cleic acid; FDA, U.S. Food and Drug Administration; DMF,
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