Design, synthesis and anti leukemia cells proliferation activities of pyrimidylaminoquinoline derivatives as DOT1L inhibitors

Article abstract of DOI:10.1016/j.bioorg.2018.07.022

A series of novel pyrimidylaminoquinoline derivatives 8(a-i) and 9(a-i) containing amino side chain, and the bisaminoquinoline analogs 3(b-e) have been designed and synthesized by structural modifications on a lead DOT1L inhibitor, 3a. All the compounds have been evaluated for their DOT1L inhibitory activities. The results showed that most of the compounds have strong anti DOT1L activities. Compounds 3e, 8h and 9e are the most potential ones from each category with the IC₅₀ values of 1.06 ± 0.35 μM, 5.72 ± 1.56 μM and 3.55 ± 1.28 μM, respectively. Such inhibitors expressed significant binding interactions with DOT1L by surface plasmon resonance (SPR)-based binding assay. The results of molecular docking experiments suggested that they could occupy the SAM binding pocket of DOT1L. Compounds 8h and 9e exhibited better inhibitory activities but poor selectivities against the both MLL-rearranged MV4-11 cells and the non MLL-rearranged Kasumi-1 cells than those of 3a and 3e, which suggested that the introduction of the amino side chain would be beneficial for their anti leukemia cells proliferation activities, possibly due to the improvement of the fat solubility. Additionally, the direct cellular inhibition activities were found that compound 9e could effectively down-regulate both the level of H3k79 methylation and MLL-rearranged leukemia gene expression of Hoxa9 and Meis1 in MV4-11 in the qRT-PCR and western blot studies. These observations suggested DOT1L was one of the potential targets but perhaps not the most pivotal one for these compounds, which made their poor selectivities against leukemia cells proliferation.

Full text of DOI:10.1016/j.bioorg.2018.07.022

Accepted Manuscript
Design, Synthesis and Anti Leukemia Cells Proliferation Activities of Pyrimi-
dylaminoquinoline Derivatives as DOT1L inhibitors
Li Zhang, Yantao Chen, Na Liu, Linjuan Li, Senhao Xiao, Xiaoliu Li, Kaixian
Chen, Cheng Luo, Shijie Chen, Hua Chen
PII:
S0045-2068(18)30295-5
DOI:
https://doi.org/10.1016/j.bioorg.2018.07.022
YBIOO 2441
Reference:
Bioorganic Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 March 2018
11 May 2018
18 July 2018
Please cite this article as: L. Zhang, Y. Chen, N. Liu, L. Li, S. Xiao, X. Li, K. Chen, C. Luo, S. Chen, H. Chen,
Design, Synthesis and Anti Leukemia Cells Proliferation Activities of Pyrimidylaminoquinoline Derivatives as
DOT1L inhibitors, Bioorganic Chemistry (2018), doi: https://doi.org/10.1016/j.bioorg.2018.07.022
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.

Bioorganic Chemistry
Design, Synthesis and Anti Leukemia Cells Proliferation Activities of
Pyrimidylaminoquinoline Derivatives as DOT1L inhibitors
Li Zhanga, Yantao Chenb,c,#, Na Liua, Linjuan Lib,c,d, Senhao Xiaob,c,d, Xiaoliu Lia, Kaixian Chenb,c, Cheng
Luob,c, Shijie Chenb,c*and Hua Chena*
aKey Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China
bDrug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai
201203, China
cUniversity of Chinese Academy of Sciences, Beijing 100049, China
dSchool of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of novel pyrimidylaminoquinoline derivatives 8(a-i) and 9(a-i) containing amino side chain,
and the bisaminoquinoline analogs 3(b-e) have been designed and synthesized by structural
modifications on a lead DOT1L inhibitor, 3a. All the compounds have been evaluated for their DOT1L
inhibitory activities. The results showed that most of the compounds have strong anti DOT1L activities.
Compounds 3e, 8h and 9e are the most potential ones from each category with the IC50 values of
1.06 0.35 μM, 5.72 1.56 μM and 3.55 1.28 μM, respectively. Such inhibitors expressed significant
binding interactions with DOT1L by surface plasmon resonance (SPR)-based binding assay. The results
of molecular docking experiments suggested that they could occupy the SAM binding pocket of
DOT1L. Compounds 8h and 9e exhibited better inhibitory activities but poor selectivities against the
both MLL-rearranged MV4-11 cells and the non MLL-rearranged Kasumi-1 cells than those of 3a and
3e, which suggested that the introduction of the amino side chain would be beneficial for their anti
leukemia cells proliferation activities, possibly due to the improvement of the fat solubility.
Additionally, the direct cellular inhibition activities were found that compound 9e could effectively
down-regulate both the level of H3k79 methylation and MLL-rearranged leukemia gene expression of
Hoxa9 and Meis1 in MV4-11 in the qRT-PCR and western blot studies. These observations suggested
DOT1L was one of the potential targets but perhaps not the most pivotal one for these compounds,
which made their poor selectivities against leukemia cells proliferation.
Revised
Accepted
Available online
Keywords:
Pyrimidylaminoquinoline
Nonnucleoside DOT1L inhibitors
Amino side chains
Mixed-linage leukemia
Histone lysine methyltransferase
2018Elsevier Ltd. All rights reserved.
#Co-first author;*Correspondence: E-mail:hua-todd@163.com; Tel & Fax.: 0086-312-5971116;
E-mail:shijiechen@simm.ac.cn; Tel & Fax.: 0086-021-50806600.

compounds 8(a-i) and 9(a-i) bearing with the amino side chains
by the privileged fragment linking of 5 and 6 (or 7). Furthermore,
the bisaminoquinoline analogs 3(b-e) were also prepared to
explore the chemistry space of the parent inhibitor 3a to increase
its structural diversity for structure activity relationships (SAR)
analysis. All of the new compounds were evaluated for their
DOT1L inhibitory activities and anti leukemia cells proliferation
activities, including the MLL-rearranged MV4-11 cells and the
non MLL-rearranged Kasumi-1 cells.
1. Introduction
Disruptor of telomeric silence 1-like (DOT1L), a histone
lysine methyltransferase (HKMTs), is responsible for
specifically catalyzing the mono-, di-, and tri- methylation of the
histone H3-lysine79 (H3K79) using (S)-adenosyl-L-methionine
(SAM, Fig 1) as the methyl donor (enzyme cofactor).1 The
aberrant methylation of H3K79 mediated by DOT1L would
induce and boost the occurrence and maintenance processes of
mixed linage leukemia (MLL) by promoting the expression of
leukemogenic genes, such as HOXA9 and MEIS1.2 Thus,
DOT1L inhibitors become the promising therapeutic tools to
treat MLL due to the critical roles of DOT1L in
leukemogonesis.3
Scheme 1. The design and synthesis of compounds 8, 9 and 3(b-e).
Conditions and reagents: (a) glycol, DIPEA, 110oC; (b) glycol, 12 N HCl, 50
Fig.1The structures of SAM, SAH, and DOT1L inhibitors.
oC.
DOT1L inhibitors have been divided into two kinds,
nucleoside and nonnucleside inhibitors. The former is designed
based on the structures of SAM and its corresponding enzymatic
reaction product (S)-adenosyl-L-homocysteine (SAH).4 Epizyme
international company,5 the Song laboratory,6 and the Structural
Genomics Contrsortium7 have developed several dozen
nucleoside inhibitors, among them, compound 1, EPZ004777,
SGC0946, and EPZ5676 (Fig 1) are the most effective and
selective inhibitors of DOT1L. As an alternative way to inhibit
DOT1L, the nonnucleside inhibitors, such as 2 (Fig 1), mainly
target to the induced binding pocket adjacent to the SAM
binding site, have been greatly developed by the Novartis.8
Recently, the Luo laboratory9 has identified 3a, the
bisaminoquinoline linked through 4-methyl pyrimidyl, as the
first novel nonnucleside DOT1L inhibitor through structure-
based virtual screening.10 Subsequently, the same lab found
inhibitor 4 (Fig 1) with triazolo-thiadizole scaffold by using
target-specific scoring function.11 Both inhibitors show high
inhibitory activities towards DOT1L, but weak activities against
MLL-rearranged cells (MV4-11) proliferation, perhaps due to
their poor cell membrane permeability. Molecular docking
analysis found that the inhibitors competitively occupies the
binding site of SAM, different from the Novartis’s ones.
2. Results and Discussions
2.1. Chemistry
Synthesis of compounds 8(a-i), 9(a-i) and the bisamino
quinoline analogs 3(a-e) was outlined in Scheme 1. Briefly, the
4,6-diamino quinoline 11a was prepared according to the
literatures12 and 11(b-c) were obtained as the intermediates in the
synthetic process of 11a (in Supporting Information). The
reaction of 11a with 2,4-dicholo-6-methyl-pyrimidine 12a in
12N HCl afforded the key intermediate 5, accompanied by side
reaction leading to the byproduct bisaminoquinoline 3a. Then,
following the same procedure, the bisquinoline analogs 3(b-e)
were synthesized by the treatment of 11(a-c) with a variety of
dicholopyrimidines 12(a-c), respectively. The various amino side
chains 6 and 7 were achieved by the reaction of the
commercially available diamines with the corresponding aryl
isocyanates (in Supporting Information). The electrophilic
substitutions of 5 with 6 or 7 provided the final products 8(a-i)
and 9(a-i), respectively. The byproduct 10 was generated when
DMF was used as the solvent.
The structures of all the newly compounds were determined
by NMR (Fig S1) and (HR) MS. Both analytical and spectral
data of compounds are in agreement with the proposed
structures.
As the putative binding modes in mind, we hypothesize that
introducing the amino side chain to 3a would increase its cell
membrane permeability, and would be beneficial to improving
its activity against leukemia cells. Herein, we would like to
report the design and synthesis of the pyrimidylaminoquinoline
2.2. DOT1L inhibitory activity

All the newly synthesized compounds 8(a-i), 9(a-i), 3(b-e), 5
and 10 were evaluated for their DOT1L inhibitory activities at
the concentrations of 20 μM and 5 μM via a 3H labeled
radioactive methylation assay. The parent compound 3a was
used as the positive control. The results are shown in Table 1 and
Fig S2. The results show that all of the tested compounds except
5 and 10 have good to potent DOT1L inhibitory activity in range
of 38%-100% at 20 μM. Among them, compounds 3d and 3e
have the strongest DOT1L inhibitory activities with near 100%
inhibition at both concentrations, similar with those of 3a.
Subsequently, the compounds with the inhibition rate above 50%
at 5 μM were chosen to further evaluate their IC50 values (Table
1, Fig S3). It could be seen that in serial of 3, the
bisaminoquinoline analogs 3d and 3e exhibited the most
potential activities against DOT1L with the IC50 values of
1.08 0.23 μM and 1.06 0.35 μM, respectively. In serial of 8,
compounds 8b, 8f, and 8i showed significant inhibition with the
IC50 values lower than 10 μM, and 8h was the most active one
with the IC50 value of 5.72 1.56 μM. In serial of 9, 9e with the
IC50 value of 3.55 1.28 μM was the most effective one, and 9b
had the good activity with the IC50 values lower than 10 μM.
However, 5 and 10 exhibited weak activities against DOT1L.
According to the structures and the inhibitory activities of the
newly synthesized compounds, 3e, 8h and 9e, the most potential
one from each category, were chosen to be further validated.
Table 1. Structures, DOT1L inhibitory and anti the leukemia cells activities of 3a and its derivatives.
anti-MV4-11c
IC50
anti-Kasumi-1d
IC50
anti-DOT1L
Cpd.
R/R1
n
Inhibition ratio Inhibition ratio
IC50
(mean SD, μM)
(mean SD, μM) (mean SD, μM)
(20 μM, %)
(5 μM, %)
NH2
OH
OMe
-
-
-
-
-
100
93.9
1.5[10]
37.1[10]
a
a
a
a
3a
3b
3c
3d
65
66
53
63
4.35 1.05
21.67 2.08
1.08 0.23
a
a
a
100
100
-
-
101
99
3e
1.06 0.35
30.54 1.32
45.75 3.14
H
H
1
2
3
4
5
1
2
1
2
1
2
3
4
5
51
85
58
52
53
84
90
83
97
66
71
66
48
52
27
71
18
18
29
53
48
54
60
36
54
31
47
51
a
a
a
8a
8b
8c
8d
8e
8f
a
a
7.79 3.05
H
a
a
a
H
a
a
a
H
a
a
a
Me
Me
Et
Et
H
6.04 1.10
a
a
a
a
a
8g
8h
8i
5.72 1.56
1.62 0.17
3.80 0.60
7.91 1.32
a
a
a
a
a
9a
9b
9c
9d
9e
H
a
a
8.77 1.16
H
a
a
a
H
a
a
a
H
3.55 1.28
1.29 0.32
4.25 1.04

Me
Me
Et
1
2
1
2
49
68
38
48
b
48
41
12
36
b
a
a
a
a
a
a
a
a
a
a
a
a
a
9f
9g
9h
9i
Et
Cl
-
-
a
a
a
a
5
28
1
a
10
a: Not determined;
b: No activity;
c: MV4-11: MLL-rearranged cell;
d: Kasumi-1: a leukemia cell line without MLL-rearrangement.
compounds showed good interactions with DOT1L. The
equilibrium dissociation constant (KD) for 3e and DOT1L was
0.80 μM, nearly the same with that of 3a.10 And the KD for 8h,
9e and DOT1L were 3.52 μM and 1.31 μM, respectively. The
values of their KD are consistent with their anti-DOT1L
activities, indicating that the inhibitors can bind to DOT1L and
then inhibit DOT1L activity in vitro.
2.3. Surface Plasmon Resonance (SPR)-Based binding
assay
To further validate the binding of DOT1L and the potent
inhibitors 3e, 8h, and 9e, the SPR assays were conducted to
determine their interactions. As shown in Fig 2, the tested
Fig.2 SPR assays of the binding between DOT1L and the inhibitors. The concentrations of the three compounds injected over the CM5 chip are indicated, and
the SPR curves for these inhibitors binding with DOT1L are shown. (A) The value of KD for 3e binding with DOT1L was 0.80 μM. (B) The value of KD for 8h
binding with DOT1L was 3.52 μM. (C) The value of KD for 9e binding with DOT1L was 1.31 μM.
compound 3a or EPZ004777. Compared to EPZ004777, though
the Pi-Pi stacking interactions between 8h, 9e and F223 were not
as strong as that between F223 and EPZ004777, cation-Pi
interactions were formed between positive charged 8h and F245,
and a salt bridge was formed between 9e and E186. The
inhibitory activities of 8h and 9e against DOT1L were slightly
lower than those of 3e and 3a possibly due to their flexible side
chains. In conclusion, the putative binding modes of the three
compounds were in consonance with their inhibitory activities
and our experimental data.
2.4. Binding mode and Structure-Activity Relationships
(SARs) analysis
In order to achieve some visual insights into the binding
interactions, compound 3e was docked into the DOT1L crystal
structure (PDB ID 3QOW) in XP mode using Glide13 module of
maestro14 to generate putative binding poses. Since compounds
8h and 9e have the structural similarities with EPZ004777
containing a urea side chain, the crystal structure of EPZ004777
in complex with DOT1L (PDB ID 4EKI) was used for the
docking studies. As shown in Fig 3A and 3B, compounds 3e, 8h,
and 9e fitted in the pocket as well as 3a, SAM and EPZ004777
did. In the predicted binding poses of the compounds (Fig 3C-3E,
Fig S4), the pyrimidine ring moiety of 3e forms Pi-Pi stacking
interactions with residue F223, similar to that of 3a and SAM.
The three compounds form hydrogen bonds with V135, D161,
G163, D222 and N241, respectively. Besides, some nonpolar
interactions like hydrophobic interactions were also formed
between DOT1L and the compounds. This was similar to that of
We further found some relationships between the compounds
structures and their anti-DOT1L activities. The structure-activity
relationships (SARs) were analyzed on the basis of the anti-
DOT1L activities. In serial of 3, the bisaminoquinoline analogs
3d and 3e exhibited the most potential activities against DOT1L,
while the 4-NH2 on quinoline ring was replaced with OH or

OMe, such as 3b and 3c, the activities reduced markedly,
especially in the case of 3c. These results suggested that the 4-
NH2 on quinoline had an important role to maintain their DOT1L
inhibitory activity, while the slight changes on the pyrimidine
linker would make subtle influence. In serial of 8, possessing the
t-butyl phenyl at the end of the amino chain, 8b, 8f, 8h and 8i
showed significant inhibition against DOT1L, which suggested
that the short chain length (n = 1 or 2) was more favorable for
their inhibitory activities, and the R group (H, Me, or Et) seemed
to have little influence on the inhibition. In serial of 9, fixed as
the terminal 3,5-ditrifluoromethyl phenyl, 9e with the long chain
(n = 5, R = H) was the most active one, and 9b (n = 2, R = H)
had the good activity, implying that H atom (R group) might be
better accommodated into the DOT1L binding site, while the big
R substituents, such as methyl and ethyl groups, would be a
negative effect on their anti-DOT1L activities. Furthermore, the
introduction of Cl atom or N,N-dimethyl group to the pyrimidine
instead of the amino side chain, such as compounds 5 and 10,
would have a detrimental effect or would lead to a markedly loss
in the activity. Above insights should help to guide further
design and synthesis of the more potent DOT1L inhibitors
derived from compound 3a.
indicating that improving the fat solubility of the quinoline
inhibitor would be beneficial to their anti leukemia cells
activities.
2.6. Cellular H3K79 methylation inhibition analysis
Since compounds 8h and 9e exhibited the enhanced anti
proliferative activities and poor selectivities against the leukemia
cells MV4-11and Kasumi-1, however, compared to 3a and 3e,
the inconsistency between the cellular and enzymatic assays was
observed. To further validate DOT1L as the target, western blot
analysis combined with qRT-PCR study15 were performed to
evaluate the direct cellular inhibition activities of these
compounds. EPZ004777 was used as the positive control and an
equal amount of DMSO was used as the negative control. As
shown in Fig 4, 3e could down-regulate the levels of H3K79
methylation and the gene expression of Hoxa9 and Meis1. The
effect was dose-dependent. Similar to 3e, compound 9e exhibited
moderate effects on Hoxa9 and Meis1 expression down-
regulation (Fig 4A). In condition of western blot, 9e was more
effective than 3e. The dose-dependent phenomenon was
observed as well (Fig 4B). In contrast to 3e and 9e, 8h revealed
weak down-regulation effect against Hoxa9 and weak inhibition
effect on H3K79 methylation at the same condition. Combined
the results of other studies together, it could draw a preliminary
conclusion that such compounds could target DOT1L in cell to
inhibit H3K79 methylation. However, the weak activity of 8h in
cellular H3K79 methylation inhibition studies suggested that
DOT1L was one of the potential targets but perhaps not the
unique target or the most pivotal one for these compounds,
because compounds 8h and 9e have the signature chemical
features of other inhibitors, such as kinase inhibitors. Other
possible targets remain to be uncovered in subsequent
exploration.
Fig.3 Putative binding mode of 3e, 8h and 9e in SAM binding site of
DOT1L. (A) SAM binding site of DOT1L (PDB ID 3QOW) occupied by 3e
aligned with 3a and SAM. (B) SAM binding site of DOT1L (PDB ID 4EKI)
occupied by 8h and 9e aligned with EPZ004777. 3a is shown as yellow
sticks, 3e is shown as marine sticks, 8h is shown as cyan sticks, 9e is shown
as tv_orange sticks, SAM and EPZ004777 are shown as hotpink sticks. The
protein structures are shown in vacuum electrostatics. (C, D, E) Close-up
view of the important interactions participated in stabilizing 3e, 8h and 9e in
the SAM binding pocket. The protein structure is shown as gray80 cartoons.
The inhibitors and key residues in surrounding are labeled and depicted as
cyan and yellow sticks respectively. Hydrogen bonds are shown as red
dashed lines.
Fig.4 Cellular H3K79 methylation inhibition analysis. EPZ004777 was used
as the positive control and an equal amount of DMSO was used as the
negative control (A) Hoxa9 and Meis1 expression levels changed after
treated with the compounds in indicated concentrations. (B) H3K79
methylation levels were influenced in MV4-11 cells after treated with the
compounds in series concentrations.
2.5. Leukemia cells activity
The anti leukemia cells proliferation activities of the
inhibitors 3e, 8h and 9e were further evaluated in the MLL-AF4-
expressing acute leukemia cell line MV4-11 and the non MLL-
rearranged Kasumi-1 cells in vitro via cell Titer-Glo luminescent
assays (Promega). The parent compound 3a (IC50=37.1 μM) was
used as the positive control. The inhibitors led to a dose-
dependent reduction in viable cells with the IC50 values of
30.54 1.32, 1.62 0.17, and 1.29 0.32 μM against MV4-11
(Table 1 and Fig S5) and 45.75 3.14, 3.80 0.60, and
4.25 0.04 μM against Kasumi-1 (Table 1 and Fig S6),
respectively. It could be seen that the bisamino quinoline
inhibitor 3e was same with 3a who shown excellent anti-DOT1L
activity but exhibited weak activities against the leukemia cells
proliferation, perhaps due to their poor cell membrane
permeability. The inhibitors 8h and 9e possessing the amino side
chain inhibited the proliferation of the cancer-cells significantly,
3. Conclusions
A series of novel pyrimidylaminoquinoline derivatives 8(a-i)
and 9(a-i) containing amino side chain and the bisamino
quinoline analogs 3(b-e) were designed, synthesized, and
evaluated for their DOT1L inhibitory activities. Most of the
compounds have strong anti DOT1L activities. Among them,
compounds 3e, 8h and 9e are the most potential one from each
category, respectively. Compounds 8h and 9e exhibited better
inhibitory activities against leukemia cells than those of the
known inhibitor 3a and its analog 3e, suggesting a beneficial role
for the newly introduced amino side chain. Additionally,

compound 9e could effectively down-regulate both the level of
H3k79 methylation and the gene expression of Hoxa9 and Meis1,
which demonstrated that DOT1L should be one of the potential
targets for these ligands as anti-tumor drug candidates.
[7] (a) Yu, W.; Chory, E. J.; Wernimont, A. K.; Tempel, W.; Scopton, A.;
Federation, A.; Marineau, J. J.; Qi, J.; Barsyte-Lovejoy, D.; Yi, J.;
Marcellus, R.; Iacob, R. E.; Engen, J. R.; Griffin, C.; Aman, A.;
Wienholds, E.; Li, F.; Pineda, J.; Estiu, G.; Shatseva, T.; Hajian, T.; Al-
Awar, R.; Dick, J. E.; Vedadi, M.; Brown, P. J.; Arrowsmith, C. H.;
Bradner, J. E.; Schapira, M. Nat. Commun., 2012, 3, 1288; (b) Yu, W.;
Smil, D.; Li, F.; Tempel, W.; Fedorov, O.; Nguyen, K. T.; Bolshan, Y.;
Al-Awar, R.; Knapp, S.; Arrowsmith, C. H.; Vedadi, M.; Brown, P. J.;
Schapira, M. Bioorg. Med. Chem., 2013, 21, 1787.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (21472208 and 81625022 to C.L.,
81703415 to S.C. and 81430084 to K.C.). This work is also
sponsored by Shanghai Sailing Program (17YF1423100 to S.C.)
and Hebei Province Natural Science Fund (B2016201031 to
X.L.).
[8] (a) Scheufler, C.; Möbitz, H.; Gaul, C.; Ragot, C.; Be, C.; Fernández, C.;
Beyer, K. M.; Tiedt, R.; Stauffer, F. ACS Med. Chem. Lett., 2016, 7, 730;
(b) Chao, C.; Zhu, H.; Stauffer, F.; Caravatti, G.; Vollmer, S.; Machauer,
R.; Holzer, P.; Möbitz, H.; Scheufler, C.; Klumpp, M.; Tiedt, R.; Beyer,
K. S.; Calkins, K.; Guthy, D.; Kiffe, M.; Zhang, J.; Gaul, C. ACS Med.
Chem. Lett., 2016, 7, 735; (c) Möbitz, H.; Machauer, R.; Holzer, P.;
Vaupel, A.; Stauffer, F.; Ragot, C.; Caravatti, G.; Scheufler, C.;
Fernández, C.; Hommel, U.; Tiedt, R.; Beyer, K. S.; Chao, C.; Zhu, H.;
Gaul, C. ACS Med. Chem. Lett., 2017, 8, 338.
References
[1] (a) Min, J. R.; Feng, Q.; Li, Z. Z.; Zhang, Y.; Xu, R. M. Cell, 2003, 112,
711; (b) Kim, W.; Choi, M.; Kim, J. E. Cell Cycle, 2014, 13, 726.
[9] Chen, S. J.; Wang, Y. L.; Zhou, W.; Li, S. S.; Peng, J. L.; Shi, Z.; Hu, J.
C.; Liu, Y. C.; Ding, H.; Lin, Y. Y.; Li, L. J.; Cheng, S. F.; Liu, J. Q.;
Lu, T.; Jiang, H. L.; Liu, B.; Zheng, M. Y.; Luo, C. J. Med. Chem., 2014,
57, 9028.
[2] (a) Klose, R. J.; Zhang, Y. Nat. Rev. Mol. Cell Biol., 2007, 8, 307; (b)
Krivtsov, A. V.; Feng, Z.; Lemieux, M. E.; Faber, J.; Vempati, S.; Sinha,
A. U.; Xia, X.; Jesneck, J.; Bracken, A. P.; Silverman, L. B.; Kutok, J. L.;
Kung, A. L.; Armstrong, S. A. Cancer Cell, 2008, 14, 355; (c) Bernt, K.
M.; Zhu, N.; Sinha, A. U.; Vempati, S.; Faber, J.; Krivtsov, A. V.; Feng,
Z.; Punt, N.; Daigle, A.; Bullinger, L.; Pollock, R. M.; Richon, V. M.;
Kung, A. L.; Armstrong, S. A. Cancer Cell, 2011, 20, 66.
[10] Chen, S.; Li, L.; Chen, Y.; Hu, J.; Liu, J.; Liu, Y. C.; Liu, R.; Zhang,Y.;
Meng, F.; Zhu, K.; Lu, J.; Zheng, M.; Chen, K.; Zhang, J.; Jiang, H.;
Yao, Z.; Luo, C. J. Chem. Inf. Model., 2016, 56, 527.
[3] (a) Anglin, J. L.; Song, Y. J. Med. Chem., 2013, 56, 8972; (b) Copeland,
R. A.; Solomon, M. E.; Richon, V. M. Nat. Rev. Drug Discov., 2009, 8,
724.
[11] Wang, Y. L.; Li, L. J.; Zhang, B. D.; Xing, J.; Chen, S. J.; Wan, W.;
Song, Y. K.; Jiang, H.; Jiang, H. L.; Luo, C.; Zheng, M. Y. J. Med.
Chem., 2017, 60, 2026.
[4] Basavapathruni, A.; Jin, L.; Daigle, S. R.; Majer, C. R.; Therkelsen, C.
A.; Wigle, T. J.; Kuntz, K. W.; Chesworth, R.; Pollock, R. M.; Scott, M.
P. Moyer, M. P.; Richon, V. M.; Copeland, R. A.; Olhava, E. J. Chem.
Biol. Drug Des., 2012, 80, 971.
[12] (a) Kermack, W.O.; Weatherhead, A. P. J. Chem. Soc., 1939, 29, 563;
(b) Barrett, P. A.; Curd, F. H. S.; Hepworth, W. J. Chem. Soc., 1953, 1,
50.
[13] (a) Glide, version 6.9, Schrödinger, LLC, New York, NY, 2015; (b)
Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.;
Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K.;
Shaw, D. E.; Francis, P.; Shenkin, P. S. J. Med. Chem., 2004, 47, 1739;
(c) Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.;
Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T. J.
Med. Chem., 2006, 49, 6177; (d) Halgren, T. A.; Murphy, R. B.;
Friesner, R. A.; Beard, H. S.; Frye, L. L.; Pollard, W. T.; Banks, J. L. J.
Med. Chem., 2004, 47, 1750.
[5] (a) Daigle, S. R.; Olhava, E. J.; Therkelsen, C. A.; Majer, C. R.;
Sneeringer, C. J.; Song, J.; Johnston, L. D.; Scott, M. P.; Smith, J. J.;
Xiao, Y.; Jin, L.; Kuntz, K. W.; Chesworth, R.; Moyer, M. P.; Bernt, K.
M.; Tseng, J. C.; Kung, A. L.; Copeland, R. A.; Richon, V. M.; Pollock,
R. M. Cancer Cell, 2011, 20, 53; (b) Stein, E. M.; Garcia-Manero, G.;
Rizzieri, D. A.; Savona, M.; Tibes, R.; Altman, J. K.; Jongen-Lavrencic,
M.; Dohner, H.; Armstrong, S.; Pollock, R. M.; Waters, N. J.; Legler,
M.; Thomson, B.; Daigle, S.; McDonald, A.; Campbell, C.; Olhava, E.;
Hedrick, E. E.; Lowenberg, B.; Copeland, R. A.; Tallman, M. S. Blood,
2014, 124, 387.
[14] Maestro, version 10.4, Schrödinger, LLC, New York, NY, 2015.
[6] (a) Yao, Y.; Chen, P.; Diao, J.; Cheng, G.; Deng, L.; Anglin, J. L.; Prasad,
B. V.; Song, Y. J. Am. Chem. Soc., 2011, 133, 16746; (b) Anglin, J. L.;
Deng, L.; Yao, Y.; Cai, G.; Liu, Z.; Jiang, H.; Cheng, G.; Chen, P.; Dong,
S.; Song, Y. J. Med. Chem., 2012, 55, 8066.
[15] Wang, C.; Jiang, H.; Jin, J.; Xie, Y.; Chen, Z.; Zhang, H.; Lian, F.; Liu,
Y. C.; Zhang, C.; Ding, H.; Chen, S.; Zhang, N.; Zhang, Y.; Jiang, H.;
Chen, K.; Ye, F.; Yao, Z.; Luo, C. J. Med. Chem., 2017, 60, 8888.

Graphical abstract

Highlights
> Novel pyrimidylaminoquinoline derivatives containing amino side chain were
synthesized.
> Most of the compounds showed strong Dot1L inhibitory activities and binding
interactions.
> Compounds 3e, 8h and 9e binds at the SAM binding pocket of DOT1L by molecular
docking.
> Compounds 8h and 9e showed significant activities against leukemia cells.
> The amino side chain was of benefit to their anti leukemia cells activities.