Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds

Article abstract of DOI:10.1016/j.bmcl.2016.08.004

Epigenetic alterations relate to various human diseases, and developing inhibitors of Kme regulatory proteins is considered to be a new frontier for drug discovery. We were inspired by the known multicyclic ligands, UNC669 and UNC926, which are the first

Full text of DOI:10.1016/j.bmcl.2016.08.004

Accepted Manuscript
Design, synthesis, and protein methyltransferase activity of a unique set of con-
strained amine containing compounds
Hao Zhou, Xin Che, Guochen Bao, Na Wang, Li Peng, Kimberly D. Barnash,
Stephen V. Frye, Lindsey I. James, Xu Bai
PII:
S0960-894X(16)30814-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.08.004
BMCL 24130
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 June 2016
1 August 2016
2 August 2016
Please cite this article as: Zhou, H., Che, X., Bao, G., Wang, N., Peng, L., Barnash, K.D., Frye, S.V., James, L.I.,
Bai, X., Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing
compounds, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.08.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Design, synthesis, and protein
Leave this area blank for abstract info.
methyltransferase activity of a unique set of
constrained amine containing compounds
Hao Zhou, Xin Che, Guochen Bao, Na Wang, Li Peng, Kimberly D. Barnash, Stephen V. Frye, Lindsey I.
James, Xu Bai

Bioorganic & Medicinal Chemistry Letters
Design, synthesis, and protein methyltransferase activity of a unique set of
constrained amine containing compounds
Hao Zhoua, Xin Chea, Guochen Baoa, Na Wanga, Li Penga, Kimberly D. Barnashb, Stephen V. Fryeb,
Lindsey I. Jamesb, Xu Baia,
aThe Center for Combinatorial Chemistry and Drug Discovery Of Jilin University, The School of Pharmaceutical Sciences , Changchun Jilin 130021, P. R.
China
bCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy,
University of North Carolina, Chapel Hill, NC 27599
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Epigenetic alterations relate to various human diseases, and developing inhibitors of Kme
regulatory proteins is considered to be a new frontier for drug discovery. We were inspired by
the known multicyclic ligands, UNC669 and UNC926, which are the first reported small
molecule ligands for a methyl-lysine binding domain. We hypothesized that reducing the
conformational flexibility of the key amine moiety of UNC669 would result in a unique set of
ligands. Twenty-five novel compounds containing a fused bi- or tricyclic amine or a spirocyclic
amine were designed and synthesized. To gauge the potential of these amine-containing
compounds to interact with Kme regulatory proteins, the compounds were screened against a
panel of 24 protein methyltransferases. Compound 13 was discovered as a novel scaffold that
interacts with SETD8 and could serve as a starting point for the future development of PKMT
inhibitors.
Keywords:
Cyclic fused and spirocyclic amines
Histone methyltransferases
Cross-screening
2015 Elsevier Ltd. All rights reserved.
Structure based design
Mounting evidence suggests that epigenetic alterations relate
to various human diseases including inflammation, brain
disorders, metabolic diseases, and cancer.1-3 One such epigenetic
modification is histone lysine methylation. Protein lysine
methyltransferases (PKMTs) catalyze the transfer of a methyl
group from the cofactor S-adenosyl-L-methionine (SAM) to
lysine residues of histone and non-histone substrates, leading to
lysine mono-, di-, and/or trimethylation. Lysine methylation is
reversible in that the methyl groups can be removed by either the
Jumonji family of 2-oxoglutarate-dependent demethylases4 or the
flavin dependent enzymes, lysine-specific histone demethylase 1
(LSD1) and LSD2.5 Lysine methylation has been identified at
various positions of the histone tails, mainly on histone 3 at
lysine 4 (K4), K9, K27, K36, and K79, and on histone 4 at K20.6
All methylated forms of lysine are cationic at physiological pH,
aromatic cage in the protein. This binding interaction is largely
the result of favorable cation-π and van der Waals interactions,
while hydrophobic desolvation effects also contribute.
Depending on the methylation state, nearby acidic residues in the
binding pocket are also known to form salt bridges with the
methylated lysine residue, offering an additional stabilizing
effect.7, 8 Kme readers are categorized into three main families by
their respective binding domains: the plant homeodomain (PHD)
zinc finger proteins, the WD40 repeat domain-containing
proteins, and the so-called Royal family of reader proteins,
including tudor, chromo, Pro-Trp-Trp-Pro (PWWP), and
malignant brain tumor (MBT) domain-containing proteins.
Overall, histone lysine methylation can be associated with
either transcriptional activation or repression. The mutation,
overexpression, and aberrant regulation of Kme regulatory
proteins have been linked to many diseases, especially cancer.3
For example, overexpression of the key developmental histone
lysine methyltransferase, EZH2, has been observed in several
types of leukemias and in various solid tumors.9 Thus,
developing inhibitors of Kme regulatory proteins is considered to
while trimethyllysine contains
irrespective of its environment.
a
fixed positive charge
In contrast to the enzymes that install and remove the methyl
groups on lysine, methyl-lysine (Kme) readers recognize and
bind the Kme marks non-covalently, most commonly via an
—inte—rac—tion between the methyl-ammonium group and an
 Corresponding author.:. Tel.: + 919-962-4870; Fax: + 919-843-8465 (L. I. James); Tel.: + 86-431-8569260; Fax: + 86-431-85188900 (X.
Bai); E-mail: ingerman@email.unc.edu (L. I. James), xbai@jlu.edu.cn (X. Bai).

be a new frontier for drug discovery. Additionally, the exact
biological mechanisms of many of these proteins still require
elucidation, and therefore small molecule chemical probes would
facilitate further study and understanding of their functions.10-12
In the preparation of compounds 2 and 3, 1-benzyl-3-piperidone
(27) was used as a starting material (Scheme 2). Treatment of 27
with allylamine gave the corresponding imine, and the crude
product was then treated with allylmagnesium bromide to
provide the aminodiene (28). Compound 29 was obtained by
protecting the secondary amino group of 28 as the
trifluoroacetamide. Treatment of 29 with Grubbs catalyst in
DCM gave spirocyclic compound 30. The trifluoroacyl group of
compound 30 was converted to a Boc protecting group in two
steps to generate 32. The key intermediate (33) was obtained by
reduction of 32 with palladium. We coupled amine 33 to 3-
bromobenzoyl chloride and removed the Boc group to provide
target compound 2. Compound 3 was achieved via installation of
a methyl group on the basic nitrogen of compound 2 via
reductive amination. The Boc protected 1,9-diazaspiroundecane
amine used to prepare compounds 4-6 was similarly synthesized
from 1-benzyl-4-piperidone.20 The reaction of 5 with methyl
iodide gave the corresponding quaternary amine containing
compound (6). It is possible that such quaternary amines may
interact more favorably with slightly larger binding pockets such
as those of Kme3 reader domains and methyltransferases that
install the trimethyl mark.
We were initially inspired by the known multicyclic ligands,
UNC669 (1a, Fig. 1a)13 and UNC926 (1b, Fig. 1b),14 which are
the first reported small molecule ligands for a methyl-lysine
binding domain, specifically the second MBT domain of both
L3MBTL1 and L3MBTL3. As shown in the high-resolution co-
crystal structure of UNC669 and L3MBTL1 (pdb 3P8H), the
pyrrolidine amine makes a key hydrogen bond with aspartic acid
D355 and the ligand also engages the aromatic binding cage
(F379, W382, Y386; Fig. 1c). We hypothesized that preparing a
variety of amines with reduced conformational flexibility relative
to the piperidine-pyrrolidine amine (Fig. 1a and 1b, red) may
generally result in ligands with enhanced affinity for proteins that
interact with methylated lysine.
Scheme 1. General procedure for target compound synthesis. (a) Et3N, DCM,
0oC to rt.
Figure 1. Structures of L3MBTL1/L3MBTL3 inhibitors. (a) Structure of
UNC669. (b) Structure of UNC926. (c) Co-crystal structure of UNC669 with
L3MBTL1 (pdb 3P8H).
Beyond targeting methyl-lysine regulatory proteins, nitrogen-
based heterocycles are of broad interest in medicinal chemistry.
Furthermore, compounds with fused ring systems and spirocyclic
heterocycles have found applications as antibacterial drugs,15
antitumour drugs,16 5-HT2C receptor agonists,17 ChK1 kinase
inhibitors,18 and CGRP receptor antagonists.19 In this article we
describe the design and synthesis of a set of compounds
containing fused bi- or tricyclic amines and spirocyclic amines
that are well poised to both interact with Kme regulatory proteins
as well as provide value to a number of medicinal chemistry
efforts.
We designed 25 fused and spirocyclic amines (Fig. 2) that: (1)
contain a basic amine, (2) are fragment-like in size (less than 200
g/mol), (3) are non-aromatic, and (4) contain a synthetic handle
for further chemistry to attach the amines to a variety of scaffolds.
Upon preparation, each amine was reacted with 3-bromobenzoyl
chloride by the general synthetic route shown in Scheme 1. When
necessary, protected amines were coupled to 3-bromobenzoyl
chloride and subsequent deprotection gave the desired products.
At this point, secondary amines could also be alkylated to give
the corresponding tertiary or quaternary amine-containing
compounds. In the end, this resulted in a unique set of fused and
spirocyclic compounds (2–26) well poised for screening efforts
and future development, and their synthesis is discussed below.
.
Figure 2. Structures of compounds containing bi- or tricyclic fused amines or
spirocyclic heterocycles. The core structure of all final compounds is shown
in Scheme 1.
The syntheses of the bi- or tricyclic amines of compounds 7-
10 were initiated with the protection of aminoacetaldehyde
dimethyl acetal as the ethyl carbamate, followed by alkylation
with allyl bromide. After deprotection with formic acid, the
desired aldehyde was obtained. A 1,3-dipolar cycloaddition of
the aldehyde and N-methylglycine, proline, piperidine-2-
While several of the proposed constrained amines or
precursors of these amines were synthesized according to
methods in the literature, a number of the amines including those
of compounds 2, 3, 18, and 19 have not been reported previously.
carboxylic acid, or N-benzylglycine provided the amines used to
prepare compounds 7-10, respectively.17,
This racemic
21
synthesis afforded the amine precursors of compounds 7–10 as

cis racemates, as has been reported previously.17 We additionally
prepared the 4-nitrobenzoyl analogue of compound 8 and
confirmed its cis-configuration by single-crystal X-ray diffraction
(Supplementary Figure 1). The fused cyclic amines of
compounds 11 and 12 were synthesized with the common
starting material, 3,3-dimethoxypropan-1-amine, using a 1,3-
dipolar cycloaddition as the key step, analogous to the
preparation of compounds 7 and 10, respectively.22 Compounds 7
and 11 were obtained after deprotection of the benzyl group upon
coupling to 3-bromobenzoyl chloride. Additionally, we prepared
an analogue of compound 11 (containing two 4-nitrobenzoyl
groups) and its cis-configuration was confirmed by single-crystal
X-ray diffraction (Supplementary Figure 2).
5,7(6H)-dione was determined to be the cis racemate by
comparison of the NMR spectra with previous literature reports.24
Compound 17 was prepared analogously to compound 16 from
3,4-pyridinedicarboxylic acid.22
Compounds 18 and 19 were prepared according to the
sequence outlined in Scheme 3. First, compound 35 was
converted to the corresponding oxime (36) which was
subsequently oxidized with TFAA/H2O2 to give the Cbz
protected 3-nitro piperidine (37). The nitro ester intermediate (38)
was obtained by a Michael addition of 37 with methyl acrylate
under mild conditions. Subsequent reduction of the nitro group
by catalytic hydrogenation over Raney Nickel gave the
corresponding amino intermediate, which spontaneously cyclized
to the spirolactam (39). Reduction of 39 by lithium aluminium
hydride lead to 7-methyl-1,7-diazaspiro [4. 5] decane, which was
subsequently acylated to give compound 18. Alternatively,
methylation of the amide of 39 by iodomethane followed by Cbz
deprotection with palladium provided intermediate 41, which
could be converted to compound 19 by a similar reduction and
acylation sequence. The diamine spirocycle scaffolds used to
prepare compounds 20 and 21 were synthesized from Cbz-
protected 4-nitropiperidine via the same route.25
The fused cyclic amine containing compounds 13-16 were
synthesized from 2,3-pyridinedicarboxylic acid. Dehydration of
the pyridinedicarboxylic acid with acetic anhydride and then
ammonolysis with benzyl ammonium gave 6-benzyl-5H-
pyrrolo[3,4-b]pyridine-5,7(6H)-dione.
Hydrogenation
with
palladium gave key intermediate 6-benzyltetrahydro-5H-
pyrrolo[3,4-b]pyridine-5,7(6H)-dione, and subsequent reduction
by lithium aluminium hydride led to the protected bicyclic fused
amine precursor used to prepare compounds 13-16.23 Key
intermediate
6-benzyltetrahydro-5H-pyrrolo[3,4-b]pyridine-
Scheme 2. Route to compounds 2 and 3. (a) i. 3-aminopropene, K2CO3, toluene, N2, 12 h; ii. 10% allylmagnesium bromide/Et2O, toluene, N2, 0 oC to rt, 8 h (two
steps, 37%-45%); (b) TFAA, DMAP, DCM, 0 oC to rt, 21 h (82%); (c) Grubbs II, DCM, Ar, 24 h, (73%); (d) K2CO3, MeOH, reflux, 5 h, (98%); (e) (Boc)2O,
MeCN, 3 d, (99%); (f) 10% Pd/C, HOAc, HCOONH4, MeOH, reflux, Ar, 5 h, (82%); (g) 3-bromobenzoyl chloride, Et3N, DCM, 0 oC to rt, 2 h, (95%); (h) i.
CF3COOH, DCM, 2 h; ii. TEA, DCM, 4 h, (95%); (i) NaCNBH4, HCHO/H2O, HOAc, MeOH, 20 h, (85%).
Scheme 3. Route to compounds 18 and 19. (a) NH2OH·HCl, CH3COONa, EtOH, 2 h (86%); (b) TFAA, 30% H2O2, urea, NaHCO3, CH3CN, reflux, 11 h (33%-
39%); (c) methyl acrylate, K2CO3, MeOH, 12 h (98%); (d) Raney Ni, H2, EtOH, 50 oC; (e) CH3I, NaH, THF, 19 h (97%); (f) Pd/C, H2, 24 h; (g) i. LiAlH4, THF,
reflux, 12 h; ii. 3-bromobenzoyl chloride, Et3N, DCM, 0 oC to rt, 2 h, (two steps, 56%-97%).
The boc protected spirocyclic amines used in the preparation
of compounds 22 and 23 were obtained by cyclization of 1-
benzyl-4-piperidinone, or 1-benzyl-3-piperidinone in the case of
24, with ethyl cyanoacetate followed by hydrolysis and
decarboxylation as reported previously.26 Finally, the methylated
spirocyclic amines of compounds 25 and 26 were prepared
Subsequent nitrile reduction and lactamization to establish the
first heterocyclic ring followed by imide formation with methyl
amine and global reduction furnished the target spirodiamines.27
With a unique set of compounds in hand containing bi- or
tricyclic fused ring systems or spirocyclic amines, we sought to
investigate the ability of these compounds to interact with a panel
of 24 lysine and arginine methyltransferases (Supplementary
utilizing
a key double alkylation of ethyl cyanoacetate.

In conclusion, we were inspired by the known multicyclic
ligands, UNC669 and UNC926, and we hypothesized that
reducing the conformational flexibility of the piperidine-
pyrrolidine amine would generate a novel set of nitrogen-based
heterocyclic ligands well poised to engage the proteins that
interact with methylated lysine, as well as provide value in other
areas of medicinal chemistry. In order to explore this hypothesis
further, we designed and synthesized a unique set of 25
compounds with bi- or tricyclic fused amines or spirocyclic
heterocycles and a simple bromobenzene core. We then
investigated the ability of this set of amine-containing
compounds to interact with a panel of protein lysine and arginine
methyltransferases, which led to the identification of compound
13 as a novel scaffold that interacts with SETD8. Despite its
weak affinity, compound 13 serves as an attractive scaffold for
further development as a SETD8 inhibitor. In addition, we
believe that the set of constrained amines developed will find
wide utility when incorporated into a variety of diverse scaffolds,
and we are presently expanding our compound set to be broadly
screened against different classes of Kme regulatory proteins.
Table 1). The activity of each enzyme was initially measured in
the presence of 50 μM compound using a radioactivity-based
Scintillation Proximity Assay.28 Of the compounds screened,
three reduced the enzymatic activity of the methyltransferase
SETD8 to less than 50% that of the untreated enzyme (Table 1).
SETD8 is the sole PKMT known for the in vivo
monomethylation of histone H4 lysine 20 (H4K20),29, 30 and it
has also been shown to monomethylate K382 of p53 and K248 of
the proliferating cell nuclear antigen (PCNA).31, 32 This enzyme
has been implicated in DNA damage response, cell cycle
progression, and the silencing of euchromatic genes.33 Due to the
growing interest in the perturbation of SETD8 activity with small
molecules, a number of inhibitors of SETD8 have recently been
discovered including the SAM-competitive inhibitor and marine
natural product, nahuoic acid A,34 and the substrate competitive
inhibitor, UNC0379 (Supplementary Figure 3).35 Most recently,
Blum and coworkers reported three irreversible SETD8 inhibitors
which exhibited modest selectivity and were active in cells.36
Table 1. Structures of preliminary SETD8 hit compounds and percent
SETD8 activity in the presence of 50 μM compound.
Compound
Structure
% SETD8 Activity
Acknowledgements
The authors are very grateful to Ms. Zhuoqi Zhang for her help
and support in the current research, in particular, LC-MS
measurements. This work was supported by a grant from the
National Natural Science Foundation of China (No. 81072526)
and Science and Technology Development Plan of Jilin Province
(No. 20140309010YY). Additional support was provided by
Changchun Discovery Sciences, Ltd. The research described here
was also supported by the National Institute of General Medical
Sciences, US National Institutes of Health (NIH, grant
R01GM100919) and the Carolina Partnership and the University
Cancer Research Fund, University of North Carolina at Chapel
Hill.
43
5
49
45
6
13
We next sought to confirm these results by determining the
IC50 values of compounds 5, 6, and 13 for SETD8. While
compounds 5 and 6 demonstrated no appreciable activity up to
200 µM (Supplementary Figure 4), compound 13 showed robust
but weak activity against SETD8 (IC50 = 39 ± 11 µM; Table 2
and Figure 3). Hoping to further characterize the activity of
compound 13 for SETD8, we performed isothermal titration
calorimetry (ITC) studies both in the presence and absence of S-
Adenosyl-L-homocysteine (SAH). While significant binding was
not observed, this is not overly surprising, as the ligand is
inherently weak which prevents the ITC studies from being
performed under optimal conditions to detect and quantify
binding, particularly considering that prior reports suggest that
we would expect a dissociation constant about 3-fold weaker
than the observed IC50.35
References and notes
1. Jones, P. A.; Baylin, S. B. Cell 2007, 128, 683.
2. Copeland, R. A.; Solomon, M. E.; Richon, V. M. Nat. Rev. Drug.
Disc. 2009, 8, 724.
3. Arrowsmith, C. H.; Bountra, C.; Fish, P. V.; Lee, K.; Schapira,
M. Nat. Rev. Drug. Disc. 2012, 11, 384.
4. Tsukada, Y. I.; Fang, J.; Erdjument-Bromage, H.; Warren, M. E.;
Borchers, C. H.; Tempst, P.; Zhang, Y. Nature 2005, 439, 811.
5. Shi, Y.; Lan, F.; Matson, C.; Mulligan, P.; Whetstine, J. R.; Cole,
P. A.; Casero, R. A.; Shi, Y. Cell 2004, 119, 941.
6. Schotta, G.; Sengupta, R.; Kubicek, S.; Malin, S.; Kauer, M.;
Callén, E.; Celeste, A.; Pagani, M.; Opravil, S.; Rosa-Velazquez, I.
A. D. L.; Espejo, A.; Bedford, M. T.; Nussenzweig, A.; Busslinger,
M.; Jenuwein, T. Genes. Dev 2008, 22, 2048.
Table 2. IC50 determination of compounds 5, 6, and 13 for SETD8.
Compound
IC50 (µM)
>200
>200
Hill Slope
7. Daze, K. D.; Hof, F. Accounts. Chem. Res. 2012, 46, 937.
8. Gao, C.; Herold, J. M.; Kireev, D.; Wigle, T.; Norris, J. L.; Frye,
S. V. J. Am. Chem. Soc. 2011, 133, 5357.
9. Simon, J. A.; Lange, C. A. Mutat. Res-Fund. Mol. O. M. 2008,
647, 21.
NA
NA
2
5
6
13
39 ± 11
10. Frye, S. V. Nat. Chem. Biol. 2010, 6, 159.
11. Bunnage, M. E.; Chekler, E. L. P.; Jones, L. H. Nat. Chem. Biol.
2013, 9, 195.
12. Workman, P.; Collins, I. Chem. Biol 2010, 17, 561.
13. Herold, J. M.; Wigle, T. J.; Norris, J. L.; Lam, R.; Korboukh, V.
K.; Gao, C.; James, L. I.; Kireev, D. B.; Senisterra, G.; Vedadi, M.;
Tripathy, A.; Brown, P. J.; Arrowsmith, C. H.; Jin, J.; Janzen, W. P.;
Frye, S. V. J. Med. Chem. 2011, 54, 2504.
14. Herold, J. M.; James, L. I.; Korboukh, V. K.; Gao, C.; Coil, K.
E.; Bua, D. J.; Norris, J. L.; Kireev, D. B.; Brown, P. J.; Jin, J.;
Janzen, W. P.; Gozani, O.; Frye, S. V. Med. Chem. Comm 2012, 3,
45.
Figure 3. Compound 13 binds SETD8 with an IC50 of 39 ± 11 µM.

15. Østergaard, C.; Sørensen, T. K.; Knudsen, J. D.; Frimodt-
Møller, N. Antimicrob. Agents. Chem. 1998, 42, 1706.
16. Shao, Y.; Zhang, H. K.; Ding, H.; Quan, H. T.; Lou, L. G.; Hu,
L. H. J. Nat. Prod. 2009, 72, 1170.
17. Huck, B. R.; Llamas, L.; Robarge, M. J.; Dent, T. C.; Song, J.;
Hodnick, W. F.; Crumrine, C.; Stricker-Krongrad, A.; Harrington, J.;
Brunden, K. R.; Bennani, Y. L. Bioorg. Med. Chem. Lett. 2006, 16,
2891.
18. Converso, A.; Hartingh, T.; Garbaccio, R. M.; Tasber, E.;
Rickert, K.; Fraley, M. E.; Yan, Y. W.; Kreatsoulas, C.; Stirdivant,
S.; Drakas, B.; Walsh, E. S.; Hamilton, K.; Buser, C. A.; Mao, X. Z.;
Abrams, M. T.; Beck, S. C.; Tao, W. K.; Lobell, R.; Sepp-Lorenzino,
L.; Zugay-Murphy, J.; Sardana, V.; Munshi, S. K.; Jezequel-Sur, S.
M.; Zuck, P. D.; Hartman, G. D. Bioorg. Med. Chem. Lett. 2009, 19,
1240.
19. Burgey, C. S.; Potteiger, C. M.; Deng, J. Z.; Mosser, S. D.;
Salvatore, C. A.; Yu, S.; Roller, S.; Kane, S. A.; Vacca, J. P.;
Williams, T. M. Bioorg. Med. Chem. Lett. 2009, 19, 6368.
20. Jenkins, I. D.; Lacrampe, F.; Ripper, J.; Alcaraz, L.; Van Le, P.;
Nikolakopoulos, G.; Leone, P. D.; White, R. H.; Quinn, R. J. J. Org.
Chem. 2009, 74, 1304.
21. Schenke, T.; Petersen, U., EP393424A2, 1990
22. Wu, Y.; Qi, M., CN101619064A, 2010
23. Zhang, W.; Yang, D.; Huang, L.; Ma, J.; Guo, A.; Jiang, L.; Ma,
R.; Chen, S., CN 102060855, 2011
24. Pallavicini, M.; Bolchi, C.; Fumagalli, L.; Piccolo, O.; Valoti, E.,
Tetrahedron-Asymmetr, 2011, 22 ,379-380.
25. Mullen, P.; Miel, H.; McKervey, M. A. Tetrahedron Lett. 2010,
51, 3216.
26. Chen, H.; Zhang, Z.; Ma, R.; Chen, S.; Li, G., CN101255160A,
2008
27. Weinberg, K.; Stoit, A.; Kruse, C. G.; Haddow, M. F.;
Gallagher, T. Tetrahedron 2013, 69, 4694.
28. Ibáñez, G.; Shum, D.; Blum, G.; Bhinder, B.; Radu, C.; Antczak,
C.; Luo, M.; Djaballah, H. Comb. Chem. High. T. Scr. 2012, 15, 359.
29. Nishioka, K.; Rice, J. C.; Sarma, K.; Erdjument-Bromage, H.;
Werner, J.; Wang, Y. M.; Chuikov, S.; Valenzuela, P.; Tempst, P.;
Steward, R.; Lis, J. T.; Allis, C. D.; Reinberg, D. Mol. Cell 2002, 9,
1201.
30. Wu, S.; Rice, J. C. Cell Cycle 2011, 10, 68.
31. Shi, X. B.; Kachirskaia, L.; Yamaguchi, H.; West, L. E.; Wen,
H.; Wang, E. W.; Dutta, S.; Appella, E.; Gozani, O. Mol. Cell 2007,
27, 636.
32. Takawa, M.; Cho, H. S.; Hayami, S.; Toyokawa, G.; Kogure,
M.; Yamane, Y.; Iwai, Y.; Maejima, K.; Ueda, K.; Masuda, A.;
Dohmae, N.; Field, H. I.; Tsunoda, T.; Kobayashi, T.; Akasu, T.;
Sugiyama, M.; Ohnuma, S.; Atomi, Y.; Ponder, B. A.; Nakamura,
Y.; Hamamoto, R. Cancer Res. 2012, 72, 3217.
33. Beck, D. B.; Oda, H.; Shen, S. S.; Reinberg, D. Genes Dev.
2012, 26, 325.
34. Williams, D. E.; Dalisay, D. S.; Li, F.; Amphlett, J.; Maneerat,
W.; Chavez, M. A. G.; Wang, Y. A.; Matainaho, T.; Yu, W.; Brown,
P. J.; Arrowsmith, C. H.; Masoud, V.; Andersen, R. J. Org. lett.
2012, 15, 414.
35. Ma, A.; Yu, W.; Li, F.; Bleich, R. M.; Herold, J. M.; Butler, K.
V.; Norris, J. L.; Korboukh, V.; Tripathy, A.; Janzen, W. P.;
Arrowsmith, C. H.; Frye, S. V.; Vedadi, M.; Brown, P. J.; Jin, J. J.
Med. Chem. 2014, 57, 6822.
36. Blum, G.; Ibanez, G.; Rao, X.; Shum, D.; Radu, C.; Djaballah,
H.; Rice, J. C.; Luo, M. ACS Chem. Biol. 2014, 9, 2471.