Design, synthesis, and evaluation of tricyclic, conformationally constrained small-molecule mimetics of second mitochondria-derived activator of caspases

Article abstract of DOI:10.1021/jm801146d

A series of tricyclic, conformationally constrained Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 6 (WS-5) binds to XIAP, cIAP-1, and cIAP-2 with K_i of 18, 1.1, and 4.2 nM, respectively. Compound 6 antagonizes XIAP in a functional assay, induces cIAP-1 degradation, inhibits cell growth with an IC₅₀ of 68 nM in the MDA-MB-231 cancer cell line, and effectively induces cancer cells to undergo apoptosis.

Full text of DOI:10.1021/jm801146d

7352
J. Med. Chem. 2008, 51, 7352–7355
Design, Synthesis, and Evaluation of
Tricyclic, Conformationally Constrained
Small-Molecule Mimetics of Second
Mitochondria-Derived Activator of Caspases
Bin Zhang,§ Zaneta Nikolovska-Coleska,‡,# Yan Zhang,§
Longchuan Bai,‡,# Su Qiu,‡,# Chao-Yie Yang,‡,#
Haiying Sun,‡,# Shaomeng Wang,*,‡,#,†,¶ and Yikang Wu*,§
State Key Laboratory of Bio-organic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China, and ComprehensiVe
Cancer Center and Departments of Internal Medicine, Pharmacology,
and Medicinal Chemistry, UniVersity of Michigan, 1500 E. Medical
Center DriVe, Ann Arbor, Michigan 48109
Figure 1. Examples of reported Smac mimetics.
Table 1. Binding Affinities of Smac Mimetics to XIAP, cIAP-1, and
cIAP-2 BIR3 Proteins, As Determined Using Competitive
Fluorescence-Polarization Assaysa
ReceiVed September 12, 2008
Ki ( SD, nM
compd
XIAP BIR3
cIAP-1 BIR3
cIAP-2 BIR3
Abstract: A series of tricyclic, conformationally constrained Smac
mimetics have been designed, synthesized, and evaluated. The most
potent compound 6 (WS-5) binds to XIAP, cIAP-1, and cIAP-2 with
Ki of 18, 1.1, and 4.2 nM, respectively. Compound 6 antagonizes XIAP
in a functional assay, induces cIAP-1 degradation, inhibits cell growth
with an IC50 of 68 nM in the MDA-MB-231 cancer cell line, and
effectively induces cancer cells to undergo apoptosis.
1
5
6
7
8
61 ( 6.0
30 ( 4.4
18 ( 10
1200 ( 500
690 ( 200
1.3 ( 0.2
3.0 ( 0.5
1.1 ( 0.5
150 ( 35
13 ( 2
4.8 ( 1.2
5.9 ( 1.0
4.2 ( 1.1
370 ( 30
20 ( 10
a Ki and standard deviation (SD) values were determined by three to
five independent experiments.
Evasion of apoptosis, or programmed cell death, is commonly
recognized as a hallmark of all cancers.1,2 Targeting critical
apoptosis regulators with a goal to promote apoptosis in cancer
cells is an attractive new cancer therapeutic strategy.2
Previous studies have firmly established that Smac interacts
with XIAP and cIAP-1/2 proteins via its AVPI tetrapeptide
motif.9,11-14 In the past few years, a number of laboratories,
including ours, have engaged in the design of small molecules,
which are called Smac mimetics, to mimic the AVPI binding
motif as antagonists of IAP proteins.15-24 Two types of Smac
mimetics have been reported, namely, monovalent and bivalent
Smac mimetics. While monovalent Smac mimetics are designed
to mimic the binding of a single AVPI binding motif to IAP
proteins,16-20 bivalent compounds contain two AVPI binding
motif mimetics tethered together through a linker.15,21-24 We
have shown that bivalent Smac mimetics can achieve much
higher affinities to XIAP and can be much more potent than
their corresponding monovalent Smac mimetic in induction of
apoptosis in tumor cells.21 However, monovalent Smac mimetics
may hold certain advantages as potential drug candidates
because of their small molecular weight (∼500). Furthermore,
monovalent Smac mimetics provide the basic templates for the
design of bivalent Smac mimetics. Herein, we report the design,
synthesis and evaluation of a series of conformationally
constrained Smac mimetics containing a tricyclic core structure.
In our previous study, we showed that 1 (Figure 1), which
contains a [7,5] bicyclic core structure, binds to the XIAP BIR3
protein with a Ki of 61 nM.19 Our subsequent binding studies
determined that 1 binds to cIAP-1 and cIAP-2 BIR3 proteins
with very high affinities and has Ki of 1.3 and 4.8 nM,
respectively (Table 1). Furthermore, 1 potently inhibits cell
growth and effectively induces apoptosis in the MDA-MB-231
breast cancer cell line but shows minimal toxicity to normal
cells.19 Hence, 1 represents a promising lead compound for
further design and optimization.
Inhibitors of apoptosis proteins (IAPsa) are a class of key
apoptosis regulators characterized by the presence of one to three
domains known as baculoviral IAP repeat (BIR) domains.3,4
Among these IAP proteins, X-linked IAP (XIAP) inhibits
apoptosis by binding to and inhibition of two effectors, caspase-
3/-7 and initiator caspase-9.4 While the third BIR domain (BIR3)
of XIAP selectively targets caspase-9, the BIR2 domain, together
with the linker immediately preceding it, inhibits caspase-3/-7.4,5
Cellular IAP-1 (cIAP-1) and cIAP-2 play a critical role in
regulation of tumor necrosis factor (TNF) receptor-mediated
apoptosis.4 Because of their central role in regulation of
apoptosis, these IAP proteins are considered as promising new
cancer therapeutic targets.5,6
Smac (second mitochondria-derived activator of caspases)
was discovered as a potent proapoptotic protein and an
endogenous antagonist of IAP proteins.7,8 Through direct
binding, Smac antagonizes XIAP and abrogates the inhibition
of caspase-3/-7 and caspase-9 by XIAP.7,9 Smac also binds to
cIAP-1/29 and can reduce the levels of cIAP-1/2 in cells.10
* To whom correspondence should be addressed. For S.W.: phone, +1-
734-615-0362; fax, +1-734-647-9647; e-mail, shaomeng@umich.edu. For
Y.W.: phone, +86 21 54925115; fax, +86 21 64166128; e-mail,
yikangwu@mail.sioc.ac.cn.
§
Shanghai Institute of Organic Chemistry.
Comprehensive Cancer Center.
Department of Internal Medicine.
Department of Pharmacology.
‡
#
†
¶
Department of Medicinal Chemistry.
a Abbreviations: IAP, inhibitor of apoptosis protein; XIAP, X-linked IAP;
cIAP-1/-2, cellular IAP 1/2; Smac, second mitochondria-derived activator
of caspases; BIR, baculoviral IAP repeats domain; BIR2, the second BIR
domain; BIR3, the third BIR domain; TNF, tumor necrosis factor; FP,
fluorescence polarization.
Our predicted binding model of 1 in complex with XIAP
BIR3 based on the crystal structure of Smac in complex with
XIAP BIR3 (PDB code 1G73)11 showed that the seven-
membered ring in 1 has van der Waals contacts with Trp323 in
10.1021/jm801146d CCC: $40.75
2008 American Chemical Society
Published on Web 11/14/2008

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23 7353
Scheme 1. Synthesis of Compounds 5-7a
Figure 2. Chemical structures of new Smac mimetics.
a Reagents and conditions: (a) (i) H2, 10% Pd-C, methanol; (ii)
N-phthaloyl-L-phenylpropanoic acid, EDC, HOBt, N-methylmorpholine,
CH2Cl2-DMF 1:1, 0 °C to room temp, overnight, 92% over two steps; (b)
CF3COOH, 4 Å molecular sieves, CHCl3, reflux, 88%; (c) trifluorosulfonic
acid, trifluorosulfonic anhydride, CH2Cl2, 98%; (d) (i) hydrazine hydrate,
methanol, 3 days; (ii) L-N-Boc-N-methylalanine, EDC, HOBt, N-methyl-
morpholine, CH2Cl2-DMF 1:1, 0 °C to room temp, overnight, 92% over
two steps; (e) (i) 2 N LiOH, then 1 N HCl; (ii) amine, EDC, HOBt,
N-methylmorpholine, CH2Cl2-DMF 1:1, 0 °C to room temp, overnight;
(iii) ZnBr2, CH2Cl2.
Figure 3. Predicted binding models of 1 and 5 in complex with XIAP
BIR3, in superposition on the crystal structure of Smac in complex
with XIAP BIR3. Protein is displayed in surface model with key binding
residues shown and labeled. Compounds 1, 5, and AVPI peptide are
shown in stick. Carbon atoms of AVPI peptide are depicted in green,
and carbon atoms of 1 and 5 are depicted in yellow. Oxygen and
nitrogen atoms in these compounds are shown in red and blue,
respectively.
Figure 4. Inhibition of cell growth by Smac mimetics in the MDA-
MB-231 human breast cancer cell line. Cells were treated for 4 days,
and cell growth was determined using a WST-8 assay.
Modeling showed that the 1-(R)-tetrahydronaphthyl group, but
not the (S)-isomer, can effectively interact with the hydrophobic
pocket in XIAP BIR3 (Supporting Information). To test the
modeling prediction, 6 and 7 with the (R)- or the (S)-
tetrahydronaphthyl group were synthesized and evaluated.
XIAP BIR3 and may contribute to its high binding affinity
(Figure 3). We have designed 5 (Figure 2), which has a phenyl
ring fused to the seven-membered ring, to investigate if further
conformational restriction is tolerated and if this phenyl ring
can further enhance the binding to XIAP.
Compounds 6 and 7 bind to XIAP BIR3 with Ki of 18 and
1200 nM, respectively. Thus, 6 is 67 times more potent than 7
in binding to XIAP. Furthermore, 6 binds to cIAP-1 and cIAP-2
proteins with Ki of 1.1 and 4.2 nM, respectively, and is >80
times more potent than 7. Consistent with its high binding
affinity to these IAP proteins, 6 achieves an IC50 of 68 nM in
inhibition of cell growth in the MDA-MB-231 cell line, while
7 has an IC50 of 401 nM (Figure 4).
We next designed and synthesized 8, in which the five-
membered proline ring in 5 is replaced by a six-membered ring,
to investigate the importance of the ring size. Modeling showed
that replacement of the five-membered proline ring in 5 by a
six-membered ring in 8 significantly weakens the contacts of 5
with Trp323, although all the hydrogen bonds are maintained
(Figure S2 of Supporting Information). Consistent with modeling
prediction, 8 binds to XIAP, cIAP-1, and cIAP-2 proteins with
Ki of 692, 13, and 20 nM, respectively, substantially less potent
than 5. These data showed that the five-membered ring in 5 is
critical in maintaining the optimal conformation for interactions
with these IAP proteins. Compound 8 is 20 times less potent
than 6 in cell growth inhibition in the MDA-MB-231 cancer
cell line (Figure 4).
Compound 5 was synthesized (Scheme 1) and evaluated for
its binding to XIAP, cIAP-1, and cIAP-2 BIR3 proteins using
fluorescence-polarization based binding assays.25 Compound 5
binds to these three IAP proteins with high affinities, having Ki
of 30, 3.0, and 5.9 nM to XIAP, cIAP-1, and cIAP-2,
respectively (Table 1). Hence, the high binding affinities of 5
to XIAP and cIAP-1/2 clearly indicated that further conforma-
tional restriction of the [7,5] core structure in 1 by a fused phenyl
ring is not detrimental for binding to these IAP proteins.
Compound 5 was evaluated for its ability to inhibit cancer
cell growth in the MDA-MB-231 breast cancer cell line, a
sensitive cell line used in previous studies.18-20 Indeed, 5
potently inhibits cell growth in this cell line with an IC50 of
468 nM (Figure 4). Hence, 5 is a potent and cell-permeable
Smac mimetic and a promising new lead compound for
optimization and structure-activity relationship studies.
We next investigated if the diphenylmethyl group in 5 can
be replaced by a tetrahydronaphthyl group, which was first
employed in the design of potent Smac peptidomimetics.18

7354 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23
Letters
Figure 7. Western blot analysis of the levels of cIAP-1, caspase-8,
pro-PARP, and cleaved PARP. MDA-MB-231 breast cancer cells were
treated with different concentrations of Smac mimetics for 24 h, and
proteins were probed with specific antibodies. GAPDH was used as
the loading control.
Figure 5. Induction of cell death by 5, 6, and 8 in the MDA-MB-231
breast cancer cell line. Cells were treated with different concentrations
of the compounds for 48 h. Cell viability was determined using a trypan
blue exclusion assay.
9 followed by condensation of the resulting amine with
N-phthaloyl-L-phenylpropanoic acid yielded amide 10. Cycliza-
tion of 10 under the catalytic conditions using trifluoroacetic
acid furnished 11. Cyclization of the enamide moiety with the
phenyl ring in 11 in the presence of trifluorosulfonic acid and
trifluorosulfonic anhydride provided 12. Conversion of the
phthalimide moiety in 12 to amine followed by condensation
of this amine with L-N-Boc-N-methylalanine generated an amide
13. Hydrolysis of the methyl ester group in 13 furnished an
acid. Condensation of this acid with corresponding amines
afforded three amides, which were deprotected with ZnBr2 to
give designed compounds 5-7.
In summary, we have designed and synthesized a series of
novel Smac mimetics containing a tricyclic core structure. The
most potent compound 6 (WS-5) binds to XIAP, cIAP-1, and
cIAP-2 with low nanomoalr affinities. Consistent with its
molecular mechanism of action, 6 effectively antagonizes XIAP
in a cell-free functional assay and efficiently induces the
degradation of cIAP-1 in cancer cells at concentrations as low
as 100 nM. Compound 6 achieves an IC50 of 68 nM in the
MDA-MB-231 cell line in a cell growth assay and effectively
induces cell death at 100 nM. Taken together, these data showed
that 6 is a promising Smac mimetic for further evaluations and
optimization for the development of a novel class of anticancer
drugs. Further in vitro and in vivo studies of 6 and its analogues
are being performed, and the results will be reported in due
course.
Figure 6. Functional antagonism of Smac mimetics against XIAP BIR3
in a cell-free functional assay. Addition of dATP and cyctochrome c
into the MDA-MB-231 cell lysates induced activation of caspase-3/-7
and XIAP BIR3 at 500 nM completely inhibited the caspase-3/-7
activity. Compounds 1 and 5-8 dose-dependently recovered the caspase
activity.
We next investigated if 5, 6, and 8 can effectively induce
cell death in the MDA-MB-231 cell line. Our data showed that
while these three Smac mimetics are capable of inducing cell
death in a dose-dependent manner, 6 is most effective and 8 is
least effective (Figure 5). Treatment of the MDA-MB-231
cancer cells with 1 µM 6 for 48 h induced 75% of cells to
undergo cell death but the treatment by 8 caused less than 20%
of the cells to die. Thus, our data showed that 6 is a potent and
effective inducer of cell death in the MDA-MB-231 cancer cell
line.
These new Smac mimetics were evaluated as antagonists of
XIAP in a cell-free functional assay. While the XIAP BIR3
protein effectively inhibits the activity of caspase-9 and caspase-
3/-7, these Smac mimetics dose-dependently antagonize the
inhibition of XIAP to caspase activity (Figure 6). Consistent
with their binding affinity data, 5 and 6 are the most potent
Smac mimetics in relieving the inhibition of XIAP in this
functional assay while 8 is the least potent.
Our binding data showed that these Smac mimetics bind to
cIAP-1 with high affinities. Several recent studies have dem-
onstrated that Smac mimetics induce rapid cIAP-1 degradation
in cells. Compounds 5, 6, and 8 were thus evaluated for their
ability to induce cIAP-1 degradation in the MDA-MB-231
cancer cell line. Western blotting showed that these three
compounds can induce cIAP-1 degradation but 6 is the most
potent one (Figure 7). Compound 6 effectively induces cIAP-1
degradation at concentrations as low as 100 nM and is more
potent than 5 and 8, consistent with their binding affinities to
cIAP-1. Compound 6 also potently and dose-dependently
induces processing of caspase-8 and cleavage of poly(ADP-
ribose) polymerase (PARP), two biochemical markers of apo-
ptosis, at concentrations as low as 100 nM within 24 h.
The synthesis of 5-7 is shown in Scheme 1, whereas the
synthesis of 8 is provided in Supporting Information. The
synthesis of the key intermediate 13 was accomplished using a
procedure similar to that published previously26 with some
modifications. Briefly, removal of the Cbz protecting group in
Acknowledgment. We are grateful for financial support from
the National Natural Science Foundation of China (Grants
20672129, 20621062, 20772143), the Chinese Academy of
Sciences(“KnowledgeInnovationProject”,GrantsKJCX2.YW.H08
and KGCX2-SW-209), the National Cancer Institute, U.S.
National Institutes of Health (Grant R01CA109025), the Breast
Cancer Research Foundation, the Susan G. Komen Foundation,
the Prostate Cancer Foundation, and the University of Michigan
Cancer Center (Core Grant P30CA046592). cIAP-1 antibody
is a kind gift from Dr. John Silke of La Trobe University,
Victoria, Australia.
Supporting Information Available: Experimental section in-
cluding information on the synthesis of 8, chemical data for 5-8,
and details of molecular modeling, fluorescence polarization-based
binding assays to XIAP, cIAP-1, and cIAP-2, the cell-free caspase
functional assay, the cell growth assay, cell viability assay, and
Western blot analysis. This material is available free of charge via
the Internet at http://pubs.acs.org.
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JM801146D