Tranylcypromine and 6-trifluoroethyl thienopyrimidine hybrid as LSD1 inhibitor

Article abstract of DOI:10.1016/j.bmcl.2019.01.017

Tranylcypromine moiety extracted from LSD1 inhibitors and 6-trifluoroethyl thienopyrimidine moiety from menin-MLL1 PPI inhibitors were merged to give new chemotypes for medicinal chemistry study. Among 15 new compounds prepared in this work, some exhibited nanomolar LSD1 activity and good selectivity over MAO-A/B, low micromolar menin-MLL1 PPI inhibitory activity, as well as submicromolar MV4-11 antiprofilative activities. Intracellular LSD1 engagement of compounds with higher enzymatic and antiproliferative activities was confirmed by CD86 mRNA up-regulation experiments.

Full text of DOI:10.1016/j.bmcl.2019.01.017

Accepted Manuscript
Tranylcypromine and 6-trifluoroethyl thienopyrimidine hybrid as LSD1 inhib-
itor
Xiaowen Wang, Mingbo Su, You Li, Tongchao Liu, Yujie Wang, Yabing Chen,
Le Tang, Yu-Peng He, Xiaoguang Ding, Fang Yu, Jingkang Shen, Jia Li, Yubo
Zhou, Yue-Lei Chen, Bing Xiong
PII:
S0960-894X(19)30027-7
https://doi.org/10.1016/j.bmcl.2019.01.017
BMCL 26254
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 October 2018
27 December 2018
16 January 2019
Please cite this article as: Wang, X., Su, M., Li, Y., Liu, T., Wang, Y., Chen, Y., Tang, L., He, Y-P., Ding, X., Yu,
F., Shen, J., Li, J., Zhou, Y., Chen, Y-L., Xiong, B., Tranylcypromine and 6-trifluoroethyl thienopyrimidine hybrid
as LSD1 inhibitor, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.
2019.01.017
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.
Tranylcypromine and 6-trifluoroethyl
thienopyrimidine hybrid as LSD1 inhibitor
Xiaowen Wang, Mingbo Su, You Li, Tongchao Liu, Yujie Wang, Yabing Chen, Le Tang, Yu-Peng He, Xiaoguang Ding,
Fang Yu, Jingkang Shen, Jia Li, Yubo Zhou, Yue-Lei Chen and Bing Xiong
N
CF3
N
S
CF3
S
menin-MLL1 PPI inhibitor pharmacophore
N
N
LSD1 inhibitor pharmacophore
NH
N
n
n
LSD1 inhibitory IC50 up to 66.13±6.58 nM;
HN
HN
menin-MLL1 PPI inhibitory IC50 up to 2.13±0.86 μM;
MV4-11 antiproliferative IC50 up to 0.29±0.11 μM.
(MV4-11 antiproliferative IC50 of GSK2879552: 1.16±0.14 μM)

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Tranylcypromine and 6-trifluoroethyl thienopyrimidine hybrid as LSD1
inhibitor
Xiaowen Wanga,b, Mingbo Suc,f, You Lib,d, Tongchao Liub,e, Yujie Wangc,f, Yabing Chenb, Le Tangb, Yu-
Peng He a, Xiaoguang Dinga, Fang Yu,a,* Jingkang Shenb,f, Jia Lic,f, Yubo Zhou c,f,*, Yue-Lei Chenb,f,  and
Bing Xiongb,f,*
a College of Chemistry, Chemical Engineering and Environmental Engineering, Liaoning Shihua University, Dandong Lu West 1, Fushun 113001, P. R. China.
bState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203; P. R.
China.
cThe National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, P. R. China
d School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P. R. China.
e Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang
110016, P. R. China.
fUniversity of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, P. R. China.
———
ARTICLE INFO
ABSTRACT
 Corresponding author. E-mail: F. Y.: fang.yu@lnpu.edu.cn; Y. Z.: ybzhou@simm.ac.cn; Y.-L. C.: chenyuelei@gmail.com; B. X.:
bxiong@simm.ac.cn.
Article history:
Received
Revised
Accepted
Tranylcypromine moiety extracted from LSD1 inhibitors and 6-trifluoroethyl thienopyrimidine
moiety from menin-MLL1 PPI inhibitors were merged to give new chemotypes for medicinal
chemistry study. Among 15 new compounds prepared in this work, some exhibited nanomolar
LSD1 activity and good selectivity over MAO-A/B, low micromolar menin-MLL1 PPI
inhibitory activity, as well as submicromolar MV4-11 antiprofilative activities. Intracellular
LSD1 engagement of compounds with higher enzymatic and antiproliferative activities was
confirmed by CD86 mRNA up-regulation experiments.
Available online
Keywords:
LSD1 inhibitor
tranylcypromine
2009 Elsevier Ltd. All rights reserved.
menin-MLL1 protein-protein interaction inhibitor
MV4-11 antiproliferative activity
structure activity relationship
LSD1 emerges as an important therapeutic target against
certain cancer and nervous system diseases.1 Some LSD1
inhibitors demonstrated substantial therapeutic value and have
been advanced into phase 2 clinical study.2 Most of these clinical
drugs bear tranylcypromine (TCP, 1) structure as key
and the binding energies were scored for each. It was found that
PRMT5 inhibitor pharmacophore was the best (Glide score -5.59
kcal) and the menin-MLL1 PPI inhibitor pharmcophore ranks
second (Glide score -5.09 kcal). 7
OH
O
O
O
O
O
HN
N
NH
NH
N
pharmacophore, which irreversibly binds to flavin adenine
N
H2N
1c
N
N
dinucleotide (FAD) moiety sat in LSD1 catalytic cavity.
A
1
2
N
4
3
large body of SAR study indicated that TCP-containing LSD1
inhibitors tolerate wide variety of structure modification on the
amino group side. 1
tranylcypromine pharmacophore adapted pharmacophore adapted
pharmacophore adapted
from EZH2 inihibitors
(racemic)
from G9a inihibitors
from KDM4 inihibitors
N
N
O
CF3
S
N
N
OH
Meanwhile,
LSD1
inhibitors
showed
synergistic
NH
NH
7
5
6
pharmacophore adapted
from PRMT5 inihibitors
pharmacophore adapted from
Menin-MLL1 PPI inihibitors
pharmacophore adapted
from BRD4 inihibitors
antiproliferative effect with inhibition of multiple epigenetic
targets, respectively.3 It is not surprising since these targets
consist of a network regulating the fate of cell. Combining above
information, we ask if new activity features could be achieved by
merging TCP structure and the key pharmacophores of inhibitors
targeting other epigenetic enzymes. 4 A pilot computational study
was made using the known pharmacophores 2~7 from G9a,1c
KDM4,1c EZH2,1c menin-MLL1 protein-protein interaction
(PPI),5 BRD4,6 and PRMT5 inhibitors1c (scheme 1), respectively.
These pharmacophores were docked into the binding site of
LSD1 prepared from the crystal structure (PDB code: 2UXX),
Scheme 1. Structure of tranylcypromine (1) and pharmacophores 2~7 used in
virtual screening.
A closer analysis of known menin-MLL1 PPI inhibitor MI-2-
25e and MI-4635b, as well as known LSD1 inhibitor ORY-10012a
and GSK-28795522b (scheme 2) indicated that the six-membered
saturated ring (scheme 2, moieties in red) could be used as a
hinge connecting the pharmacophores of menin-MLL1 PPI
inhibitor (scheme 2, moieties in green) and LSD1 inhibitor

N
N
CF3
17a
S
a
c
(scheme 2, moieties in blue). Thus, two types of new structures
(scheme 2, type-1 and type-2) were designed using hinges
containing different six-membered saturated rings. In such design,
TCP moiety should be located at the solvent-exposed region of
the menin-MLL1 interaction site, when the new inhibitor
engaged with menin-MLL1 complex. Similarly, 6-trifluoroethyl
thienopyrimidine moiety should stay outside of the enzyme
when the molecule interacts with LSD1.
b
Boc
Boc
HN
(HCl)2
N
N
N
R
R
O
R
1
2
, R = R
17b
17c
, R = R
1
2
14
1
15a
15b
15c
, R = R
16a
16b
16c
, R = R
3
, R = R
2
, R = R
, R = R
3
3
(HCl)2
, R = R
, R = R
Scheme 4. Preparation of type-1 compounds 17a, b, c. Reaction conditions: a)
9a, or 9b, or 9c, NaBH3CN, HOAc, MeOH, 0 °C, 2 h, 25-45%; b) 4 M HCl in
1,4-dioxane, DCM, RT, 2 h, 82-99%; c) Compound 12, DIPEA, water,
isopropanol, RT, 2-3 h; then DCM, 2 M HCl in ether, RT, 0.5 h, 18-55%.
HO
O
For type-2 structures, amine 18 was condensed directly with
chloride 12, which was subjected to reductive amination with 9a,
b, c to give trans-20a, b, c and cis-20a, b, c, respectively
(scheme 5).
N
N
CF3
S
NH2
N
N
HN
n
HN
N
HN
N
N
CF3
CF3
S
CF3
S
S
N
O
N
N
NH
NH
NH
a
b
+
ORY-1001
(RG-6016)
(HCl)2
(HCl)2
R
type-1
R
GSK2879552
NH3Cl
1
1
2
-20a
-20b
-20c
cis
cis
cis
, R = R
-20a
-20b
-20c
trans
, R = R
O
2
18
, R = R
trans
trans
, R = R
3
N
3
CF3
19
S
, R = R
, R = R
N
CF3
S
N
Scheme 5. Preparation of type-2 compounds trans-20a,b,c. and cis-20a,b,c.
Reaction conditions: a) Compound 12, DIPEA, water, isopropanol, 60 °C,
overnight, 68%; b) Compound 19, NaBH3CN, HOAc, MeOH, 0 °C, 2.5 h;
then DCM, 2 M HCl in ether, RT, 0.5 h, 5-54%.
N
N
S
CF3
NH
HN
N
n
N
N
N
HN
S
N
Similarly, amine 21 was condensed with chloride 12 and then
oxidized to aldehyde 23, which underwent reductive amination
with 9a, b, c to give 24a, b, c, respectively (scheme 6).
NH
NC
type-2
MI-2-2
MI-463
N
N
N
CF3
CF3
Scheme 2. Two types of new structures were designed by merging the
S
S
CF3
OH
S
tranylcypromine and 6-trifluoroethyl thienopyrimidine pharmacophores.
N
N
N
c
a
b
NH
NH
NH
1
To implement above design, 6 type-1 and 9 type-2 molecules
were prepared, subjected to biological evaluation. Several
molecules were revealed, showing good LSD1 inhibitory activity,
moderate menin-MLL1 PPI inhibitory activity, as well as
promising submicromolar antiproliferative activities. The details
will be reported herein.
24a
24b
24c
, R = R
R
NH3Cl
2
, R = R
(HCl)2
OH
O
3
22
21
23
, R = R
Scheme 6. Preparation of type-2 compounds 24a, b, c. Reaction conditions: a)
Compound 12, DIPEA, water, isopropanol, 60 °C, overnight, 72%; b) Dess-
Martin periodinane, DCM, RT, 4 h, 44%; c) 9a, or 9b, or 9c, NaBH(OAc)3,
HOAc, 4 Å molecular sieve, 1,2-dichloroethane, RT, 3 h; then DCM, 2 M
HCl in ether, RT, 0.5 h, 15-79%.
Ketone 8 was subjected to reductive amination with several
TCP derivatives including R1H (9a, 1R, 2S-isomer), R2H (9b, 1S,
2R-isomer), and R3H (9c, 1R, 2S-isomer) (scheme 3) to give
products 10a, b, c, respectively. After removal of N-Boc
protection, 11a, b, c were condensed with compound 12 to give
type-1 target products 13a, b, c, respectively.
All target products were subjected to biological evaluation and
the results were shown in table 1. Type-1 compounds 13a, b, c
showed good LSD1 inhibitory activity ranging from
211.35±27.79 nM to 692.15±126.36 nM and the selectivity over
MAO-A and MAO-B were moderate to good. Meanwhile,
compounds 13a, b showed low micromolar menin-MLL1 PPI
inhibitory activity. On MV4-11 cells, compound 13a showed
good antiproliferative activity of 0.29±0.11 μM, better than that
of MI-2-2 and GSK2879552. Compound 13b containing 1S, 2R-
TCP moiety showed decreased cellular activity, and compound
13c bearing difluorophenyl substituted TCP lost its activity on
MV4-11 for unknown reasons (table 1, entries 4~6). Type-1
compounds 17a, b, c showed improved LSD1 inhibitory activity
ranging from 61.04±9.79 nM to 252.33±75.75 nM and slightly
improved selectivity for LSD1 over MAO-A and MAO-B.
Against menin-MLL1 PPI, compounds 17a, c showed low
micromolar activity, while 17b was inactive. MV4-11 Cellular
activities were moderate for 17a,b and poor again for 17c (table 1,
entries 7~9).
N
N
R
Boc
CF3
Boc
a
S
b
c
N
N
NH
N
N
R
CF3
O
R
S
(HCl)2
N
1
1
10a
10b
10c
, R = R
8
11a
11b
11c
, R = R
12
2
Cl
2
, R = R
, R = R
(HCl)2
3
3
, R = R
, R = R
1
2
13a
13b
13c
, R = R
F
F
, R = R
H
N
H
N
H
3
N
, R = R
R1
=
R2
=
R3
=
Scheme 3. Preparation of type-1 compounds 13a,b,c. Reaction conditions: a)
R1H R-mandelate (9a), or R2H S-mandelate (9b), or R3H R-mandelate (9c),
NaBH3CN, HOAc, MeOH, 0 °C, 2 h, 30-82%; b) 4 M HCl in 1,4-dioxane,
DCM, RT, 2 h, 91-99%; c) Compound 12, DIPEA, water, isopropanol, RT, 2-
3 h; then DCM, 2 M HCl in ether, RT, 0.5 h, 58-86%.
In a similar fashion, aldehyde 14 underwent reductive
amination with 9a, b, c to give intermediates 15a, b, c,
respectively, which were again deblocked and condensed with 12
to give type-1 target products 17a, b, c, respectively (scheme 4).
Type-2 compounds trans-20a, b, c and cis-20a, b, c showed
good LSD1 activity ranging from 66.13±6.58 nM to
303.35±40.23 nM and their selectivity for LSD1 over MAO-A
and MAO-B were moderate to good. Against menin-MLL1 PPI,
cis-20c showed improved activity of 2.13±0.86 μM, trans-20a
and cis-20a, b showed low micromolar activity, while trans-20b,

a except for entry 2, all cellular activities were measured at 7th day. Cellular
activity of entry 2 was measured at 10th day.
c were inactive. For MV4-11 cellular activities, trans-20a and
cis-20c displayed submicromolar activities, while other
compounds showed low micromolar activities (table 1, entries
10~15). Type-2 compounds 24a, b, c also showed good LSD1
activity ranging from 109.35±11.67 nM to 359.7±60.95 nM and
their selectivity for LSD1 over MAO-A and MAO-B were
moderate to good. Perhaps due to the longer hinge moiety, 24a, b,
c showed significantly decreased menin-MLL1 PPI inhibitory
activities. Their cellular activity remained at low micromolar,
largely caused by the LSD1 activities (table 1, entries 16~18).
Since CD86 up-regulation serves as a surrogate cellular
biomarker for LSD1 pharmacological inhibition,8 LSD1
inhibition effect of type-1 compound 13a as well as type-2
compounds trans-20a and cis-20c was further evaluated for their
CD86 mRNA expression enhancement in MV-4-11 cells (table 2).
Compared with GSK2879552, our compounds showed more
potential to induce the CD86 mRNA expression, consistent with
their enzymatic and cellular activities.
Table 1. Type-1 and type-2 compounds were assayed for their enzymatic and
cellular activity, in comparison with positive controls.
Table 2. CD86 mRNA expression analysis of selected compounds.
menin-
MLL1 PPI
inhibitory
activity
(IC50)
118.30±4.5
3 nM
MV4-11
antiprolif
erative
activity
(IC50) a
2.60±0.2
1 μM
LSD1
inhibitory
activity
(IC50)
MAO-A/B
inhibitory
activity
Entry
Compound
CD86 expression fold on MV-4-11 a (IC50)
No.
compd.
MI-2-2
1
2
3
4
GSK2879552
13a
15.22±1.44 @ 1000 nM
22.32±0.41 @ 500 nM
16.39±0.78 @ 500 nM
7.59±0.74 @ 100 nM
(IC50)
trans-20a
cis-20c
1
2
n.a.
n.a.
GSK287
9552
Tranylcy
promine
(1)
1200.00±
33.94 nM
>100 /
>100 μM
1.02±0.10 /
0.56±0.13
μM
12.46±3.40
/
40.25±11.7
5 μM
8.27±2.92 /
36.70±13.6
9 μM
56.44±6.86
/
1.16±0.1
4 μM
a Q-PCR measurements were performed in triplicate.
n.a.
21.85±3.
19 μM
> 100
μM
According to above results, on biochemical assays, 1R, 2S-
TCP, 1S, 2R-TCP, and 1R, 2S-difluorophenyl cyclopropanamine
derivatives showed no significant difference in terms of their
LSD1 inhibitory activities. Incorporation of 6-trifluoroethyl
thienopyrimidine moiety resulted in higher LSD1 inhibitory
activity compared with GSK2879552. With 6-trifluoroethyl
thienopyrimidine, the selectivity over MAO-A/B was also
improved compared with that of tranylcypromine (1).
Nevertheless, the menin-MLL1 PPI inhibitory activity of new
compounds was compromised and only low micromolar value
could be recorded. At cellular level, 1R, 2S-TCP and 1S, 2R-TCP
derivatives showed also no major difference in their
antiproliferative activities. For several cases, 1R, 2S-
difluorophenyl cyclopropanamine derivatives showed no cellular
activities, although they have similar physicochemical properties
to other analogues. The antiproliferative effect of above new
compounds is not likely caused by synergistic effect due to the
low menin-MLL1 PPI inhibitory activity. Meanwhile, for
compounds showing higher enzymatic and antiproliferative
activities, their LSD1 target engagement in MV4-11 cell was
further confirmed by CD86 mRNA up-regulation experiments.
3
4
5
6
n.a.
211.35±2
7.79 nM
10.24±4.30
0.29±0.1
1 μM
13a
13b
13c
μM
692.15±1
26.36 nM
34.54±5.18
7.31±0.0
9 μM
μM
240.50±3
4.08 nM
> 100
μM
> 100 μM
95.61±20.0
7 μM
2.23±0.22 /
1.16±0.21
μM
9.19±1.39 /
9.63±1.16
μM
84.38±6.
34 nM
17.33±3.25
11.36±0.
53 μM
7
8
17a
17b
μM
61.04±9.
79 nM
5.97±1.4
2 μM
> 100 μM
20.79±7.02
/
49.51±9.79
μM
252.33±7
5.75 nM
30.94±17.7
1 μM
> 100
μM
9
17c
65.88±12.6
6 / >100
μM
4.55±1.33 /
6.05±0.91
μM
trans-
20a
303.35±4
0.23 nM
36.93±14.0
5 μM
0.49±0.1
9 μM
10
11
In summary, we have merged TCP moiety from LSD1
inhibitors and 6-trifluoroethyl thienopyrimidine moiety from
menin-MLL1 PPI inhibitors to create new chemotypes showing
good LSD1 activity and selectivity over MAO-A/B, moderate
menin-MLL1 PPI inhibitory activity, as well as moderate to good
MV4-11 antiprofilative activities. In particular, compounds 13a,
trans-20a, and cis-20c demonstrated promising submicromolar
cellular activity, several folds higher than that of MI-2-2 and
GSK2870552 and could be used for further medicinal chemistry
study.
124.05±1
5.49 nM
50.75±21.4
0 μM
2.49±0.1
7 μM
cis-20a
12.89±6.81
/
28.77±4.84
μM
>100 /
75.63±23.4
3 μM
47.47±5.76
/
71.61±24.4
9 μM
trans-
20b
187.00±1
4.00 nM
3.60±0.3
3 μM
12
13
14
> 100 μM
241.95±2
7.22 nM
24.73±4.49
3.42±0.3
7 μM
cis-20b
μM
trans-
20c
146.35±3
1.61 nM
2.01±0.3
7 μM
> 100 μM
Acknowledgements
40.86±17.0
9 /
1.21±0.12
μM
4.10±0.65 /
4.81±0.27
μM
8.57±2.29 /
21.98±0.57
μM
66.13±6.
58 nM
2.13±0.86
0.51±0.1
6 μM
This work was supported by the National Natural Science
Foundation of China (21877121, 81673309, 81330076,
81703544), National Science & Technology Major Project “Key
New Drug Creation and Manufacturing Program”, China
(2014ZX09507-002). We are grateful to the Foundation of
Liaoning Science and Technology Agency (Grant No.
20180550899) for the financial support.
15
cis-20c
μM
109.35±1
1.67 nM
2.96±0.1
9 μM
16
17
24a
24b
>100 μM
> 100 μM
184.15±2
2.56 nM
5.55±0.9
0 μM
20.99±2.84
/
20.35±0.64
μM
Supplementary data
359.7±60
.95 nM
6.96±0.5
1 μM
18
24c
> 100 μM

1
Experimental procedures as well as copies of the H NMR
and 13C NMR spectra of new compounds are provided.
References and notes
1.
(a) Przespolewski A, Wang E. Expert Opin Inv Drug.
2016;25:771-780.
(b) Fu X, Zhang P, Yu B. Future Med Chem. 2017;9:1227-1242.
(c) Kaniskan HÜ, Martini ML, Jin J. Chem Rev. 2018;118:989-
1068 and references therein.
(d) Castelli G, Pelosi E, Testa U. Oncotargets Ther. 2018;11:131-
155.
(e) Ji Y.-Y., Lin S.-D., Wang Y.-J. Eur
J Med Chem.
2017;141:101-112.
2.
3.
(a) Maes T, Mascaró C, Tirapu I. Cancer Cell. 2018;33:495-511
(b) Mohammad H. P, Smitheman K. N, Kamat C. D. Cancer Cell.
2015;28:57-69.
(a) Haydn T, Metzger E, Schuele R. Cell Death Dis. 2017;8:
e2879.
(b) Feng Z, Yao Y, Zhou C. J Hematol Oncol. 2016;9:24.
https://doi.org/10.1186/s13045-016-0252-7.
(c) Han H, Yang X, Pandiyan K. Plos One. 2013;8:e75136.
(d) Ellis L, Atadja P W, Johnstone R W. Mol Cancer Ther. 2009;
8:1409-1420.
4.
5.
(a) de Lera A R, Ganesan A. Clin Epigenetics. 2016;8:105.
https://doi.org/10.1186/s13148-016-0271-9.
(b) Ganesan. ChemMedChem. 2018;11:1227-1241.
(c) Kalin J H, Wu M, Gomez A V. Nat Commun. 2018;9:53. DOI:
10.1038/s41467-017-02242-4.
(a) Wang Z H, Li D D, Chen W L. Bioorganic Med Chem.
2018;26:356-365.
(b) Borkin D, Klossowski S, Pollock J.
2018;61:4832-4850.
J Med Chem.
(c) Xu S, Aguilar A, Xu T. Angew Chem Int Edit. 2018;57:1601-
1605.
(d) Ren J, Xu W, Tang L. Bioorg Med Chem Lett. 2016;26:4472-
4476.
(e) Shi A., Murai M. J., He, S. Blood 2012;120;23:4461-4469.
(a) Zhao L, Wang Y, Cao D. J Med Chem. 2015;58:281-1297.
(b) Liu Z, Wang P, Chen H. J Med Chem. 2017;60:4533-4558.
(c) Huang W, Zheng X, Yang Y. Mini-Rev Med Chem.
2016;16:1403-1414.
6.
7.
8.
See supplementary data for details.
James T, Mark J, James R. Analytical Biochemistry. 2013; 442:
104–106.