Organocatalytic Asymmetric Synthesis of Spiro-oxindole Piperidine Derivatives That Reduce Cancer Cell Proliferation by Inhibiting MDM2-p53 Interaction

Article abstract of DOI:10.1021/acs.orglett.7b03516

Asymmetric synthesis of pharmacologically interesting piperidine-fused spiro-oxindole derivatives has been achieved via an organocatalytic Michael/aza-Henry/hemiaminalization cascade reaction. Chiral compounds synthesized by this strategy potently inhibit

Full text of DOI:10.1021/acs.orglett.7b03516

Letter
Cite This: Org. Lett. 2017, 19, 6752−6755
pubs.acs.org/OrgLett
Organocatalytic Asymmetric Synthesis of Spiro-oxindole Piperidine
Derivatives That Reduce Cancer Cell Proliferation by Inhibiting
MDM2−p53 Interaction
†
,§
,†
†
‡
‡
†
Ming-Cheng Yang, Cheng Peng,* Hua Huang, Lei Yang, Xiang-Hong He, Wei Huang,
§
,‡
,†
Hai-Lei Cui, Gu He,* and Bo Han*
†
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, Chongqing 402160, China
‡
§
*
S Supporting Information
ABSTRACT: Asymmetric synthesis of pharmacologically interesting piperidine-
fused spiro-oxindole derivatives has been achieved via an organocatalytic
Michael/aza-Henry/hemiaminalization cascade reaction. Chiral compounds
synthesized by this strategy potently inhibited the proliferation of several breast
cancer cell lines. Mechanistic studies suggest that the most potent compound 9e
can directly interfere with MDM2−p53 interactions and elevate protein levels of
p53 and p21, thereby inducing cell cycle arrest and mitochondrial apoptosis.
esign and synthesis of small-molecule inhibitors to block
the MDM2−p53 interaction is an active research area in
Scheme 1. (a) Racemic Spiro-piperidine Oxindole Derivatives
for in Vitro Activity Assays and (b) Strategies for Asymmetric
Synthesis of Chiral Spiro-piperidine Oxindoles
D
medicinal chemistry because these inhibitors may have strong
anticancer potential. By liberating the tumor suppressor p53
from MDM2, these inhibitors allow p53 to exert its
1
antiproliferative effects. Diverse privileged scaffolds for
2
preparing potential inhibitors have been described, including
derivatives of imidazoline, piperidinone, benzodiazepine,
chromenotriazolopyrimidine, terphenyl, isoindolinone, and
3
pyrrolidine, as well as C3-spirocyclic oxindoles.
C3-modified spiro-oxindoles with a rigid nitrogen heterocyclic
system are more effective at inhibiting cancer cell proliferation
than oxygen- or sulfur-containing heterocyclic C3-substituted
4
molecules. C3 modifications have been reported using five-
5
13
membered N-heterocyclic rings (such as pyrrolidine, thiazoli-
NHC catalysis (Scheme 1b). Inspired by these successes and
6
7
dine, isoxazoline ); the purpose of this modification is to
provide a hydrophobic moiety to insert into the Leu26 and
Phe19 pockets of the binding site on MDM2. Recently, several
six-membered piperidine- or piperidone-based spiro-oxindole
derivatives have been shown to inhibit MDM2−p53 interaction
motivated by our continuing interest in constructing medicinally
relevant scaffolds via chiral amine catalysis,
14,15
we envisaged a
three-step organocatalytic relay cascade involving a Michael/aza-
Henry/hemiaminalization relay reaction to achieve the asym-
metric synthesis of spirocyclic oxindole skeletons containing a
densely functionalized piperidine with diverse substituents and
contiguous stereogenic centers (Scheme 2). Our approach took
advantage of the fact that the chiral γ-nitroaldehyde intermediate
3, easily obtained from the amine-catalyzed asymmetric Michael
reaction of nitroalkene 1 and aldehyde 2, could react with
ketimine substrate 4 to generate the chiral spiro-piperidine
8
with submicromolar IC values, although so far, only racemic
5
0
mixtures have been screened (Scheme 1a). Wang’s group has
demonstrated that stereochemistry was critical to the therapeutic
efficacy of spirocyclic oxindoles: the least and most potent
stereoisomers of a given spirocyclic oxindole may bind to MDM2
9
with affinities varying by >100-fold. This highlights the need to
16
framework. We also hoped to use our approach to create a
chiral heterocycle library for identifying the lead compound
inhibitors of MDM2−p53.
develop convenient, efficient asymmetric syntheses of chiral
spiro-oxindole derivatives bearing six-membered N-heterocycle
moieties.
Several groups have achieved enantioselective synthesis of
1
0
spiro-piperidine oxindoles using metal catalysis, phosphoric
Received: November 13, 2017
Published: December 6, 2017
1
1
12
acid catalysis, bifunctional hydrogen-bonding catalysis, or
©
2017 American Chemical Society
6752
DOI: 10.1021/acs.orglett.7b03516
Org. Lett. 2017, 19, 6752−6755

Organic Letters
Letter
Scheme 2. Asymmetric Construction of Pharmacologically
Interesting Scaffolds via [2 + 2 + 2] Annulation
To realize this proposed organocatalytic cascade, we selected
E)-nitrostyrene 1a, n-propanal 2a, and N-Bn-isatin ketimine 4a
(
as substrates. The first Michael reaction proceeded in the
presence of Hayashi−Jørgensen secondary amine catalyst (10
mol %) in toluene at room temperature for 3 h. Adding a toluene
solution of 4a and triethylamine in a one-pot operation resulted
in successive aza-Henry and hemiaminalization reactions. The
cascade process proceeded smoothly to afford the desired
products 5a, albeit in low yield. Direct dehydroxylation of the
hemiaminal using Et SiH and TFA at −60 °C gave the
3
corresponding stable spiro-piperidine oxindole 6a with good
diastereoselectivity and excellent enantioselectivity (Scheme 3a).
Scheme 3. Optimization of the Model Reaction
To improve the yield and stereocontrol, more reaction
parameters were screened (Table S1 in Supporting Information).
Conducting the reaction in MeCN at 40 °C with DBU as base
delivered the product 6a in 61% yield, 94% ee, and 90:10 dr
Figure 1. Substrate scope of the cascade reaction. Yield was calculated
from the isolated pure diastereomer; dr value was determined by H
1
NMR analysis of the crude reaction mixture; ee value was determined by
chiral HPLC analysis. The absolute configuration of 6p was determined
by X-ray analysis (CCDC 1582063), and other products were assigned
by analogy. 5 was dehydrated with 3 equiv of p-Tos acid at −60 °C to
(
Scheme 3b). These optimal conditions were used for the
substrate scope investigation (Figure 1).
We evaluated the tolerance of the reaction to various
1
functional groups at position R on β-aryl-substituted nitro-
yield 7. 6a was treated with TFA in CH
Cl at rt for 24 h to yield 8a. 6a
2 2
alkenes 1. The reaction proceeded well for substituents with
different electronic properties (Cl, Br, F, Me, iPr, MeO) at
different positions (ortho, meta, para); the expected domino
adducts 6b−6i were obtained efficiently. Using naphthyl, furyl,
or thienyl groups led to the corresponding target products 6j, 6k,
or 6l, albeit with slightly lower ee or dr values. Linear aliphatic
aldehydes and branched α,β-unsaturated aldehydes proved to be
suitable substrates 2, giving the corresponding products 6m and
was treated with TFA in CH Cl at rt for 10 min to yield 9a.
2
2
lipo-hydro partition coefficient and number of hydrogen bond
donors/acceptors. In this way, we generated the spiro-
tetrahydropyridine oxindole derivatives (7a−7g) and regiose-
lectively deprotected products (8a and 9a).
Having synthesized a series of chiral six-membered N-
heterocycle-fused spiro-oxindoles, we evaluated their ability to
bind to MDM2 and inhibit proliferation of two breast cancer
lines expressing wild-type p53 (MCF-7, ZR-75-1) and a breast
cancer line expressing mutated p53 (BT-474) (Figure 2a and
Table S2). In these experiments, the compound concentration
was always 20 μM. Compounds 6a−6s and 7a−7g showed little
bioactivity, while 8a and 9a showed moderate inhibitory activity
against MCF-7 and ZR-75-1 cells. Thus, a series of
regioselectively deprotected derivatives 8 and 9 were synthesized
and screened (Figure 2b,c). Compounds 9a−9f were more
6n with excellent stereoselectivities. The reaction tolerated
electronically different substituents at positions C5−C7 of the
isatin ketimines, but the alkyl-subsituted substrate afforded lower
yield than halogen-substituted analogues (6o vs 6p and 6q).
Benzyl, acetyl, and Boc protecting groups were well tolerated (6r
and 6s). To demonstrate that our approach could be combined
with efforts to increase “druglikeness” based on Lipinski’s rule,
we eliminated the hydroxy of the hemiaminal moiety and
deprotected the resulting molecule, thereby ensuring a desirable
6
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DOI: 10.1021/acs.orglett.7b03516
Org. Lett. 2017, 19, 6752−6755

Organic Letters
Letter
oxindole can interact with MDM2 via hydrogen-bonding and
hydrophobic interactions analogously to p53 residues Trp23,
Phe19, and Leu25 (Figure S1). The main hydrogen-bonding
interaction between 9e and MDM2 appears to involve residue
Leu54 (Table S3).
To begin to understand how 9e inhibits proliferation of breast
cancer cells, we examined its ability to promote apoptosis in
MCF-7 cells. Incubating cells for 24 h with 2.0 μM 9e led to
apoptotic nuclear fragmentation (Figure 3a). Proportions of cells
Figure 3. (a) MCF-7 breast cancer cells were treated with 2.0 μM 9e,
and nuclear morphology was examined using Hoechst 33258. Arrows
indicate fragmented nuclei. (b) Apoptosis in MCF-7 cells treated with
Figure 2. (a) Heat map of mean inhibitory ratios of compounds 6−9
against MDM2 and against breast cancer cell lines. The ability of
compounds to inhibit the MDM2−p53 interaction was measured using
a homogeneous time-resolved fluorescence assay, and their cytotoxicity
to cells was assessed using the MTT method. In all assays, compound
concentration was 20 μM. The mean inhibitory ratio was calculated
from duplicate measurements in three independent experiments. (b)
Structures of 8a−8f and 9a−9f. (c) Mean IC values of 8a−8f and 9a−
9
e was quantitated based on dual staining with Annexin V and
propidium iodide, followed by flow cytometry. (c) Cell cycle analysis of
MCF-7 cells treated with 9e. (d) Effects of 9e on expression levels of
MDM2, p53, p21, and apoptosis-related proteins after 24 h incubation.
5
0
9
f against MDM2 after 2 h incubation. (d) Mean IC50 values of 9e
in early or late stages of apoptosis were measured based on
double staining with Annexin V and propidium iodide (PI). The
proportion of cells in late apoptosis (Annexin-V+, PI+) was
significantly higher after incubation with 5 μM 9e (10.8 ± 2.10%)
than after incubation with 2 μM 9e (2.93 ± 0.4%, p < 0.05) or no
inhibitor (0.33 ± 0.1%, p < 0.05; Figure 3b). However, similar
proportions of cells were found to be in early stages of apoptosis
against a panel of breast cancer cell lines after 24 h incubation. Orange
indicates WT p53 cell lines, blue indicates MUT p53 cell lines. (e) Main-
chain rmsd fluctuations in a MD simulation of a 9e−MDM2 complex.
(
f) Potential modes of 9e binding to MDM2. The binding mode of p53
peptide to MDM2 is shown in green as a reference. (g) 2D schematic of
the potential binding mode of 9e to MDM2.
(
Annexin V+, PI−) after incubation with 5 μM 9e (24.6%) or 2
bioactive than 8a−8f despite sharing similar substitutions (see
Supporting Information for the preliminary SAR discussion).
None of the compounds we tested showed cytotoxicity against
BT-474 cells, suggesting that the p53 status determines much of
the efficacy of these potential inhibitors.
μM 9e (27.5%). In addition, 9e at submicromolar concentration
induced cell cycle arrest in the G0/G1 phase rather than
apoptosis (Figure 3c). Incubating MCF-7 cells with 9e also
increased levels of p53 and p21 but slightly reduced levels of
MDM2, based on Western blotting. This suggests that 9e inhibits
MDM2-mediated p53 degradation, and 9e is not a specific
MDM2 inhibitor since it fails to increase MDM2 protein. At the
same time, 9e treatment led to higher levels of the apoptosis
activator Bax, cleavage of caspase-9, and activation of PARP
(Figure 3d). These results suggest that 9e may activate the
mitochondrial apoptosis pathway.
We suspected that an N-Boc group on the piperidine ring
could strengthen bioactivity, so we tested 9e for bioactivity. It
inhibited the interaction between MDM2 and p53 peptide with
an IC of 0.91 ± 0.12 μM, and it suppressed proliferation of five
50
breast cancer lines: MCF-7 (IC50 2.5 μM), ZR-75-1 (3.3 μM),
BT-474 (35.5 μM), MDA-MB-231 (47.3 μM), and SKBR-3
(
41.8 μM) (Figure 2d).
To begin to understand how 9e and potentially other
Herein, we describe an organocatalytic, asymmetric cascade
reaction of nitroalkenes, aldehydes, and ketimines in the
presence of chiral secondary amine. This reaction efficiently
generates spiro-piperidine oxindole derivatives in good yields
with high diastereoselectivities and excellent enantioselectivities.
Compound 9e in this library displayed the most potent MDM2
inhibition and antiproliferative effects on breast cancer cells
expressing wild-type p53. Molecular dynamics simulations
suggest that 9e binds to MDM2 analogously to p53. The
compound may induce cell cycle arrest at G0/G1 as well as
molecules with a spiro-oxindole scaffold may bind to MDM2,
we performed a 100 ns molecular dynamics simulation, which
showed that the complexes of 9e and MDM2 reached
equilibrium after 5 ns and that main-chain rmsd, which fluctuated
less than 0.05 nm, averaged 0.25 nm for 9e on its own and 0.12
nm for the complex (Figure 2e). Binding modes along the
trajectory between 6 and 100 ns were analyzed in detail (Figure
2
f,g). It appears that N-Boc and 4-chlorophenyl groups on the
6
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DOI: 10.1021/acs.orglett.7b03516
Org. Lett. 2017, 19, 6752−6755

Organic Letters
Letter
mitochondrial apoptosis by up-regulating p53 and p21. Further
chemical modification and biological exploration of this lead
compound are underway in our laboratory.
(5) (a) Zhao, Y.; Yu, S.; Sun, W.; Liu, L.; Lu, J.; McEachern, D.;
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ASSOCIATED CONTENT
Supporting Information
■
McEachern, D.; Przybranowski, S.; Li, X.; Luo, R.; Wen, B.; Sun, D.;
Wang, H.; Wen, J.; Wang, G.; Zhai, Y.; Guo, M.; Yang, D.; Wang, S. J.
Med. Chem. 2017, 60, 2819.
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03516.
(
6) Bertamino, A.; Soprano, M.; Musella, S.; Rusciano, M. R.; Sala, M.;
Vernieri, E.; Di Sarno, V.; Limatola, A.; Carotenuto, A.; Cosconati, S.;
Grieco, P.; Novellino, E.; Illario, M.; Campiglia, P.; Gomez-Monterrey,
I. J. Med. Chem. 2013, 56, 5407.
Experimental details and analytical data (PDF)
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CCDC 1582063 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
Franz, A. K. ACS Comb. Sci. 2012, 14, 285. (b) Reddy, B. V. S.; Swain,
M.; Reddy, S. M.; Yadav, J. S.; Sridhar, B. Eur. J. Org. Chem. 2014, 2014,
■
*
*
*
3
̃
313. (c) Holmquist, M.; Blay, G.; Munoz, M. C.; Pedro, J. R. Adv. Synth.
E-mail: pengcheng@cdutcm.edu.cn.
E-mail: hegu@scu.edu.cn.
E-mail: hanbo@cdutcm.edu.cn.
Catal. 2015, 357, 3857. (d) Zheng, H.; Liu, X.; Xu, C.; Xia, Y.; Lin, L.;
Feng, X. Angew. Chem., Int. Ed. 2015, 54, 10958.
(11) (a) Badillo, J. J.; Silva-Garcia, A.; Shupe, B. H.; Fettinger, J. C.;
Franz, A. K. Tetrahedron Lett. 2011, 52, 5550. (b) Duce, S.; Pesciaioli, F.;
Gramigna, L.; Bernardi, L.; Mazzanti, A.; Ricci, A.; Bartoli, G.;
Bencivenni, G. Adv. Synth. Catal. 2011, 353, 860. (c) Shi, F.; Xing, G.-
J.; Zhu, R.-Y.; Tan, W.; Tu, S. Org. Lett. 2013, 15, 128. (d) Dai, W.; Lu,
H.; Li, X.; Shi, F.; Tu, S.-J. Chem. - Eur. J. 2014, 20, 11382. (e) Zhang, H.-
H.; Sun, X.-X.; Liang, J.; Wang, Y.-M.; Zhao, C.-C.; Shi, F. Org. Biomol.
Chem. 2014, 12, 9539.
ORCID
Gu He: 0000-0002-1536-8882
Bo Han: 0000-0003-3200-4682
Notes
The authors declare no competing financial interest.
(
12) (a) Zhang, X.-N.; Chen, G.-Q.; Dong, X.; Wei, Y.; Shi, M. Adv.
Synth. Catal. 2013, 355, 3351. (b) Montesinos-Magraner, M.; Vila, C.;
Canton, R.; Blay, G.; Fernandez, I.; Munoz, M. C.; Pedro, J. R. Angew.
ACKNOWLEDGMENTS
■
́
́
̃
We are grateful for financial support from the National Natural
Science Foundation of China (81573588, 81630101, 81773889,
and 21772131), the Science & Technology Department of
Sichuan Province (2017JQ0002).
Chem., Int. Ed. 2015, 54, 6320. (c) Zhu, Y.; Li, Y.; Meng, Q.; Li, X. Org.
Chem. Front. 2016, 3, 709.
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Zhang, C.-L.; Gao, Z.-H.; Ye, S. Org. Chem. Front. 2016, 3, 77.
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Org. Lett. 2017, 19, 6752−6755