Assessment of the trifluoromethyl ketone functionality as an alternative zinc-binding group for selective HDAC6 inhibition

Article abstract of DOI:10.1039/c8md00107c

Recent studies point towards the possible disadvantages of using hydroxamic acid-based zinc-binding groups in HDAC inhibitors due to e.g. mutagenicity issues. In this work, we elaborated on our previously developed Tubathian series, a class of highly sele

Full text of DOI:10.1039/c8md00107c

MedChemComm
View Article Online
View Journal
RESEARCH ARTICLE
Assessment of the trifluoromethyl ketone
functionality as an alternative zinc-binding group
Cite this: DOI: 10.1039/c8md00107c
for selective HDAC6 inhibition†
Yves Depetter,abc Silke Geurs,a Flore Vanden Bussche,a Rob De Vreese,a
a
Jorick Franceus,d Tom Desmet,d Olivier De Wever bc and Matthias D'hooghe
*
Recent studies point towards the possible disadvantages of using hydroxamic acid-based zinc-binding
groups in HDAC inhibitors due to e.g. mutagenicity issues. In this work, we elaborated on our previously
developed Tubathian series, a class of highly selective thiaheterocyclic HDAC6 inhibitors, by replacing the
benzohydroxamic acid function by an alternative zinc chelator, i.e., an aromatic trifluoromethyl ketone. Un-
fortunately, these compounds showed a reduced potency to inhibit HDAC6 as compared to their hydro-
xamic acid counterparts. In agreement, the most active trifluoromethyl ketone was unable to influence the
growth of SK-OV-3 ovarian cancer cells nor to alter the acetylation status of tubulin and histone H3. These
data suggest that replacement of the zinc-binding hydroxamic acid function with a trifluoromethyl ketone
zinc-binding moiety within reported benzohydroxamic HDAC6 inhibitors should not be considered as a
standard strategy in HDAC inhibitor development.
Received 26th February 2018,
Accepted 4th May 2018
DOI: 10.1039/c8md00107c
rsc.li/medchemcomm
small molecules has proven to be an effective strategy in
cancer therapy.3
Introduction
The acetylation status of proteins is regulated by the subtle
interplay between histone acetyltransferases (HATs) and his-
tone deacetylases (HDACs). These enzymes respectively add or
remove an acetyl group on lysine residues in specific proteins,
thus influencing many important cell processes such as pro-
liferation and protein degradation.1,2 In light of this extensive
impact on cellular functions, it is clear that aberrant HDAC
activity is an important actor in a vast amount of diseases,
including different types of cancer, inflammation and neuro-
degenerative disorders.3–5 The HDAC family consists of 18
members (isozymes), which are divided into four classes: the
zinc-dependent class I (HDAC1–3 and 8), class II (HDAC4–7
and 9–10) and class IV (HDAC11), and the NAD+-dependent
class III (SIRT1–7).6,7 The inhibition of these enzymes by
Most HDAC inhibitors consist of three parts that contrib-
ute to the overall biological effect: a ‘cap’-group, interacting
with the enzyme surface, a linker unit, and a zinc-binding
group (ZBG), which binds the zinc atom in the catalytic
pocket. Currently, four HDAC inhibitors (HDACi's), i.e.,
Vorinostat 1, Romidepsin 2, Belinostat 3 and Panobinostat 4,
are approved by the FDA as anticancer agents and are used
in the clinic (Fig. 1). However, these inhibitors display a vari-
ety of side effects, possibly resulting from their non-selective
character, meaning that they interfere with multiple zinc-
dependent HDAC isozymes.8,9 To circumvent these problems,
recent studies focus on the development of isoform-selective
HDACi's. In particular, the selective inhibition of HDAC6 has
proven to be of interest due to the cellular location and sub-
strate specificity of this isozyme.10 The first selective HDAC6
inhibitor, Tubacin 5, showed good activity and selectivity,
although its high lipophilicity and poor drug likeness
hampered further applications.11 Since then, a variety of
selective HDAC6 inhibitors has been designed, with the dis-
covery of Tubastatin A 6 as an important milestone due to its
excellent activity, selectivity and pharmacological profile.12–14
Our group recently developed a series of sulfur-containing
Tubastatin A analogues, denoted as Tubathians 7, demon-
strating an excellent activity and selectivity against HDAC6 in
enzymatic and cellular assays, as well as desirable ADME-Tox
properties.15,16 The most promising candidates within our
series comprise a sulfoxide/sulfone-containing ‘cap’-group
a SynBioC Research Group, Department of Green Chemistry and Technology,
Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000
Ghent, Belgium. E-mail: matthias.dhooghe@UGent.be
b Laboratory of Experimental Cancer Research, Department of Radiation Oncology
and Experimental Cancer Research, Ghent University, Corneel Heymanslaan 10,
B-9000 Ghent, Belgium
c Cancer Research Institute Ghent (CRIG), Ghent, Belgium
d Centre for Synthetic Biology (CSB), Department of Biotechnology, Faculty of
Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent,
Belgium
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8md00107c
This journal is © The Royal Society of Chemistry 2018
Med. Chem. Commun.

View Article Online
Research Article
MedChemComm
Fig. 1 Structure of reported HDAC inhibitors.
and an aromatic linker unit bearing a para-positioned hydro-
xamic acid functionality. This hydroxamic acid moiety acts as
a powerful zinc chelator, making it the most widely used
and the most effective zinc-binding group in HDACi develop-
ment to date.17 However, recent literature points to the
possible downsides of this particular ZBG, such as low bio-
availability, toxicity due to non-specific metal binding, and
mutagenicity.18–23 In light of these drawbacks, various other
groups have been proposed as alternatives for the hydro-
xamic acid functionality, such as thiols, sulfonamides,
boronic acids and many more, with rather mixed results.24
Recent work on HDAC6 inhibitors by our team focused on
the optimization of the ‘cap’-group and linker unit of
Tubathian analogues 7, keeping the ZBG constant.16 On the
other hand, the present study aimed at replacing the poten-
tially hazardous hydroxamic acid by another ZBG, namely a
trifluoromethyl ketone (TFMK), in an attempt to further opti-
mize this promising class of Tubathian HDAC6i's. The TMFK
functionality has proven to be an effective metal chelator in
various HDAC inhibitors, successfully replacing the hydro-
xamic acid group in for example Vorinostat 1.25 Inspired by
these results, multiple trifluoromethyl ketone derivatives
have been constructed in recent years, mainly containing an
alkyl linker unit connected to a variety of ‘cap’-groups, such
as tetrapeptides, 1,2,4-oxodiazoles and bisthiazoles.26–28 Fur-
thermore, the use of an aromatic thiophene or furan linker
resulted in a set of highly active and selective class II HDAC
inhibitors.29,30 These literature results provided a clear ratio-
nale for the replacement of the hydroxamic acid within our
previously developed HDAC6 inhibitors by a TFMK in order
to further explore the structure–activity relationships (SAR) of
this class of compounds (Fig. 2).
Fig. 2 Extended SAR of Tubathian analogues and target structures 8.
Med. Chem. Commun.
This journal is © The Royal Society of Chemistry 2018

View Article Online
MedChemComm
Research Article
Results and discussion
obtained by transformation of the methyl ester using
Ruppert's reagent (TMSCF3), yielding the potential HDAC6 in-
hibitors 8 in moderate yields and high purity.31 In earlier ex-
periments, the reaction of 4-bromo-(or 4-iodo-)benzyl bro-
mide with the ‘cap’-group 13 was performed as well, after
which the introduction of the trifluoromethyl ketone ZBG
was attempted via either Grignard reaction or halogen–lith-
ium exchange (using BuLi) with ethyl trifluoroacetate, albeit
without any success. The final ester-to-CF3 ketone functional
group interconversion step was also evaluated using sulfide-
and sulfone-containing ‘cap’-groups (the S- and SO2-
counterparts of structures 15), only leading to complex reac-
tion mixtures. Nonetheless, since the sulfoxide analogues of
the previously synthesized hydroxamic acid-containing
Tubathians showed the best pharmacokinetic properties, no
further attempts were made to obtain the sulfide and sulfone
derivatives, and the biological potential of the unprecedented
aromatic trifluoromethyl ketone structures 8 was assessed
next.
The two newly synthesized trifluoromethyl ketones 8a,b
were first tested for their ability to inhibit HDAC6 on an enzy-
matic level. The percentage of HDAC6 inhibition using 10
μM of both compounds was observed to be 17 and 25%, re-
spectively (see ESI†). This stands in high contrast to the effect
of the hydroxamic acid analogue 7b, which gave a 100% inhi-
bition of the same enzyme at this concentration, suggesting
that the trifluoromethyl ketone ZBG exerts a lower activity
than the potent hydroxamic acid. A drop in inhibitory activity
has also been reported when comparing the hydroxamic acid
with the trifluoromethyl ketone analogue of Vorinostat 1,
confirming the superiority of the former functionality.25 The
most active trifluoromethyl ketone 8b was then screened for
its ability to inhibit HDAC enzymes on an cellular level by in-
vestigating the effect of the compound on the acetylation
Prior to exploring the laboratory synthesis of novel Tubathian
analogues 8 containing a trifluoromethyl ketone ZBG, in silico
docking studies were performed using one of the envisioned
compounds (8b) with respect to HDAC6 (Fig. 3). The trifluo-
romethyl ketone was docked as a hydrate 9, since this func-
tional group exhibits its metal-chelating properties as such
under physiological circumstances.24 The binding energy
obtained for this molecule was comparable to that of the cor-
responding hydroxamic acid-containing Tubathian 7b (7.7
and 8.1 kcal mol−1, resp.). The ZBG of both compounds (7b
and 9) interacted with the zinc atom, but the analogue with
the trifluoromethyl ketone group also seemed to form a hy-
drogen bond with residue Tyr782. The positions of the linker
group in the tubular access channel and the ‘cap’-group near
the protein surface were comparable for both molecules, with
no notable different interactions. This result suggests a possi-
ble inhibitory activity of the proposed compounds, justifying
lab synthesis and further biological evaluation of these poten-
tial new HDAC6i's (for more information regarding these
docking studies, see ESI†).
The synthesis of the proposed structures is based on our
previous work regarding the preparation of Tubathians,15
starting with the formation of the tricyclic ‘cap’-group via a
bismuth nitrate-catalyzed Fischer-indole synthesis using
phenylhydrazine hydrochlorides 10 and tetrahydrothiopyra-
none 11 (Scheme 1). The sulfur atom present in the tricyclic
structure was then selectively oxidized to a sulfoxide moiety
using one equivalent of meta-chloroperbenzoic acid at low
temperatures. Introduction of the aromatic linker unit was
performed by N-deprotonation and subsequent nucleophilic
substitution on methyl 4-(bromomethyl)benzoate 14.15,16 In
the next step, the desired trifluoromethyl ketone ZBG was
Fig. 3 A) Structures of docked compounds. B) Docking of compound 9 in catalytic domain CD2 of HDAC6 (hydrogen bonds are depicted in red).
C) Overlap between hydrate 9 and the corresponding hydroxamic acid 7b.
This journal is © The Royal Society of Chemistry 2018
Med. Chem. Commun.

View Article Online
Research Article
MedChemComm
Scheme 1 Synthesis of trifluoromethyl ketones 8.
status of tubulin (an HDAC6 substrate) and histone H3 (nu-
clear HDACs substrate) in SK-OV-3 ovarian cancer cells via
immunoblotting (Fig. 4, representative figure of three repli-
cates is shown, see ESI†). As expected, no effect occurred
when using 1 μM, but also no rise in acetylated tubulin was
observed when using 10 and 50 μM, pointing to no (or very
low) inhibition of the HDAC6 enzyme at these concentra-
tions. This result contrasts with the effect observed when
using the hydroxamic acid derivative 7b, which showed an in-
crease in acetylated tubulin at a concentration as low as 1
μM. Both trifluoromethyl ketone 8b and hydroxamic acid 7b
showed no increase in acetylated H3 at the concentrations
used, indicating that no inhibition of nuclear HDACs oc-
curred. The non-selective inhibitor Vorinostat 1 was deployed
as a positive control and did result in an increase of the level
of acetylated tubulin and H3 at a concentration of 10 μM.
These immunoblotting results indicate that, although
possessing some enzymatic HDAC6 activity, compound 8b is
not capable of inhibiting the HDAC enzymes (both nuclear
and cytoplasmatic) in cellular assays.
To confirm this, a functional cellular growth assay was
performed using the trifluoromethyl ketone 8b (with
Vorinostat 1 as a positive control). The inhibition of class I
HDACs using Vorinostat 1 has been shown to suppress the
growth of SK-OV-3 cancer cells, and the inhibition or knock-
down of class II enzymes has been reported to have similar
effects in various cancer cell lines.32–35 IncuCyte® ZOOM
technology was used to measure the confluency of the SK-OV-
3 cells in a 96-well plate, under control (0.1% DMSO) or treat-
ment (as indicated) conditions (Fig. 5, representative graph
of three replicates is shown, see ESI†). As expected, no impact
was observed when using trifluoromethyl ketone 8b in con-
centrations ranging between 1 and 50 μM, confirming the im-
munoblotting data.
To further investigate whether or not the lack of HDAC6
inhibitory activity is directly linked to the change in the ZBG,
Fig. 4 Levels of acetylated tubulin and histone H3 in SK-OV-3 cells treated with different concentrations of 8b, 7b and control compound
Vorinostat 1. GAPDH was used as a loading control.
Med. Chem. Commun.
This journal is © The Royal Society of Chemistry 2018

View Article Online
MedChemComm
Research Article
scoring functions applied by docking methods have been
reported to be particularly unreliable when the binding affini-
ties for multiple highly similar ligands are being compared.38
This disadvantage emphasizes the need for experimental vali-
dation of the structure–activity relationships of HDAC
inhibitors.
Recent HDAC-related research focuses on the development
of isoform-selective HDAC inhibitors, mostly applying the
hydroxamic acid function as the zinc-binding group.39
Although the use of aromatic linker units is known to induce
class II HDAC selectivity, as indicated by the success of
benzohydroxamic acid-based HDAC6 inhibitors, only two
phenyl trifluoromethyl ketones have been designed so
far.25,29 One of these compounds showed moderate inhibi-
tion of HDAC6 with an IC50-value of 2.5 μM in an enzymatic
assay, but was not tested in a cellular context.29 The second
compound has only been evaluated in a nuclear HDAC-
extract mainly containing HDAC1 and 2, showing no activ-
ity.25 These data are in line with the lack of activity we ob-
served in our newly developed trifluoromethyl ketone-
containing Tubathians 8 and in the trifluoromethyl ketone
derivative of benzohydroxamic acid 17. In contrast, the use of
an aromatic thiophene linker unit has been reported to result
in class II selective HDACi's, exerting low nanomolar activity
against HDAC6.29 Nonetheless, these compounds also failed
to induce cellular effects due to enzymatic reduction of the
TFMK function to the inactive alcohol by carbonyl reductases
present in the cells.40 The susceptibility of (aromatic)
trifluoromethyl ketones to enzymatic transformations in a
cellular environment, can, next to the poor enzymatic activity,
possibly contribute to the ineffectiveness of compound 8b in
SK-OV-3 ovarian cancer cells as well.
Fig. 5 Effects of trifluoromethyl ketone 8b on the proliferation of SK-
OV-3 cells in different concentrations. Vorinostat 1 (10 μM) was used
as a positive control. Mean + SEM is shown, N = 6.
we decided to compare the enzymatic HDAC6 inhibition of
commercially available benzohydroxamic acid 16 and its
trifluoromethyl ketone derivative 17 (Fig. 6) as a starting
point, inspired by the literature information that potent and
selective HDAC6 inhibition does not require a surface-
binding motif.36 The percentages of HDAC6 inhibition at 10
μM by 16 and 17 were observed to be 88% and 0%, respec-
tively, confirming that the replacement of the hydroxamic
acid function by a trifluoromethyl ketone leads to a severe re-
duction of HDAC6 inhibitory efficacy. Benzohydroxamic acid
16, being a potent and selective ‘cap’-less HDAC6 inhibitor
itself,36 comprises a vital part (linker unit and ZBG) of many
distinguished HDAC6 inhibitors such as Tubastatin A,
Nexturastat A and our Tubathian series. Consequently, due to
the lack of activity in TFMKs 8 and 17, it can be concluded
that a similar replacement in other benzohydroxamic acid-
containing HDAC6 inhibitors will be pointless.
Conclusion
The biological evaluation of the newly synthesized
trifluoromethyl ketones proved to be inconsistent with the re-
sults of their in silico molecular docking. The docking studies
showed no clear difference between the compounds con-
taining a trifluoromethyl ketone 9 or hydroxamic acid 7b
ZBG in both binding energy and pose. However, only the latter
In conclusion, the replacement of the hydroxamic acid ZBG
in benzohydroxamic HDAC6 selective inhibitors with
a
trifluoromethyl ketone, although being an effective strategy
for non-selective inhibitors such as Vorinostat 1, appears to
be detrimental with regard to enzymatic and cellular activity.
These data suggest that, for the development of HDAC6 selec-
tive inhibitors incorporating an alternative zinc-binding
group, the promising results of a structurally distinct inhibi-
tor with a specific zinc chelator do not guaranty success
when transferred to a new linker and ‘cap’-group.
was shown to be
a potent HDAC6 inhibitor in vitro.
Molecular docking is widely regarded to be a helpful tool for
determining the correct conformation of a ligand in a protein
binding pocket, but the accuracy of its binding energy esti-
mations is known to be rather limited.37 Furthermore, the
Author contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
Conflicts of interest
Fig. 6 Comparison of HDAC6 activity between benzohydroxamic acid
16 and its TFMK derivative 17.
The authors declare no competing interests.
This journal is © The Royal Society of Chemistry 2018
Med. Chem. Commun.

View Article Online
Research Article
MedChemComm
Acknowledgements
23 W. C. Groutas, P. K. Giri, J. P. Crowley, J. C. Castrisos and
M. J. Brubaker, Biochem. Biophys. Res. Commun., 1986, 141,
741–748.
24 T. Suzuki and N. Miyata, Curr. Med. Chem., 2005, 12,
2867–2880.
The Authors are indebted to the Ghent University Special
Research Fund (BOF) for financial support.
25 R. R. Frey, C. K. Wada, R. B. Garland, M. L. Curtin, M. R.
Michaelides, J. Li, L. J. Pease, K. B. Glaser, P. A. Marcotte,
J. J. Bouska, S. S. Murphy and S. K. Davidsen, Bioorg. Med.
Chem. Lett., 2002, 12, 3443–3447.
References
1 M. Dokmanovic, C. Clarke and P. A. Marks, Mol. Cancer Res.,
2007, 5, 981–989.
2 H.-J. Kim and S.-C. Bae, Am. J. Transl. Res., 2011, 3, 166–179.
3 J. E. Bolden, M. J. Peart and R. W. Johnstone, Nat. Rev. Drug
Discovery, 2006, 5, 769–784.
26 J.-I. Lai, L. J. Leman, S. Ku, C. J. Vickers, C. A. Olsen, A.
Montero, M. R. Ghadiri and J. M. Gottesfeld, Bioorg. Med.
Chem. Lett., 2017, 27, 3289–3293.
4 L. Di Marcotullio, G. Canettieri, P. Infante, A. Greco and A.
Gulino, Biochim. Biophys. Acta, Rev. Cancer, 2011, 1815,
241–252.
5 N. A. A. Shein and E. Shohami, Mol. Med., 2011, 17,
448–456.
6 A. J. M. de Ruijter, A. H. van Gennip, H. N. Caron, S. Kemp
and A. B. P. van Kuilenburg, Biochem. J., 2003, 370, 737–749.
7 I. V. Gregoretti, Y.-M. Lee and H. V. Goodson, J. Mol. Biol.,
2004, 338, 17–31.
8 T. C. Karagiannis and A. El-Osta, Leukemia, 2007, 21, 61–65.
9 E. A. Thomas, Mol. Neurobiol., 2009, 40, 33–45.
10 G. I. Aldana-Masangkay and K. M. Sakamoto, J. Biomed.
Biotechnol., 2011, 2011, 875824.
27 E. Muraglia, S. Altamura, D. Branca, O. Cecchetti, F.
Ferrigno, M. V. Orsale, M. C. Palumbi, M. Rowley, R.
Scarpelli, C. Steinkuhler and P. Jones, Bioorg. Med. Chem.
Lett., 2008, 18, 6083–6087.
28 C.-J. Gong, A.-H. Gao, Y.-M. Zhang, M.-B. Su, F. Chen, L.
Sheng, Y.-B. Zhou, J.-Y. Li, J. Li and F.-J. Nan, Eur. J. Med.
Chem., 2016, 112, 81–90.
29 P. Jones, M. J. Bottomley, A. Carfi, O. Cecchetti, F. Ferrigno,
P. Lo Surdo, J. M. Ontoria, M. Rowley, R. Scarpelli, C.
Schultz-Fademrecht and C. Steinkuhler, Bioorg. Med. Chem.
Lett., 2008, 18, 3456–3461.
30 J. M. Ontoria, S. Altamura, A. Di Marco, F. Ferrigno, R.
Laufer, E. Muraglia, M. C. Palumbi, M. Rowley, R. Scarpelli,
C. Schultz-Fademrecht, S. Scrafini, C. Steinkuhler and P.
Jones, J. Med. Chem., 2009, 52, 6782–6789.
11 J. C. Wong, R. Hong and S. L. Schreiber, J. Am. Chem. Soc.,
2003, 125, 5586–5587.
12 K. V. Butler, J. Kalin, C. Brochier, G. Vistoli, B. Langley and
A. P. Kozikowski, J. Am. Chem. Soc., 2010, 132, 10842–10846.
13 J. H. Kalin, K. V. Butler, T. Akimova, W. W. Hancock and
A. P. Kozikowski, J. Med. Chem., 2012, 55, 639–651.
14 K. V. Woan, M. Lienlaf, P. Perez-Villaroel, C. Lee, F. Cheng,
T. Knox, D. M. Woods, K. Barrios, J. Powers, E. Sahakian,
H. W. Wang, J. Canales, D. Marante, K. S. M. Smalley, J.
Bergman, E. Seto, A. Kozikowski, J. Pinilla-Ibarz, A. Sarnaik,
E. Celis, J. Weber, E. M. Sotomayor and A. Villagra, Mol.
Oncol., 2015, 9, 1447–1457.
15 R. De Vreese, T. Verhaeghe, T. Desmet and M. D'hooghe,
Chem. Commun., 2013, 49, 3775–3777.
16 R. De Vreese, Y. Depetter, T. Verhaeghe, T. Desmet, V.
Benoy, W. Haeck, L. Van Den Bosch and M. D'hooghe, Org.
Biomol. Chem., 2016, 14, 2537–2549.
17 F. F. Wagner, M. Weiwer, M. C. Lewis and E. B. Holson,
Neurotherapeutics, 2013, 10, 589–604.
18 E. L. Strevel and L. L. Siu, Eur. J. Cancer, 2009, 45, 318–331.
19 K. Munakata, H. Mochida, S. Kondo and Y. Suzuki,
J. Pharmacobio-Dyn., 1980, 3, 557–561.
20 D. Johnson and R. Walmsley, Mutat. Res., Genet. Toxicol.
Environ. Mutagen., 2013, 751, 96–100.
21 S. Shen and A. P. Kozikowski, ChemMedChem, 2016, 11,
15–21.
31 R. P. Singh, G. Cao, R. L. Kirchmeier and J. N. M. Shreeve,
J. Org. Chem., 1999, 64, 2873–2876.
32 M.-Y. Chen, W. S. L. Liao, Z. Lu, W. G. Bornmann, V.
Hennessey, M. N. Washington, G. L. Rosner, Y. Yu, A. A.
Ahmed and R. C. Bast Jr, Cancer, 2011, 117, 4424–4438.
33 T. Hideshima, J. E. Bradner, J. Wong, D. Chauhan, P.
Richardson, S. L. Schreiber and K. C. Anderson, Proc. Natl.
Acad. Sci. U. S. A., 2005, 102, 8567–8572.
34 Y.-S. Lee, K.-H. Lim, X. Guo, Y. Kawaguchi, Y. Gao, T.
Barrientos, P. Ordentlich, X.-F. Wang, C. M. Counter and
T.-P. Yao, Cancer Res., 2008, 68, 7561–7569.
35 Z. Wang, W. Wu, H. Yan, Z. Sun and Y. Tang, Zhongguo
Zhongliu Linchuang, 2013, 40, 698–701.
36 F. F. Wagner, D. E. Olson, J. P. Gale, T. Kaya, M. Weiwer, N.
Aidoud, M. Thomas, E. L. Davoine, B. C. Lemercier, Y.-L.
Zhang and E. B. Holson, J. Med. Chem., 2013, 56, 1772–1776.
37 Z. Wang, H. Sun, X. Yao, D. Li, L. Xu, Y. Li, S. Tian and T.
Hou, Phys. Chem. Chem. Phys., 2016, 18, 12964–12975.
38 D. Ramirez and J. Caballero, Int. J. Mol. Sci., 2016, 17, 1–15.
39 R. De Vreese and M. D'hooghe, Eur. J. Med. Chem.,
2017, 135, 174–195.
40 R. Scarpelli, A. Di Marco, F. Ferrigno, R. Laufer, I. Marcucci,
E. Muraglia, J. M. Ontoria, M. Rowley, S. Serafini, C.
Steinkuhler and P. Jones, Bioorg. Med. Chem. Lett., 2008, 18,
6078–6082.
22 M. S. Lee and M. Isobe, Cancer Res., 1990, 50, 4300–4307.
Med. Chem. Commun.
This journal is © The Royal Society of Chemistry 2018