Synthesis of N-Carbonyl Acridanes as Highly Potent Inhibitors of Tubulin Polymerization via One-Pot Copper-Catalyzed Dual Arylation of Nitriles with Cyclic Diphenyl Iodoniums

Article abstract of DOI:10.1002/adsc.201901460

A novel Copper-catalyzed cascade reaction between six-membered cyclic diaryliodonium salts and nitriles is reported for the facile access to a variety of N-carbonyl acridanes in good to excellent yields (up to 82%). The reaction is efficient and atom-economical with a broad substrate scope (e. g. both aryl / alkyl nitriles and substituted / unsubstituted cyclic diaryliodonium salts compatible in the system). This method is particularly useful for the synthesis of substituted N-carbonyl acridanes which are present in many pharmaceutically important compounds, but are not easy to obtain in conventional approaches. Furthermore, one of the newly synthesized acridanes displayed high antiproliferative activity against MB-468 cancer cells (IC₅₀=26 nM, comparable to paclitaxel and colchicine) by inhibiting tubulin polymerization. Together, these findings might grant a rapid access to a novel molecular scaffold with potential anticancer utilities. (Figure presented.).

Full text of DOI:10.1002/adsc.201901460

Title: Synthesis of N-Carbonyl Acridanes as Highly Potent Inhibitors
of Tubulin Polymerization via One-Pot Copper-Catalyzed Dual
Arylation of Nitriles with Cyclic Diphenyl Iodoniums
Authors: Xiaopeng Peng, Ling Li, Yichang Ren, Huanxin Xue, Jin Liu,
Shjijun Wen, and Jianjun Chen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901460
Link to VoR: http://dx.doi.org/10.1002/adsc.201901460

10.1002/adsc.201901460
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201901460
Synthesis of N-Carbonyl Acridanes as Highly Potent Inhibitors
of Tubulin Polymerization via One-Pot Copper-Catalyzed Dual
Arylation of Nitriles with Cyclic Diphenyl Iodoniums
Xiaopeng Penga, Ling Lia, Yichang Rena, Huanxin Xuea, Jin Liua, Shijun Wenb, and
Jianjun Chena,*
a
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510060, P. R. China
(+86)- (0)20-62789423. e-mail: jchen21@smu.edu,cn
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative innovation
b
Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P. R. China.
Received: (will be filled in by the editorial staff)
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A novel Copper-catalyzed cascade reaction of the newly synthesized acridanes displayed high
between six-membered cyclic diaryliodonium salts and antiproliferative activity against MB-468 cancer cells (IC50 =
nitriles is reported for the facile access to a variety of N- 26 nM, comparable to paclitaxel and colchicine) by
carbonyl acridanes in good to excellent yields (up to 82%). inhibiting tubulin polymerization. Together, these findings
The reaction is efficient and atom-economical with a broad might grant a rapid access to a novel molecular scaffold with
substrate scope (e.g. both aryl / alkyl nitriles and substituted / potential anticancer utilities.
unsubstituted cyclic diaryliodonium salts compatible in the
system). This method is particularly useful for the synthesis
of substituted N-carbonyl acridanes which are present in many
pharmaceutically important compounds, but are not easy to
obtain in conventional approaches. Furthermore, one
Keywords: Cyclic diphenyl iodoniums; C-N cross-
coupling; N-carbonyl acridanes; Anticancer activity;
Tubulin polymerization inhibitor
The frequent occurrence of acridanes in bioactive
compounds has encouraged the synthesis of
structurally-diverse acridane analogs, especially N-
Introduction
Heterocyclic compounds have a wide range of carbonyl acridanes. Several elegant methodologies have
applications in medicinal chemistry.[1] Acridines and been reported from different research groups for
acridanes, as two types of the most common nitro- preparing N-carbonyl acridanes.[8] One of the earliest
containing heterocyclic molecules, are present in many syntheses of N-carbonyl acridanes is achieved by
pharmaceutically important compounds.[2] Especially, coupling an acridane with an acid chloride under basic
acridanes represent a significant class of subunits in conditions.[9] However, the acridanes as starting
drugs and drug candidates as well as bioactive natural material are not easily available. Recently, Simon et.al
products.[3]
For
example,
acridane-containing disclosed a new method for the preparation of N-
Dimetacrine[4] is a useful antidepressant used for the carbonyl acridanes based on a two-step process, which
treatment of various types of depression. 3-ATA[5], includes the synthesis of the tertiary benzylic compound
Elacridar[6] and BisPA[7]are also acridane derivatives by reacting acetanilides with styrenes under Iridium-
that exhibit high anticancer activity. (Figure 1)
catalyzed conditions followed by an intramolecular C-
N cross-coupling to generate the target compounds
(Scheme 1a).[10] Although current methods are efficient
to prepare various N-carbonyl acridanes, the major
drawbacks such as harsh reaction conditions limited the
application of these methods to substrates with broad
substitution patterns.[11] Therefore, practical and highly
functional-group tolerant strategies for accessing
structurally diversified N-carbonyl acridanes are still
desirable. Diaryliodonium salt, as environmentally
benign reagents with low toxicity, are often used in the
synthesis of arylated compounds or macrocyclic
Figure 1. Representative molecules containing acridane.
1
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10.1002/adsc.201901460
Advanced Synthesis & Catalysis
supramolecular compounds.[12] Due to the excellent
usability, cyclic diaryliodonium salts have been
extensively applied in dual arylation processes for the
formation of C−C and C−heteroatom bonds or in other
cascade reactions to construct more complicated
molecules. [13] In the past five years, significant progress
has been made in the tandem arylation–cyclization
reactions initiated by diaryliodonium salts and
nucleophiles such as alkenes,[14] alkynes,[15] amines, [16]
and sulfide,[13d, 17] etc., to generate different polycycles
including methylidene fluorenes, phenanthrenes, and
sulfur containing heterocycles.
that CuCl gave superior results, while the reaction with
CuTc worked with marginally low efficiency (entries 2-
5). The impact of the solvent was then investigated
(entries 6-11), and the reaction did not take place when
THF or MeOH was used as the solvent (entry 9-10). To
our delight, 3a was prepared in 36% when
DCE/Toluene mixture solvent was employed (entry 11).
Subsequent optimizations were focused on changingthe
bases (entries 12-16) and ligands (entries 17-19). No
desired acridane product 3a was detected when organic
bases such as TEA (Triethylamine) or DBU (1,8-
Diazabicyclo [5.4.0] undec-7-ene) was employed (entry
15 and 16). Whereas the yield increased dramatically to
77%
when
TMHD
(2,2,6,6-tetramethyl
heptanedione) was used as the ligand (entry 18).
Diminished yields were observed when the reactions
were performed at elevated or decreased temperatures
(entries 20-21). It is worth noting that the reaction did
not happen in the absence of either bases or H2O (data
not shown). After optimization, the best conditions were
established as follows: 1a (0.2 mmol), 2a (0.24 mmol),
CuCl (0.02 mmol), TMHD
Table 1. Optimization for the synthesis of N-carbonyl
acridanes.
Scheme 1. Current approaches for the synthesis of N-
carbonyl acridanes.
It is well-known that nitriles are considered to be
relatively inert and do not easily participate in reactions,
especially in an arylation reaction.[18] Therefore,
arylation with a nitrile group would be of great
significance. In a continuation of our research interest
in the diaryliodonium salt chemistry[19], we envisioned
that N-carbonyl acridanes could be accessed if a nitrile
was employed as an arylation acceptor. Herein, we
report a practical and inexpensive method to rapidly
synthesize N-carbonyl acridanes 3 from six-membered
cyclic diaryliodonium salt 1 and commercially available
Yield
Entry Catalyst
Solvent
Base
Ligand
(%) a)
1
Cu(OTf)2 DCE
Cu(OAc)2 DCE
Na2CO3 AKOS 92891
9
AKOS 92891
AKOS 92891
AKOS 92891
AKOS 92891
AKOS 92891
AKOS 92891
AKOS 92891
AKOS 92891
AKOS 92891
AKOS 92891
AKOS 92891
AKOS 92891
AKOS 92891
AKOS 92891
AKOS 92891
L-proline
2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
5
3
CuCl
CuTc
CuI
DCE
15
2
4
DCE
5
DCE
7
6
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
Toluene
DMF
DMSO
THF
20
11
12
-
nitrile derivatives
(Scheme 1b).
2 through copper-catalyzation
7
8
9
10
11
12
13
14
15
16
17
18
19
MeOH
-
Results and Discussion
Mixture b) Na2CO3
Mixture b) K2CO3
Mixture b)
Mixture b)
K3PO4
Mixture b)
Mixture b)
DBU
Mixture b)
Mixture b)
K3PO4
Mixture b)
36
28
37
58
-
With these considerations in mind, we selected the six-
membered cyclic diaryliodonium salt 1a and
benzonitrile 2a as model substrates to optimize the
NaHCO3
reaction
conditions.
Six-membered
cyclic
TEA
diaryliodonium salt 1a was mixed with benzonitrile 2a,
with Cu(OTf)2 as a catalyst, 1,10-phenanthroline
(AKOS 92891) as the ligand, and Na2CO3 as the base,
the reaction was heated to 100 oC in 5 mol%H2O/DCE
(1,2-dichloroethane) in a sealed tube for 17 h. As
anticipated, a small amount of the desired N-carbonyl
acridane 3a was obtained (Table 1, entry 1), which
encouraged us to further optimize the reaction condition.
Initial attempts were made by changing the catalyst
sources. After the first-round screening, it was found
-
K3PO4
47
77
53
30
66
TMHD
K3PO4
Valine
Mixture b)
Mixture b)
20c) CuCl
21d) CuCl
K3PO4
K3PO4
TMHD
TMHD
a) Isolated yield, b) mixture: DCE/Toluene, c) 70 oC, d) 130 oC.
2
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10.1002/adsc.201901460
Advanced Synthesis & Catalysis
trimethoxyl group afforded the acridane alkaloid
analogue 3i with 77% yield. It is noteworthy that aryl
nitriles bearing biologically important functional groups,
such as 4-trifluromethoxy and 4-trifluromethyl were
well tolerated to give the corresponding acridane
derivatives (3j, 3k) with decent yields of 78% and 51%,
respectively, offering further synthetic functionalization
potential. Interestingly, 1-naphthonitrile was also
applicable to this reaction and successfully produced the
N-carbonyl naphthyl acridane 3n in excellent yield
(78%), suggesting a broad substrate scope for the aryl
nitrile components. Gratifyingly, all the substrates with
different halogenated functionalities (e.g. F, Cl, Br and
I) were effective in this reaction by generating the
desired products (3o-3s) in good to excellent yields
(57%-76%), the halo-substituted products may undergo
further transformations to build other complex
molecular scaffolds. Additionally, the piperonylonitrile
and 6-cyanophthalide were also compatible substrates
for this reaction (3t，3u), and the respective ketone
moieties represent an important class of subunits in
(0.04 mmol), K3PO4 (0.5 mmol), DCE/Toluene
(V/V=1/1, 5.0 mL), 5 mol% H2O addition, at 100 °C for
17 h, N2 (entry 18).
With the optimized conditions, we first examined the
scope of aryl nitriles for this cascade dual C-N cross-
coupling reaction. As shown in Figure 2, aryl nitriles
with alkyl, aryl, or ester groups proceeded smoothly
under standard conditions and gave the expected N-
carbonyl acridanes in moderate to excellent yields.
Generally, the aryl nitrile derivatives with either a
strong electron-donating (3e–3i) or withdrawing (3k–
3m) substituents worked smoothly and delivered the
corresponding products. Notably, aryl nitriles with
strong electron-donating groups (such as methoxy)
were favorable for this transformation but increasing the
number of electron-donating groups in the meta position
did not further improve the yields (3e vs. 3i). Besides,
substrates with the same substituents at different
positions exhibited similar results (3e vs. 3f, 3g),
confirming the reaction efficiency was not significantly
affected by substituent positions. The aryl nitrile
drugs or drug candidates,[20] and natural products [21]
.
bearing
a
frequent, naturally-occurring 3,4,5-
Figure 2. Arylation of various aryl nitriles.
Next, we further expanded the substrate scope for
phenyl-containing
2-phenylacetonitrile,
3-
this reaction. Pleasingly, the reaction proceeded
uneventfully when heterocyclic nitrile derivatives
were used as the coupling partner, as shown in Figure
3. 3-Cyanothiophene and 2-furonitrile worked
phenylpropionitrile and 4- phenylbutyronitrile were
equally effective as the nitrile sources (3x–3ab). The
results revealed that the length between the phenyl and
cyanide had a slightly negative impact on the reactivity
smoothly and provided the corresponding products (3v, of this transformation, the longer the chain, the lower
3w) in excellent yields (71% and 66%). However,
cyanopyridine derivatives didn’t undergo this reaction
to provide the expected products presumably due to
their electron deficiency. Importantly, we also found
that alkyl nitriles such as acetonitrile, butyronitrile,
the yields (3z vs. 3aa, 3ab). Moreover, a series of
alicyclic acridanes 3ac–3ae were successfully
produced when alicyclic nitrile species were employed.
Collectively, these results demonstrated a broad
substrate scope for this reaction, and a variety of
3
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10.1002/adsc.201901460
Advanced Synthesis & Catalysis
diaryliodonium salts were examined. Remarkably,
most of the tested assymmetrical cyclic
diaryliodonium salts give the desired acridane
derivatives (4e-4h) with modest to good yields (59%-
72%). It is worth pointing out that the substrates
containing reactive halogens (e.g. fluorine and
trifluoromethyl) are suitable for further derivatization.
Considering that the acridone motif is important in
natural products and pharmacologically important
compounds such as Luvungaside A,[22] Arborinine,[23]
Citropsine A[24] and Elacridar,[25] we also synthesized
some of these functionalized acridone analogs (4i-4l)
and tested their antiproliferative activities as described
below. Overall, with readily available nitriles and
cyclic iodonium salts as substrates, various valuable
N-carbonyl acridanes with different functionalities
were made quickly and efficiently.
As mentioned above, many acridane-containing
compounds possess important biological activities (e.g.
anticancer property). Therefore, we tested the
antiproliferative activities of the newly synthesized
compounds against four cancer cell lines using a well-
established MTT assay. The two well-known
antimitotic anticancer agents, colchicine and paclitaxel,
were used as positive controls. As shown in Table 2,
several compounds displayed potent antiproliferative
activities with IC50 values in the low micromolar or
nanomolar range (e.g. 0.026-10 M). The best
compound 3i, with a 3,4,5-trimethoxy on the benzoyl
ring, had IC50 values ranging from 26 nM to 1.2 M
which was comparable to that of paclitaxel and
colchicine; while compounds 3e, 3f or 3h, with one or
two methoxyls, exhibited relatively low potency. The
results revealed that the number of methoxy
substituent on the benzoyl ring had a significant
impact on the antiproliferative activity. Further
Figure 3. Arylation of various heterocyclic nitriles and alkyl
nitriles.
acridanes with an N-carbonyl substitution could be
quickly obtained.
To fully establish the scope of this one-pot dual C-
N cross-coupling process, a range of functionalized
six-membered cyclic diaryliodonium salts were
prepared according to Olofsson’s method utilizing the
above-described method and subjected to the
optimized reaction protocol with benzonitrile
derivatives (Figure 4). First, the symmetric six-
membered cyclic diaryliodonium salts with p-
tolunitrile or anisonitrile were tested (4a-4d), we
found that both the fluoro and chloro groups were well
tolerated. Next, a series of assymmetrical cyclic
structural
optimization and
structure-activity
relationship study of these new scaffolds are currently
in progress.
Table 2: In vitro antiproliferative activity of the N-carbonyl
acridanes.
IC50 ±SEM（μM）
Compounds
MCF-7
A549
MB-468
Hela
3e
7.209±0.9
4.717±0.6
6.995±0.5
0.077±0.011
3.713±0.7
8.128±1.1
3.928±0.8
0.057±0.008
0.002±0.001
1.933±0.3
7.059±0.9
2.953±0.6
0.057±0.011
4.053±0.7
9.885±1.6
3.122±0.9
0.091±0.009
0.043±0.006
3.683±0.1 10.445±1.8
3f
4.035±0.3
4.725±0.6
0.026±0.005
>10
3.244±0.7
>10
3h
3i
1.202±0.1
>10
3k
3ac
5.849±0.6
1.87±0.3
>10
4b
>10
Colchicine
Paclitaxel
0.018±0.002
0.005±0.001
0.311±0.017
0.133±0.002
Considering our newly synthesized N-carbonyl
acridane compounds having a structural similarity to
the N-benzoylated phenoxazine and phenothiazine
analogs which reportedly inhibited tubulin
polymerization (Figure S1, Supporting Information),
Figure 4. The scope of six-membered cyclic
diaryliodonium salt.
[26]
we hypothesized that the N-carbonyl acridane
4
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10.1002/adsc.201901460
Advanced Synthesis & Catalysis
derivatives
might
also
intervene
tubulin
polymerization. Therefore, we performed a tubulin
polymerization assay for the most potent compound 3i
using a known tubulin polymerization inhibitors CA-4
and colchicine as controls [27]. As shown in Figure 5A,
3i showed a dose dependent inhibition of tubulin
polymerization, with almost 100% inhibition at 6 and
12.5 M. Furthermore, 3i inhibited tubulin
polymerization with an IC50 of 1.6 M (Figure 5B),
which was similar to CA-4 (IC50=1.4 M, Figure 5C)
and better than colchicine (IC50=7.0 M, Figure 5D).
These results clearly indicated that 3i effectively
inhibited tubulin polymerization.
Figure 6. Effects of tested compounds on microtubules.
MB-468 cells were treated with 0.1% DMSO (A), CA-4
(100 nM) (B) or 3i (100 nM) (C) for 6 h. Microtubules were
visualized with an anti-β-tubulin antibody (green), and the
cell nucleus was visualized with 4,6-diamidino-2-
phenylindole (DAPI) (blue). Fluorescence images were
collected by Carl Zeiss inverted microscope with plan-
apochromat 63x/1.40 objective.
Figure 5. 3i exhibited a dose-dependent inhibition of
tubulin polymerization (A). The inhibition of tubulin
polymerization by 3i (B), CA-4 (C) and colchicine (D).
To experimentally validate whether the newly
synthesized compounds maintain the mechanisms of
action as tubulin polymerization inhibitors, 3i was
evaluated for in vitro microtubule polymerisation
activity. CA-4 was employed as the reference
compound. In the control experiment (DMSO), a hair
like microtubule network of slim, fibrous microtubules
(green) wrapped around the cell nucleus (blue) was
visualized upon immunofluorescence staining of MB-
468 cells (Figure 6A). However, the microtubule
network was disrupted when cells were treated with
100 nM of CA-4 (Figure 6B) or 100 nM of 3i (Figure
6C) for 6 h. These results suggest that the mode of
action of 3i is to inhibit tubulin polymerization, similar
to that of CA-4.
To better understand how the newly synthesized
compound interact with tubulin, molecular docking
simulation of 3i at the colchicine binding site in the
tubulin dimer was investigated. The 3D model of 3i
and DJ101 (Figure 7A) showed that 3i fitted well to
the colchicine site, and overlapped with DJ101.[28]
Compared with DJ101, one hydrogen bond was
observed between the carbonyl group and ASP-249
(Figure 7B and 7C). This hydrogen bond along the
hydrophobic interactions provided by the aromatic
rings, could contribute to the high binding affinity of
3i to tubulin.
Figure 7. The 3D model of 3i and DJ101 in the colchicine
site of tubulin (PDB code: 5H7O). The pocket was
represented by the gray part (A); The 2D model of 3i (B)
and DJ101 (C).
Conclusion
In summary, we have developed a one-pot reaction to
generate a broad range of functionalized N-carbonyl
acridanes via dual C-N cross-coupling using cyclic
diaryliodonium salts and relatively inert nitrile species.
Moreover, halogens including fluorine, chlorine,
bromine and iodine are well tolerated in the reactions,
providing an opportunity to further functionalize the
obtained acridanes. The method could be applied to the
preparation of acridone derivatives that are found in
many bioactive compounds and are hard to synthesize.
More importantly, the screening of our new synthetic
acridanes successfully leads to the discovery of several
novel N-carbonyl acridane derivatives with high
antiproliferative activities by inhibiting tubulin
polymerization. Therefore, our method provides facile
access to novel structural scaffolds as potential
anticancer agents.
5
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10.1002/adsc.201901460
Advanced Synthesis & Catalysis
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Experimental Section
General Procedure for the Construction of N-
carbonyl acridanes 3.
[7]
[8]
A Schlenk tube was charged with six-membered cyclic
diaryliodonium triflate 1 (100 mg), K3PO4 (2.5 equiv.),
CuCl (10% mmol), and TMHD (20% mmol). The tube
was evacuated and backfilled with argon three times,
and a solution of 2 (2.0 equiv.) in DCE/Toluene
(V/V=1/1, 5.0 mL) was added via a syringe under
argon protection with 5 mol% H2O additional. The
tube was sealed and heated to 100°C in an oil bath.
After 17 h, the reaction mixture was diluted with
dichloromethane (20 mL), washed with H2O (2 mLx
3), dried over anhydrous Na2SO4 and concentrated
under vacuum. The residue was purified by column
chromatography on silica gel (petroleum to 5% EtOAc
in petroleum) to give N-carbonyl acridanes 3.
[9]
[10]
[11]
[12]
Acknowledgement
This work was supported by scientific research project
of high level talents (No. C1051008) in Southern
Medical University of China; Thousand Youth Talents
Program (No. C1080092) from the Organization
Department of the CPC Central Committee, China;
and International Science and Technology
Cooperation Projects of Guangdong Province (No.
G819310411).
[13]
a) K. Zhu, K. Xu, Q. Fang, Y. Wang, B. Tang, F.
Zhang, ACS Catalysis. 2019; b) B. Wu, N.
Yoshikai, Angew. Chem. Int. Ed. 2015, 54, 8736-
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