Scaffold Hopping-Driven Optimization of 4-(Quinazolin-4-yl)-3,4-dihydroquinoxalin-2(1 H)-ones as Novel Tubulin Inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.9b00352

Scaffold hopping-driven lead optimizations were performed based on our prior lead 7-methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (2a) by C-ring expansion and isometric replacement of the A/B-ring, successively, aimed at finding new potential alternative drug candidates with different scaffold(s), high antitumor activity, and other improved properties to replace prior, once promising drug candidates that failed in further studies. Two series of new compounds 7 (a-d) and 13 (a-j) were synthesized and evaluated for antitumor activity, leading to the discovery of three highly potent compounds 13c, 13d, and 13e with different scaffolds. They exhibited similar high antitumor activity with single digital low nanomolar GI₅₀ values (4.6-9.6 nM) in cellular assays, comparable to lead 2a, clinical drug candidate CA-4, and paclitaxel in the same assays. Further biological evaluations identified new active compounds as tubulin polymerization inhibitors targeting the colchicine binding site. Moreover, 13d showed better aqueous solubility than 2a and a similar log P value.

Full text of DOI:10.1021/acsmedchemlett.9b00352

Note
pubs.acs.org/acsmedchemlett
Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Scaffold Hopping-Driven Optimization of 4‑(Quinazolin-4-yl)-3,4-
dihydroquinoxalin-2(1H)‑ones as Novel Tubulin Inhibitors
Li Jiang,† Masuo Goto,‡ Dong-Qing Zhu,† Pei-Ling Hsu,‡ Kang-Po Li,‡ Mutian Cui,† Xiaoyang He,§
Susan Lynne Morris-Natschke,‡ Kuo-Hsiung Lee,*,‡,∥ and Lan Xie*,†,‡
†Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
‡Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North
Carolina 27599, United States
§Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, China
∥Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan
S
* Supporting Information
ABSTRACT: Scaffold hopping-driven lead optimizations
were performed based on our prior lead 7-methoxy-4-(2-
methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one
(2a) by C-ring expansion and isometric replacement of the A/
B-ring, successively, aimed at finding new potential alternative
drug candidates with different scaffold(s), high antitumor
activity, and other improved properties to replace prior, once
promising drug candidates that failed in further studies. Two
series of new compounds 7 (a−d) and 13 (a−j) were
synthesized and evaluated for antitumor activity, leading to the
discovery of three highly potent compounds 13c, 13d, and
13e with different scaffolds. They exhibited similar high
antitumor activity with single digital low nanomolar GI50 values (4.6−9.6 nM) in cellular assays, comparable to lead 2a, clinical
drug candidate CA-4, and paclitaxel in the same assays. Further biological evaluations identified new active compounds as
tubulin polymerization inhibitors targeting the colchicine binding site. Moreover, 13d showed better aqueous solubility than 2a
and a similar log P value.
KEYWORDS: Tubulin polymerization inhibitors, scaffold hopping, lead optimization, N-aryl-3,4-dihydroquinoxalin-2(1H)-ones,
colchicine binding site
polymerization inhibitors with novel structures or unique
uring the past decade, numerous small molecules
Dtargeting the tubulin colchicine site (CS) have been binding to the colchicine site should continue to determine the
intensely investigated.1,2 The natural tubulin inhibitor
optimal drug candidates.
In our prior studies on novel antitumor agents (Figure 2),
two series of lead compounds N-aryl-1,2,3,4-tetrahydronquio-
lines (1)5,6 and 4-(quinazolin-4-yl)-3,4-dihydroquinoxalin-
2(1H)-ones (2)7 were successively discovered and identified
as novel classes of tubulin polymerization inhibitors. Both
series of leads showed high cytotoxicity in human tumor cells
and inhibitory activity in tubulin assembly and colchicine
binding assays. However, the 2-series leads generally showed
higher antitumor activity than corresponding 1-series com-
pounds. For example, 2a exhibited low nanomolar GI50 values
of 1.9−3.2 nM against several human tumor cell lines and a
low submicromolar IC50 value of 0.77 μM to inhibit tubulin
polymerization; it was more potent than corresponding 1a
(GI50 11−18 nM and IC50 1.0 μM, respectively) as well as
combretastatin A-4 (CA-4) and its phosphate prodrug CA-
4P (Figure 1) have been advanced in clinical trials for cancer
therapies,3,4 such as anaplastic thyroid cancer, ovarian cancer,
and nonsmall cellular lung cancer (NSCLC), but so far, neither
compound has been approved as a new drug by the FDA.
Therefore, the discovery and development of new tubulin
Received: July 31, 2019
Accepted: December 16, 2019
Figure 1. Colchicine, CA-4, and related clinical trial drug candidates.
© XXXX American Chemical Society
A
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Figure 2. Prior leads 1 and 2 and current scaffold-hopping optimization strategies.
a
Scheme 1. Preparation of 7a−c
a
(i) i-PrOH, HCl, rt, 1 h; (ii) H2, Pd/C, EtOH/EtOAc, 50 psi, 2 h; (iii) carbonyl chloride, acetone, K2CO3, −5 °C−rt, 1 h; (iv) DMA, K2CO3, rt
or 100 °C, 1 h; (v) 2-chloroethylamine, 1,1′-carbonyldiimidazole, Et3N, THF, rt, 3 h.
positive control drug paclitaxel in the same assays. Further
biologic studies indicated that active 2a8 possesses high
antitumor potency in vivo, extremely high antiproliferative
activity in the NIH-NCI 60 human tumor cell line panel with
low to subnanomolar GI50 values, and desirable drug-like
properties. Mechanism studies identified 2a as a novel tumor-
VDA targeting the tubulin-colchicine binding site. Therefore,
compound 2a served as a promising drug candidate for further
development. Meanwhile, our prior iterativite lead optimiza-
tions also revealed some structure−activity relationships
(SARs) and correlative structure−property relationships
(SPRs) of lead 1- and 2-series. Their scaffold structures
include a fused aromatic heterocycle (A/B-ring), a p-
methoxyphenyl ring (D-ring), and a cyclic N-linker built as a
C-ring to connect two aryl rings (A/B and D). In comparison,
the lactam C-ring in the 2-series is preferred compared to the
tetrahydropyridine C-ring in the 1-series for enhanced
antitumor activity, and a 10-membered aromatic heterocycle
(such as quinazoline) is a favorable moiety compared with
pyridinyl, purinyl, naphthalenyl, and isoquinolinyl moieties. In
addition, the methoxy group on the phenyl ring (D-ring) is
necessary for antitumor activity, whereas the 2-substituent on
the A-ring could alter the antitumor activity and improve drug-
like properties.
driven lead opitimation based on lead 2a was recently carried
out to explore the effects of the core structure on antitumor
activity and possibly find new compounds with different
scaffold(s) and high antitumor activity as new alternative drug
candidates to replace once promising drug candidates that
failed in further studies. Our scaffold-hopping strategies
(Figure 2) focused successively on expansion of the C-ring,
isometric replacement of the A/B ring, and introduction of
additional substituents on the B-ring. The new compounds
were tested for antiproliferative activity in a human tumor cell
line (HTCL) panel, including A549 (lung carcinoma), MDA-
MB-231 (triple-negative breast cancer), KB (identical to AV-3
as a cervical carcinoma HeLa derivative), multidrug-resistant
(MDR) KB subline KB-VIN, and MCF-7 (estrogen receptor-
positive breast cancer). Furthermore, we were also interested
in determining whether new active compounds obtained from
scaffold hopping and prior lead 2a share the same mechanism
of action. Subsequently, new active compounds were selected
for additional cell-based biological evaluations, such as impacts
on cell cycle progression and microtubule formation. Thus,
recent results about two series of new compounds 7 and 13 are
reported herein, including chemical synthesis, antitumor
activity in vitro, target identification, molecular modeling
elucidation, and SAR analysis.
As a part of our systematic lead optimizations to
Based on the structure of lead 2a, we first tried to expand the
complement prior structural optimizations, scaffold hopping-
lactam ring (C-ring) to investigate the effects of the lactam ring
B
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Table 1. Antiproliferative Activities of New Compounds 7a−7d in a Human Tumor Cell Line (HTCL) Panel
a
GI50 (nM) SD
Compound
n
A549
2
5,900 160
>10,000
>2,000
3.2 0.7
5.5 0.1
MDA-MB-231
KB
KB-VIN
MCF-7
7a
7b
7c
7d
2
3
4
2
1
838
95 37
9,700 1300
>10,000
725 22
5,700 100
>10,000
>2,000
2.3 0.5
3.6 0.8
696 39
5,556 95
>10,000
>2,000
2.2 0.4
3.8 1.1
933 10
10,500 600
>10,000
>2,000
>2,000
b
c
2a
NT
NT
d
CA-4
8.2 0.0
84
8
a
The GI50 values are the concentrations corresponding to 50% cell growth inhibition and are expressed as the mean SD from the dose−response
b
c
d
curves of at least three independent experiments. Data published in ref 10. NT: not tested. Combretastatin A4 (CA-4) served as positive control
in the same assays.
a
Scheme 2. Preparation of 13a−j
a
(i) i-PrOH, HCl, or H2SO4, rt−70 °C, 1 h−overnight; (ii) (a) Zn/CH3COOH, CH2Cl2, −5 °C; (b) 2-chloroacetyl chloride, acetone, K2CO3, −5
°C; (iii) DMA, K2CO3, rt, overnight or 100 °C for 1 h; (iv) see Supporting Information.
size on antitumor activity. With one, two, or three methylene
(CH2) units inserted into the C-ring, related compounds 7a−c
have an expanded 7-, 8-, or 9-membered lactam ring,
respectively, whereas the amide group remains the same as
in 2a. To compare the effect as a different amide type on the
molecular activity, compound 7d was designed with a reversed
amide group in a 7-membered lactam ring. As depicted in
Scheme 1, compounds 7a−c were prepared from the
intermediate 510 by a three-step reaction sequence: reduction
of the nitro group by hydrogenation with Pd/C, acylation with
3-chloropropionyl chloride, 4-chlorobutyryl chloride, or 5-
chlorovaleroyl chloride to produce corresponding amide
compounds 6a−c, respectively, and subsequent intramolecular
cyclization in N,N-dimethylacetamide (DMA) in the presence
of K2CO3. The 7-membered lactam ring closure (7a)
proceeded easily at room temperature, while the 8-membered
(7b) and 9-membered (7c) ring closures required heating at
100 °C. In contrast, 7d was prepared by treating commercially
available 2-amino-5-methoxy benzoic acid (4b) with 2-
chloroethylamine to form amide 8, followed successively by
a coupling reaction with 4-chloro-2-methylquinazole (3) and
then the intramolecular cyclization described above.
The new 7-series compounds were evaluated for anti-
proliferative activity in cellular assays against a HTCL panel as
mentioned above in parallel with CA-4 as an experimental
control. Their biologic activity in the cellular assay was
determined by using the established sulforhidamine B (SRB)
method as GI50 values and related data are summarized in
Table 1. As the lactam size expanded from seven to eight to
nine atoms (7a → 7b → 7c), the activity decreased.
Compound 7a displayed sub-μM GI50 values (0.69−0.93
μM), 7b showed around 8-fold lower activity (GI50 5.5−10.5
μM) than 7a, and 7c was inactive with GI50 values greater than
10 μM. Also, compound 7d with a reversed amide group was
much less potent (GI50 > 2 μM) than 7a, although both
compounds have a 7-membered lactam ring. Finally, compared
with the highly potent lead 2a (GI50 2.2−3.5 nM), all four new
compounds with expanded lactam rings were less active. Thus,
expansion of the 6-membered lactam C-ring decreased or
abolished the molecular antitumor activity.
C
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Table 2. Antiproliferative Activities of New Compounds 13a−j against Human Tumor Cell Lines
To better understand how different lactam ring size could
affect the cytotoxic activity, a molecular modeling study was
conducted by using the CDOCKER program in the Discovery
Studio 3.0 software and the tubulin crystal structure (PDB
code 1SA0).9,10 The lead compound 2a, which acts as a tubulin
polymerization inhibitor binding at the colchicine binding site,
and less active 7a were docked into the colchicine binding
pocket on tubulin, and both compounds were superimposed
with the original ligand DAMA-colchicine (Figure 1). The
results (figure in the Supporting Information) indicated that
the aromatic rings of the three compounds superimposed well
in the binding site, but in contrast to 2a, the less active
compound 7a (green stick) assumed a reversed orientation in
the same binding pocket. Thus, an interaction with the key
amino acid βCys241 was lost, which likely decreased affinity
with the biological target. However, H-bonds were present
D
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Figure 3. Effects of compounds on cell cycle. MDA-MB-231 cells were treated for 24 h with vehicle (CTRL) or with the indicated compound at
the concentration of 3 × IC50 values. DMSO was used as control. EtOH-fixed cells were stained with propidium iodide (PI) in the presence of
RNase. PI-stained cells were analyzed by flow cytometer. The Y-axis represents the cell count, and the X-axis represents PI fluorescence on a linear
scale.
between the carbonyl and NH in the lactam of 7a with
αSer178 and αThr179, respectively, at the colchicine binding
site of tubulin, like those formed by the side chain at the 7-
position on the B-ring of DAMA-colchicine. Moreover, we
tried to dock 7b into the colchicine-binding site but were
unsuccessful using the same method under the same
conditions. We postulated that a molecule with a large lactam
ring containing more than six atoms might be too bulky to
anchor into the colchicine-binding pocket due to twist
conformation(s) of the C-ring. These modeling results
supported our biological data and also confirmed our previous
result that the six-membered lactam ring (C-ring) in 2 with a
rigid planar conformation is very crucial for high antitumor
activity.
Next, our scaffold hopping turned to isometric replacement
of the A/B ring moiety (quinazoline), while the lactam C-ring
in 2a was maintained, to investigate how A/B ring alterations
as well as their substituents affected antitumor activity. We
replaced the quinazoline with fused aromatic heterocycles with
the same size and same topological shape but more or fewer
nitrogen atoms, pyrido[2,3-d]pyrimidine (a), pyrido[3,4-b]-
pyrazine (b), 2-chloropyrido[3,2-d]pyrimidine (c), 2-methyl-
quinoline (d), and multisubstituted quinazoline (e and f) (see
Scheme 2). The new 4-aryl-7-methoxy-3,4-dihydroquinoxalin-
2(1H)-ones (13a−j) were synthesized based on our previous
synthetic methods as shown in Scheme 2. Aryl chloride
reagents 10a−f, either easily synthesized (10a−b) or
commercially available (10c−f), were individually coupled
with 4-methoxy-2-nitroaniline (4a) in the presence of a
catalytic amount of HCl or H2SO4 to afford corresponding
N-aryl-4-methoxy-2-nitroanilines 11a−f, respectively. The
nitro group of 11 was reduced by reaction with mild reagent
zinc dust in acetic acid at room temperature. Without further
purification, the intermediate amines were immediately treated
with 2-chloroacetyl chloride to provide corresponding amides
12. Next, an intramolecular cyclization of 12 produced
corresponding target compounds 13a−f with various aromatic
A/B-heterocyclic ring moieties. However, reduction of 11b
generated two products in a ratio of 4:1; one compound was
the expected amine product (only nitro group reduced), and
the other compound was an over-reduced amine-1,4-
dihydropyrazine byproduct (both nitro group and pyrazine
(B ring) reduced). The ultimate products 13b and 13g were
separated after the following amidation and cyclization steps.
Moreover, several multisubstituted quinazoline derivatives
13h, 13i, and 13j were prepared from 13f by converting the
2-chloro on the quinazoline to a 2-methoxy, methylamino, or
2-(3-hydroxypropyl)amino group, respectively. All synthesized
1
new compounds were identified by H NMR and MS spectra.
New compounds 13a−j exhibited a broad range of
antiproliferative potency in the same cellular assays; the data
are shown in Table 2. Although they have different A/B
moieties, the most active compounds 13c (nitrogen at C-1, -3,
-5), 13d (nitrogen at C-1), and 13e (nitrogen at C-1, -3)
showed similar high antiproliferative activities with low single
digit nM IC50 values (4.6−9.6 nM) in the tested HTCL panel,
comparable to those of prior lead 2a, CA-4, and paclitaxel in
the same assays, thus indicating that the A/B-ring system is
changeable and favorable bioisosteres include 2-chloropyrido-
[3,2-d]pyrimidine, 2-methylquinoline, and 6-bromoquinazo-
line moieties. However, compounds 13a (nitrogen at C-1, -3,
-8) (GI50 0.48−2.29 μM) and 13b (nitrogen at C-3, -5, -8)
(GI50 0.61−0.92 μM) displayed 100-fold lower potency than
13c, even though each compound contains three N atoms
within the A/B system. Therefore, we hypothesize that the
molecular activity might be dependent on the N atom position
and the nature of the aromatic heterocycle (A/B ring system).
Notably, 13g with a 1,4-dihydropyrido[3,4-b]pyrazine was
inactive (GI50 > 40 μM) in the cellular assays; thus, the loss of
the aromatic character in the B-ring resulted in complete loss
of molecular antitumor activity. Among several 6,7-dimethox-
yquinazoline analogues, 2-chloro substituted 13f and 2-
methylamino substituted 13i exhibited moderate antitumor
activity with GI50 values of 45−82 nM and 51−84 nM,
respectively, except 13i was less active against paclitaxel-
resistant KBvin cells (GI50 507 nM). Otherwise, derivatives
13h with a 2-methoxy group and 13j with a longer side chain
at the 2-position showed reduced potency (GI50 0.5−1.0 μM).
The results from 13e−f and 13h−j confirmed our prior results
that the type of 2-substituent on the A-ring of the quinazoline
is related to the molecular antitumor activity. In addition,
certain substituents on the B-ring of the quinazoline are
E
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Note
Figure 4. Effect of 13d on microtubule formation. MDA-MB-231 cells were treated with compound 13d for 24 h at the concentration of 3 × IC50
values. DMSO or CS agent CA-4 was used as negative control or tubulin polymerization inhibitor, respectively. Cells were fixed in 4% PFA/PBS
followed by labeling with antibody to α-tubulin (green) and DAPI (blue) for DNA. Stained cells were observed by confocal fluorescence
microscopy, and images were represented as a projection of 15−20 confocal images.
tolerated and, thus, modifiable chemical space is available on
the B-ring for further optimizations to improve drug-like
properties without loss of potency.
noxalin-2(1H)-ones (13a−j). Fourteen compounds were
designed, synthesized, and evaluated for antitumor activity in
cellular assays. Three new compounds 13c, 13d, and 13e with
different scaffolds displayed extremely high antiproliferative
activity with low single digit nanomolar GI50 values ranging
from 4.6 to 9.4 nM, comparable to those of prior lead 2a, the
clinical drug candidate CA-4, and paclitaxel in the same cellular
assays. These three compounds were also efficient against
paclitaxel-resistant KBvin cell growth with at least 340-fold
higher potency than paclitaxel (1.96 μM). Based on further
biological evaluations, such as the induction of cell cycle arrest
at G2/M by inhibiting tubulin polymerization and immuno-
fluorescence, we concluded that our new active compounds
reported herein are CS agents. Current SAR studies revealed
that (1) the six-membered lactam ring (C-ring) is a very
crucial core-structure for highly potent antitumor activity,
because its expansion substantially decreased antitumor
potency; (2) aromatic heterocycles pyrido[3,2-d]pyrimidine,
quinoline, and quinazoline are bioisoteres that are replaceable
as the A/B ring system for high potency; (3) molecular
antitumor activity is dependent on the nature of isometric A/B
heterocycles, such as size, topologic shape, and the N-atom(s)
position regardless of the numbers of N-atoms; and (4)
introducing additional substituents on the B-ring, like the 6-
and 6,7-positions of the quinazoline, can be tolerated to
potentially improve drug-like properties. Additionally, drug-like
property assessments indicated that the new active compound
13d has improved aqueous solubility and a similar log P value
compared with 2a. Therefore, these new-scaffold lead
To identify the action mechanism of new active compounds,
selected compounds 7a, 13a, 13c−f, and 13h−i were further
investigated for effects on cell cycle progression in MDA-MB-
231 cells11 in parallel with CA-4, a known tubulin polymer-
ization inhibitor arresting cells in G2/M phase. As shown in
Figure 3, the assay results demonstrated that all compounds
induced cell cycle arrest in G2/M, like CA-4 as well as our
previously reported CS agents. Thus, the new compounds
most likely also target tubulin. Furthermore, immunocyto-
chemistry studies were performed by immunofluorescence
staining of MDA-MB-231 cells12 to confirm the effect of
selected compound 13d on microtubule formation. Filamen-
tous microtubules (Figure 4) were clearly seen in control cells,
while no microtubules were observed in the cells treated with
13d or CA-4. These observations demonstrated that 13d
inhibits tubulin polymerization in MDA-MB-231 cells. The
aqueous solubility and log P value of 13d were measured
according to methods described previously.13 The results at
pH 7.4 were 10.9 μg/mL and 2.96, respectively; thus,
compound 13d showed improved drug-like properties
compared with 2a (8.28 μg/mL and 2.97, Figure 2). Thus,
new compound 13d could be a potential alternate drug
candidate for further development.
In summary, our scaffold-hopping-driven optimization of
prior lead 2a led to two series of new compounds, 4-(N-
lactamphenyl)quinazolines (7a−d) and N-aryl-3,4-dihydroqui-
F
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Hamel, E.; Cui, M. T.; Zhu, D. Q.; Goto, M.; Morris-Natschke, S. L.;
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00352.
■
S
(7) Wang, X. F.; Guan, F.; Ohkoshi, E.; Guo, W. J.; Wang, L. L.;
Zhu, D. Q.; Wang, S. B.; Wang, L. T.; Hamel, E.; Yang, D. X.; Li, L.
N.; Qian, K. D.; Morris-Natschke, S. L.; Yuan, S. J.; Lee, K. H.; Xie, L.
Optimization of 4-(N-Cycloamino)phenylquinazolines as a Novel
Class of Tubuline Polymerization Inhibitors Targeting the Colchicine
Site. J. Med. Chem. 2014, 57, 1390−1402.
Synthetic experimental details, related spectroscopic data
of intermediate and target compounds, and biological
assay protocols (PDF)
AUTHOR INFORMATION
Corresponding Authors
*(L.X.) E-mail: lxie@email.unc.edu.
*(K.-H.L.) E-mail: khlee@unc.edu.
■
(8) Cui, M. T.; Jiang, L.; Goto, M.; Hsu, P. L.; Li, L.; Zhang, Q.;
Wei, L.; Yuan, S. J.; Hamel, E.; Morris-Natschke, S. L.; Lee, K. H.;
Xie, L. In Vivo and Mechanistic Studies on Antitumor Lead 7-
Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-
one and Its Modification as a Novel Class of Tubulin-Binding Tumor-
Vascular Disrupting Agents. J. Med. Chem. 2017, 60, 5586−5598.
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S.; Sobel, A.; Knossow, M. Insight into Tubulin Regulation From a
Complex with Colchicine and a Stathmin-like Domain. Nature 2004,
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ORCID
Masuo Goto: 0000-0002-9659-1460
Kuo-Hsiung Lee: 0000-0002-6562-0070
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript. Conceived project (L.X.), performed experi-
ments (L.J., M.G., D.-Q.Z., M.C., P.-L.H., K.-P.L., X.H., L.X.),
analyzed data (L.X., M.G.), and prepared manuscript (L.X.,
M.G., S.L.M.-N., K.-H.L.). All authors reviewed the manu-
script.
́
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V.; Knossow, M. Variations in the Colchicine-binding Domain
Provide Insight into the Structural Switch of Tubulin. Proc. Natl. Acad.
Sci. U. S. A. 2009, 106, 13775−13779.
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H.; Goto, M. Development of a Novel Class of Tubulin Inhibitor
from Desmosdumotin B with a Hydroxylated Bicyclic B-Ring. J. Med.
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Notes
The authors declare no competing financial interest.
(12) Zhang, Y.; Goto, M.; Oda, A.; Hsu, P. L.; Guo, L. L.; Fu, Y. H.;
Morris-Natschke, S. L.; Hamel, E.; Lee, K. H.; Hao, X. J.
Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alka-
loids from Bousigonia mekongensis Inhibit Tubulin Polymerization.
Molecules 2019, 24, 1256−1265.
(13) Sun, L. Q.; Zhu, L.; Qian, K.; Qin, B.; Huang, L.; Chen, C. H.;
Lee, K. H.; Xie, L. Design, Synthesis, and Preclinical Evaluations of
Novel 4-Substituted 1,5-Diarylanilines as Potent HIV-1 Non-nucleo-
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ACKNOWLEDGMENTS
■
We wish to thank the Microscopy Service Laboratory (UNC-
CH) for its expertise in the confocal microscopy studies. This
investigation was supported by grant 81120108022 from the
Natural Science Foundation of China (NSFC) awarded to L.
Xie and NIH grant CA177584 from the National Cancer
Institute awarded to K.-H. Lee. This study was also supported
in part by the Eshelman Institute for Innovation awarded to M.
Goto.
ABBREVIATIONS
■
CS, colchicine site; HTCL, human tumor cell line; PDB,
protein database; SAR, structure−activity relationship; VDAs,
vascular disrupting agents
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DOI: 10.1021/acsmedchemlett.9b00352
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