Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors

Article abstract of DOI:10.1039/c4md00274a

G9a is a histone lysine methyltransferase (HKMT) involved in epigenetic regulation via the installation of histone methylation marks. 6,7-Dimethoxyquinazoline analogues, such as BIX-01294, are established as potent, substrate competitive inhibitors of G9a. With an objective to identify novel chemotypes for substrate competitive inhibitors of G9a, we have designed and synthesised a range of heterocyclic scaffolds, and investigated their ability to inhibit G9a. These studies have led to improved understanding of the key pharmacophoric features of BIX-01294 and the identification of a new core quinoline inhibitory scaffold, which retains excellent potency and high selectivity. Molecular docking was carried out to explain the observed in vitro data. This journal is

Full text of DOI:10.1039/c4md00274a

Volume 5 Number 12 December 2014 Pages 1771–1900
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Themed issue: Epigenetics
ISSN 2040-2503
CONCISE ARTICLE
Matthew J. Fuchter et al.
Identification of 2,4-diamino-6,7-dimethoxyquinoline
derivatives as G9a inhibitors

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CONCISE ARTICLE
Identification of 2,4-diamino-6,7-
dimethoxyquinoline derivatives as G9a inhibitors†
Cite this: Med. Chem. Commun., 2014,
5, 1821
Nitipol Srimongkolpithak,ab Sandeep Sundriyal,a Fengling Li,c Masoud Vedadic
a
*
and Matthew J. Fuchter
G9a is a histone lysine methyltransferase (HKMT) involved in epigenetic regulation via the installation of
histone methylation marks. 6,7-Dimethoxyquinazoline analogues, such as BIX-01294, are established as
potent, substrate competitive inhibitors of G9a. With an objective to identify novel chemotypes for
substrate competitive inhibitors of G9a, we have designed and synthesised a range of heterocyclic
scaffolds, and investigated their ability to inhibit G9a. These studies have led to improved understanding
of the key pharmacophoric features of BIX-01294 and the identification of a new core quinoline
inhibitory scaffold, which retains excellent potency and high selectivity. Molecular docking was carried
out to explain the observed in vitro data.
Received 24th June 2014
Accepted 25th August 2014
DOI: 10.1039/c4md00274a
www.rsc.org/medchemcomm
chemistry efforts from a number of groups has led to a series
of optimised diaminoquinazoline analogues including
UNC0224,11 UNC0321,12 UNC0631,13 UNC0638,14 UNC0646,13
UNC0965,15 E72,16 and UNC0642,17 which is suitable for in vivo
work. Recently, 2-amino-indole derivatives have also been
reported as substrate competitive G9a inhibitors.18 There is
little doubt that the provision of such high quality inhibitors
has dramatically facilitated the study of G9a biology,14,15,19,20 and
related targets, especially in a disease context.21–24
Introduction
G9a (also known as EHMT2) is a histone-lysine N-methyl-
transferase (HMKT), which catalyses the addition of one or
two methyl groups to lysine 9 of histone H3 (H3K9me1
and H3K9me2) within a chromatin environment.1 Due to its
central role in epigenetic control, the methylation of H3K9 is
associated with many biological pathways and is aberrantly
regulated in several diseases including cancer2 and AIDS.3
According to a genome-wide analysis of histone modications,4
mono-methylation of histone H3 (H3K9me1) is associated
with permissive chromatin, while di- and tri-methylation
(H3K9me2/3) label a repressed chromatin state. Overexpression
of G9a has been found in many types of cancer and is associated
with a poor prognosis.5,6 Furthermore, G9a has been reported
the methylate a variety of non-histone targets including the
chromatin-modifying factor Tip49a7 and CDYL1.8
BIX-01294 and its optimised analogues are composed of a
quinazoline heterocyclic core, substituted at positions 2, 4 and 7
(Fig. 1). The co-crystallized structure of UNC0224 with G9a (PDB
Like the majority of HKMTs, the SET (Su(var), E(z) and Tri-
thorax) domain of G9a mediates catalysis and is comprised of
two binding pockets; one for the cofactor S-adenosylmethionine
(SAM), the other for the protein substrate. It is increasingly
being realised that both pockets are ‘druggable’ and occupancy
of either with a small molecule inhibitor is an effective strategy
to block HKMT mediated methylation.9 The rst substrate-
competitive inhibitor of G9a, BIX-01294, was discovered using
high throughput screening (Fig. 1).10 Focused medicinal
aDepartment of Chemistry, Imperial College London, London SW7 2AZ, UK. E-mail: m.
fuchter@imperial.ac.uk; Fax: +44 (0)2075945805; Tel: +44 (0)2075945815
bInstitute of Chemical Biology, Imperial College London, London SW7 2AZ, UK
cStructural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7,
Canada
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4md00274a
Fig.
inhibitors.
1 Representative examples of substrate-competitive G9a
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fused-pyrimidinediones 9a–9c following reported reaction
conditions.28,29 The desired dichloropyrimidines 10a–10c were
obtained by heating 9a–9c to reux in the presence of phos-
phoryl chloride, while the commercially available fused pyr-
imidinediones 9d and 9e were converted to 10d and 10e using
pyrophosphoryl chloride30 and phosphoryl chloride, respec-
tively. Key intermediates 10a–10e were then substituted with
4-amino-1-benzylpiperidine at C-4 to yield 11a–11e which were
further heated with a variety of secondary amines to obtain the
fully substituted heterocyclic compounds 12–25 (Table 1).
As an alternative strategy to completely replacing the
benzenoid ring of the original quinazoline analogues, a number
of derivatives were prepared where the dimethoxy functionality
had been altered or removed. Thus, the commercially available
benzonitrile 26 was nitrated, followed by reduction of the nitro-
group with sodium dithionite to give amine 27 (Scheme 2).
Acylation of 27 using methyl chloroformate, followed by cycli-
sation under basic conditions, resulted in quinazoline-dione
28a. The synthesised quinazoline-dione 28a and commercially
available desmethoxyquinazoline-dione 28b were both chlori-
nated and substituted with amines as described previously11,27
to provide 31–37 (Table 1).
Finally, the pyrimidine ring portion of the quinazoline
scaffold was varied. In light of the ligand–G9a interaction
analysis above (Fig. 2), we decided to remove the N-3 nitrogen,
since obvious interactions with G9a were not apparent. Thus,
dimethoxyquinoline derivatives 41 and 42 were synthesised
(Scheme 3). Unlike the synthesis of the related quinazoline
derivatives, the regioselective synthesis of our target 2,4-dia-
minoquinolines was challenging. We found very few examples
of such compounds in the literature, one example being from
Campbell and co-workers, who have previously reported the
synthesis of quinoline analogues of the antihypertensive dia-
minoquinazoline drug, prazosin.26,31 With a slight modication
of their methodology, we were able to prepare free-amino
quinoline derivatives 40a and 40b. Thus, the commercially
available 38 was converted to an intermediate amino-
benzonitrile and it was then treated with triethylorthoacetate
under slightly reduced pressure to yield an imidate, which was
heated with either methylpiperazine or methylhomopiperazine
Fig. 2 A summary of the interactions between UNC0224 and G9a
(PDB code 3K5K). Salt bridges, cation–p interactions and hydrogen
bonds are depicted as pink, golden and green dashed lines,
respectively.
code 3K5K)11 reveals important interactions between the
inhibitor and the substrate pocket of G9a. Key binding inter-
actions include (Fig. 2): (1) a salt bridge between N-1 of the
quinazoline core, which is expected to be protonated at physi-
ological pH,25,26 and Asp1088; (2) a hydrogen bond between the
C-4 NH functionality and Asp1083; (3) a hydrogen bond between
the protonated ‘lysine mimic’ amine at C-7 with the backbone of
Leu1086, as well as a cation–p interaction between the same
protonated amine and Tyr1154.
Whilst the prior studies, particularly those of Jin and co-
workers,11–17 have established important G9a structure–activity
relationships (SAR) with respect to the side chains of the qui-
nazoline core, it was apparent to us that the pharmacophoric
features of the central heterocycle were yet to be determined.
Thus we set out to better dene the important features of the
central inhibitor scaffold, while attempting to maintain the
aforementioned interactions within the substrate pocket of the
enzyme.
Chemistry
BIX-01294 (1) and other quinazoline derivatives (2–4, Table 1), to yield corresponding derivatives 39a and 39b, respectively
were synthesised following the established two step (Scheme 3). The ring closure of 39a and 39b was carried out by
synthesis.11,27
treatment with zinc chloride, which occurs presumably via the
Initially the importance of the dimethoxy-benzenoid ring of enamine tautomer.32,33 Finally, the free-amino quinoline
BIX-01294 was explored, while retaining the substituted analogues 40a and 40b were converted to target compounds 41
pyrimidine ring. Hence, compounds 12 to 25 were synthesised and 42 via reductive amination with 1-benzyl-4-piperidone.
(Table 1) containing a pyrimidine ring fused to a furan, thio-
phene, imidazole, or cyclopentane ring.
Results and discussion
Amino furan 8a was synthesised using a slight modication
of a previously reported method (Scheme 1).28 The carboxyl All the compounds synthesised were evaluated for G9a inhibi-
group of furan 5 was converted to a Boc protected amine 6 in a tory activity using a previously reported SPA assay.17 The
single step via a Curtius rearrangement. Treatment of amino preliminary screen was conducted at three concentrations (50,
furan 6 with n-butyllithium, followed by a methyl chloroformate 10, 1 mM), with full dose response data derived for compounds
quench, resulted in the isolation of product 7. Boc deprotection with >20% inhibition at the 1 mM dose. UNC0638 (Fig. 1) was
of 7 yielded the desired intermediate 8a with a free amino group used as a positive control and gave a comparable activity to that
at position 3. Amino furan 8a and its commercially available observed previously (IC50 ꢀ 2.5 nM). Expectedly, BIX-01294 and
analogues 8b and 8c were then converted to the corresponding the other quinazolines (2–4) exhibited IC50 values in the
1822 | Med. Chem. Commun., 2014, 5, 1821–1828
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Table 1 SAR, biological and computational results of the BIX-01294 derivativesa
Activity%
Docking score
compoundb (mM)
(kcal molꢁ1
)
c log Pd
N-1 pKa
SP
XP
c
e
Compound ID
Scaffold
R2
50
10
1
IC50 (mM)
1 (BIX-01294)
6
5
6
6
11
19
0.067 ꢂ 0.003
0.101 ꢂ 0.010
3.9
3.5
8.13 (ꢂ2.22)
5.60 (ꢂ2.22)
ꢁ7.859
ꢁ6.995
na
2 (HKMTI-1-005)
ꢁ6.380
3 (HKMTI-1-022)
4 (HKMTI-1-011)
7
9
35
79
0.472 ꢂ 0.017
3.190 ꢂ 0.080
4.7
4.4
7.47 (ꢂ1.47)
8.10 (ꢂ1.47)
ꢁ5.789
ꢁ4.244
15
31
na
na
12
13
99
98
102
100
99
—
—
2.9
2.5
4.57 (ꢂ0.70)
4.66 (ꢂ0.70)
na
na
na
na
107
14
15
97
96
98
101
107
—
—
3.7
3.4
5.31 (ꢂ0.70)
5.77 (ꢂ0.70)
na
na
na
na
102
16
17
47
62
82
83
91
—
—
3.9
3.5
5.68 (ꢂ0.70)
5.77 (ꢂ0.70)
na
na
na
na
105
18
19
91
102
105
114
98
—
—
4.8
4.5
6.42 (ꢂ0.70)
6.88 (ꢂ0.70)
na
na
na
na
104
20
21
81
88
96
92
91
—
—
3.9
3.5
3.28 (ꢂ2.22)
3.35 (ꢂ2.22)
na
na
na
na
105
22
93
105
105
—
4.8
3.86 (ꢂ2.22)
na
na
23
24
67
90
90
101
97
—
—
2.6
3.4
3.15 (ꢂ2.22)
3.73 (ꢂ2.22)
na
na
na
na
101
25
55
84
96
—
3.2
6.62 (ꢂ0.70)
na
na
31
32
33
63
78
91
95
98
98
96
96
—
—
—
3.2
4.4
4.2
5.58 (ꢂ2.22)
7.45 (ꢂ1.47)
8.08 (ꢂ1.47)
na
na
na
na
na
na
109
34
35
18
27
46
59
93
94
—
—
3.8
3.5
8.06 (ꢂ2.22)
5.53 (ꢂ2.22)
na
na
na
na
36
37
72
97
82
94
—
—
4.7
4.4
7.40 (ꢂ2.22)
8.03 (ꢂ2.22)
na
na
na
na
108
104
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Table 1 (Contd.)
Activity%
Docking score
compoundb (mM)
(kcal molꢁ1
)
c log Pd
N-1 pKa
SP
XP
c
e
Compound ID
Scaffold
R2
50
10
1
IC50 (mM)
41 (HKMTI-1-248)
42 (HKMTI-1-247)
5
5
4
6
6
7
0.013 ꢂ 0.001
0.031 ꢂ 0.003
4.5
4.1
10.57 (ꢂ2.22)
9.84 (ꢂ2.22)
ꢁ7.522
ꢁ6.904
ꢁ6.476
na
a
R1 is the same for all compounds: R1 ¼
, SP ¼ standard precision mode, XP ¼ extra precision mode, na ¼ no desired pose found.
b
The experiment was conducted in duplicate. c The assay was conducted in triplicate at Km of both substrates (0.8 mM peptide [H3 1–25] and 8 mM
d
e
SAM) for G9a (5 nM).17 c log P values were calculated using the freely available program RDkit.34 ‘Sequential’ pKa values were calculated at pH 7.0,
with water as the solvent model, using the Epik 2.7 program implemented in Schrodinger (see ESI).
nanomolar to low micromolar range. For the derivatives where with a recent report on related analogues,35–42 and demonstrates
the benzenoid ring had been replaced with a furan, thiophene, that these substituents are also of importance. A number of
imidazole or a cyclopentane ring (12–25), no signicant G9a theoretical and experimental studies have shown that ortho-
inhibitory activity was observed. While obvious interactions are dimethoxybenzenes prefer to adopt a co-planar conformation,
not apparent for this region of the quinazoline G9a inhibitors with the sp2 oxygen lone pairs projecting towards each other and
(vide supra), except when a ‘lysine mimic’ is present at C-7, it the corresponding methyl groups angled away from each other.
would seem the benzenoid ring does play an important role in Indeed, such a conformation is apparent in the inhibitor-G9a/
binding. Interestingly, the recently reported G9a inhibitor A-366 GLP crystal structures (such as PDB 3FPD,43 3K5K (Fig. 2),11 and
shares a similar structural feature with BIX-01294 in this 3RJW14). Thus, analogues 31–33 (Table 1) were prepared where
regard.18
the methoxy groups were replaced by a dioxalone ring; forcing the
Since the benzenoid ring is important for inhibitory activity, oxygen lone pairs to point in the opposite direction. Interestingly,
the role of the dimethoxy substituents on this ring should be these analogues were also found to be largely devoid of G9a
questioned. Desmethoxyquinazoline derivatives (34–37) were inhibitory activity, suggesting the conformational preference of
found to be far less active against G9a, which is in agreement the dimethoxy functionality to be important for G9a activity.
Scheme 1 The synthesis of fused-pyrimidine derivatives. Reagents and conditions: (a) DPPA, TEA, t-BuOH, reflux; (b) CH3OCOCl, TMEDA,
n-BuLi, THF; (c) TFA, DCM, rt, (d) ClSO2NCO, DCM, aq. NaOH, aq. HCl or urea, 190 ꢃC (neat), microwave; (e) POCl3, DMF, reflux or O(POCl2)2,
145 ꢃC, sealed tube, 2 day; (f) 4-amino-1-benzylpiperidine, DIEA, THF, rt, 24 h or 4-amino-1-benzylpiperidine, TEA, n-butanol, sealed tube,
overnight; (g) cyclic amine, 185 ꢃC (neat), microwave, 30 min.
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Scheme 2 The synthesis of desmethoxy and dioxoloquinazoline derivatives. Reagents and conditions: (a) HNO3, Ac2O, rt; (b) Na2S2O4, TBAB,
DCM/H2O, rt; (c) ClCOOCH3, DIEA, DMA/DCM; (d) H2O, NaOH, EtOH, reflux; (e) POCl3, PhNEt2, MeCN, reflux; (f) 4-amino-1-benzylpiperidine,
DIEA, THF, rt; (g) cyclic amine, 185 ꢃC (neat), microwave, 30 min or amine, toluene, reflux, overnight.
In inhibitor designs where the dimethoxybenzenoid moiety quinoline activity based on pKa dependent interactions has
was retained, but N-3 (Fig. 1) replaced by carbon atom (41 and been described earlier for the design of a1-adrenoreceptor
42), signicant activity was observed. Indeed, to our delight, 41 antagonists.25,26
and 42 were found to be ꢀ5-fold more potent than the parental
In light of this trend, we measured the experimental pKa
inhibitor BIX-01294. This result is clearly in agreement with our values for compounds 1 (BIX-01294) and 41 in the pH
initial inhibitor-G9a crystal structure analysis (vide supra), range 2–12 using UV-vis spectroscopy. As expected, both
which suggested that the N-3 nitrogen of the quinazoline scaf- compounds were found to be tribasic due to the presence of
fold might not be essential for G9a binding (Fig. 2). Comparison two aliphatic basic centres (the benzylpiperidine nitrogen
of the calculated pKas revealed that N-1 of the quinolines 41 and and the homo piperazine nitrogen) in addition to N-1. The
42 is more basic than the corresponding nitrogen of quinazo- experimental pKa values of BIX-01294 (1) were 6.94 ꢂ 0.01,
lines 1 and 2 (Table 1). This computational prediction is in 8.24 ꢂ 0.05 and 9.22 ꢂ 0.04. The experimental pKa values of
agreement with experimental data which demonstrates dia- quinoline 41 were 7.14 ꢂ 0.01, 8.05 ꢂ 0.02 and 9.50 ꢂ 0.01.
minoquinolines to be more basic than the analogous quinazo- Since the largest spectral change for 1 and 41 would be
lines.25,26 N-1 of the quinoline derivatives were predicted to have expected upon ring protonation, the UV-vis spectra observed
the highest pKas (10.57 and 9.84 for 41 and 42, respectively) of upon each protonation event can be used to assign the pKa of
all the analogues prepared (Table 1). Interestingly, the N-1 atom N-1 (see Fig. S5 and S6, ESI†). We therefore assign the pKa of
in all inactive molecules (12–25, Table 1) were predicted to have N-1 of quinazoline 1 to be 6.94 ꢂ 0.01 and N-1 of quinoline 41
lower pKa values. A similar analysis between quinazoline and to be 9.50 ꢂ 0.01.
Scheme 3 The synthesis of quinoline derivatives. Reagents and conditions: (a) HNO3, Ac2O, rt; (b) Na2S2O4, TBAB, DCM/H2O, rt; (c)
CH3C(OCH2CH3)3, 150 ꢃC, (d) 1-methylhomopiperazine or 1-methylpiperazine, pTsOH, 100 ꢃC; (e) ZnCl2, DMA, reflux; (f) 1-benzyl-4-
piperidone, AcOH, toluene, reflux, Dean–Stark, then a reducing agent (NaBH4 or NaBH(OAc)3), AcOH, THF, reflux.
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This data is highly suggestive that a protonated N-1 position overlaid perfectly with UNC0224, with the protonated N-1
is required for good G9a binding, through a strong electrostatic functionality interacting with Asp1088. Similarly, other active
interaction with Asp1088. Indeed, using the Henderson–Has- compounds 1–3 exhibited a similar binding mode (see ESI,
selbalch equation, under the given assay conditions (pH 8), Fig. S1–S4†). Overall, the docking scores gave a qualitative
96.9% of 41 will be in the N-1 protonated form, whereas for BIX- correlation with the IC50 data; compounds 1 and 41 giving
01294 (1), 8.0% of the molecule will be N-1 protonated. We note higher scores than 2 and 3.
however that there is an alternative explanation of the excellent
Interestingly, the docking study reinforced the importance of
potency of our quinoline hit compounds: the enthalpy loss due dimethoxy structural feature in acquiring the correct pose. For
to breakage of a hydrogen bond between N-3 and water before example, quinazoline derivatives either lacking dimethoxy
ligand binding is not been compensated for upon ligand groups (34–37) or with the bridged methoxy groups (31–33) did
binding to G9a.44 Despite this trend in N-1 pKa, inactive qui- not display the desired pose which is in agreement to their lack
nazolines 31–37 are predicted to have N-1 pKa values that are of in vitro activity. Also, moderately active derivative 4 could not
similar to active derivatives 1–4. Therefore clearly both the reproduce the expected pose in spite of possessing dimethoxy
dimethoxybenzenoid ring system and basic N-1 functionality groups, plausibly due to the large pyridylpiperazine substituent
are important features for G9a binding and hence inhibitory at position 2.
activity.
In light of the excellent potency of our quinoline inhibitors
Our initial design of the new fused heterocyclic scaffolds was 41 and 42 against G9a, the selectivity of these compounds was
based on the hypothesis that they could bind to the substrate examined in a methyltransferase enzyme panel, and compared
binding pocket of G9a with a pose comparable to that of the to BIX-01294. This panel consisted of twenty three additional
quinazoline co-crystallized ligand (Fig. 2). In light of the in vitro methyltransferases including sixteen HKMTs, six protein argi-
data obtained, all molecules prepared were docked without nine methyltransferases (PRMTs), and one DNA methyl-
constraints into the substrate pocket of G9a to see if active and transferase (DNMT) (see ESI, Table S1†).17 Compound 41 and 42
inactive molecules could be differentiated computationally. The were found to be equipotent against G9a and GLP (G9a-like
G9a X-ray structure co-crystallised with UNC0224 (PDB code protein, EHMT1), which is not surprising given the high degree
3K5K)11 was used, employing both standard precision (SP) and of homology between the G9a and GLP SET domains. Such dual
extra precision (XP) modes of the Glide program (Schrodinger, G9a/GLP activity is a common feature of the diaminoquinazo-
see ESI†).
line inhibitors17 and was shared by BIX-01294. However to our
Interestingly, analysis of the top scoring poses revealed that delight, quinoline inhibitors 41 and 42 were found to be inac-
none of the inactive molecules could reproduce the expected tive against all other methyltransferases in the panel, with the
pose in either SP or XP mode (Table 1). On the other hand all exception of SETD2 and EZH2 for which a moderate inhibitory
active derivatives were predicted to bind to G9a in a comparable activity was at the highest concentrations surveyed (50 mM).
manner to UNC0224, in at least one of the precision modes. For
example, the poses of quinolines 41 (Fig. 3) and 42 (see ESI†)
Conclusions
In summary, we have designed and synthesised a variety of
heterocyclic derivatives in order to identify novel G9a inhibitors
and better dene the pharmacophoric features associated with
the core heterocycle. These efforts resulted in the identication
of potent and selective G9a/GLP inhibitors 41 and 42 based on a
quinoline scaffold. Activity and computational data highlight
the importance of the dimethoxy groups on the benzenoid ring
of this scaffold and a basic nitrogen at position 1 for potent G9a
activity. The ability of molecular docking to predict inhibitor
activity based on the UNC0224 binding pose, once further
validated, may be helpful in the future for predicting and pri-
oritising novel G9a/GLP inhibitors.
Acknowledgements
N.S. was supported by a Royal Thai Government Scholarship
and the EPSRC-funded Institute of Chemical Biology Doctoral
Training Centre. S.S. acknowledges European Commission for
awarding Marie Curie International Incoming Fellowship
(Agreement no. 299857). The SGC is a registered charity
Fig. 3 Docking pose of quinoline analogue 41 (grey sticks) overlaid
with the co-crystallized quinazoline derivative, UNC0224 (pink sticks;
PDB 3K5K), in the G9a substrate binding pocket. Purple dashed lines
display H-bonds. As expected, protonated the N-1 and 4-amino
(number 1097737) that receives funds from AbbVie, Boehringer
Ingelheim, the Canada Foundation for Innovation, the Cana-
dian Institutes for Health Research, Genome Canada through
moiety of 41 were shown to interact with Asp1088 and Asp1083,
respectively.
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the Ontario Genomics Institute [OGI-055], GlaxoSmithKline,
Janssen, Lilly Canada, the Novartis Research Foundation, the
Ontario Ministry of Economic Development and Innovation,
Pzer, Takeda, and the Wellcome Trust [092809/Z/10/Z].
A. Tripathy, A. Edwards, B. L. Roth, W. P. Janzen,
B. A. Garcia, A. Petronis, J. Ellis, P. J. Brown, S. V. Frye,
C. H. Arrowsmith and J. Jin, Nat. Chem. Biol., 2011, 7, 566–
574.
15 K. D. Konze, S. G. Pattenden, F. Liu, D. Barsyte-Lovejoy, F. Li,
J. M. Simon, I. J. Davis, M. Vedadi and J. Jin, ChemMedChem,
2014, 9, 549–553.
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