Exploring aigialomycin D and its analogues as protein kinase inhibitors for cancer targets

Article abstract of DOI:10.1021/ml200067t

The natural product aigialomycin D (1) is a member of the resorcylic acid lactone (RAL) family possessing protein kinase inhibitory activities. This paper describes the synthesis of aigialomycin D and a series of its analogues and their activity for the i

Full text of DOI:10.1021/ml200067t

LETTER
pubs.acs.org/acsmedchemlett
Exploring Aigialomycin D and Its Analogues as Protein Kinase
Inhibitors for Cancer Targets
Jin Xu,†,‡ Anqi Chen,*,† Mei-Lin Go,‡ Kassoum Nacro,§ Boping Liu,§ and Christina L. L. Chai*,†,‡
†Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 8 Biomedical Grove,
Neuros #07-01, Singapore 138665
‡Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543
§Experimental Therapeutic Centre (ETC), Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos Level 3,
Singapore 138669
S Supporting Information
b
ABSTRACT: The natural product aigialomycin D (1) is a member of the
resorcylic acid lactone (RAL) family possessing protein kinase inhibitory
activities. This paper describes the synthesis of aigialomycin D and a series
of its analogues and their activity for the inhibition of protein kinases
related to cancer pathways. A preliminary study of these compounds in the
inhibition of CDK2/cyclin A kinase has found that aigialomycin D and
analogues 11 and 23 are moderate CDK2/cyclin A inhibitors with IC50
values of ca. 20 μM. Kinase profiling of aigialomycin D against a panel of kinases has led to the identification of MNK2 as a promising
target (IC50 = 0.45 μM), and preliminary structureꢀactivity relationship studies have been carried out to identify the essential
functional groups for activity.
KEYWORDS: Aigialomycin D, CDK2, MNK, kinase inhibitor, resorcylic acid lactone
inases are essential components of cellular signaling net-
works and play key roles in the regulation of many important
acceptor nature of the cis-enone system, which enables covalent
binding to the cysteine residue in the ATP-binding pocket of a
subgroup of kinases.22,23 In contrast, aigialomycin D (1)24ꢀ28
does not possess an enone system and yet is a cyclin-dependent
kinase (CDK) 1 and 5 inhibitor albeit with less activity (IC50 ∼6
μM).26 This suggests that different RAL scaffolds may inhibit
different kinases via various mechanisms. To understand this
further, a structureꢀactivity relationship (SAR) study of aigialo-
mycin D and analogues is necessary. At the outset of this study,
we examined the kinase inhibitory activity of aigialomycin D and
analogues against CDK2, a validated target for anticancer drug
development29ꢀ31 yet unexplored for RALs.
The target compounds for SAR studies were designed to
identify the functionalities that are critical to their kinase inhibi-
tion activity. Specifically, compounds 22ꢀ24 and 27 were
synthesized to examine the nature of the substitution on the
aromatic ring of the RAL scaffold while other compounds enabled
the SAR study of the macrocyclic system. The analogues were
synthesized based on the route previously reported by us for
aigialomycin D (Scheme 1).27 The aromatic fragment 2 was
coupled with alcohols (3aꢀc) via the Mitsunobu reaction, provid-
ing the benzoates (4aꢀc) in excellent yields (>90%). The benzo-
ates (4aꢀc) were then acylated at the benzylic position by depro-
tonation with lithium diisopropylamide (LDA) followed by
condensation with the Weinreb amides (9 and 10)28 to access
K
biological processes relating to cell growth, differentiation, apopto-
sis, etc. Studies on the inhibition of protein kinase signaling path-
ways over the last two decades have developed into a major
paradigm for the discovery of new drugs, primarily in the area of
oncology, and others such as inflammation and cardiovascular
disease.1ꢀ4 Currently, there are 11 kinase inhibitors that have
been approved as drugs for the treatment of various types of
cancers.5 All of these approved drugs, along with most of the
known protein kinase inhibitors, contain at least one N-aromatic
heterocyclic motif. However, with increasing reports of resis-
tance responses among patients to these drugs6ꢀ8 as well as the
need to develop new drugs for different types of cancers, small
molecule kinase inhibitors with new scaffolds are actively being
sought. One of the more promising groups of natural products
that have recently emerged as new lead structures for kinase
inhibition is the resorcylic acid lactones (RALs),9ꢀ11 which are
β-resorcylic acid derivatives possessing a 14-membered macro-
lactone ring. To date, more than 30 naturally occurring RALs
have been reported, and these have a broad spectrum of biological
activities, particularly as potent and selective inhibitors of protein
kinases, such as transforming growth factor-β-activated kinase 1
(TAK1), mitogen-activated protein (MAP) kinase, and MAP
kinase kinase (MEK).9ꢀ11 Among the most extensively investi-
gated RALs are those containing a cis-enone moiety (e.g.,
hypothemycin,12ꢀ14 LL-Z-1640-2,15ꢀ19 and L-78327720,21) be-
cause of their potent kinase inhibitory properties (Figure 1). The
mechanism of inhibition is thought to be due to the Michael
Received: March 9, 2011
Accepted: July 17, 2011
Published: July 17, 2011
r
2011 American Chemical Society
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the dienes (5aꢀd). The dienes (5aꢀd) were cyclized by ring-
closing olefin metathesis (RCM) to give the macrocyclic com-
pounds (6aꢀd) in high yields. Reduction of the C-20 carbonyl
group followed by mesylation and elimination installed the trans-
10,20-double bond. Finally, global deprotection of the protect-
ing groups afforded aigialomycin D and its analogues (1 and
11ꢀ13).
two C2-phenol methylated analogues 24 and 27 were also
prepared. Because C2-phenol is less reactive than C4-phenol
due to intramolecular hydrogen bonding, the synthesis of 24 and
27 require a sequence of multistep transformations. In the
sequence of transformations to 24, the more reactive C2-
methoxymethyl (MOM) group and the acetonide group in 25
were removed using 0.2 M TFA in methanol to give intermediate
26. The C2-phenol of 26 was then methylated followed by the
deprotection of the C4-MOM group to provide analogue 24.
Compound 27 was obtained through a sequence of similar but
slightly different order of transformations from the ketone 6a.
More analogues were accessed from aigialomycin D (1)
(Scheme 3). Full saturation of the two double bonds in aigialo-
mycin D (1) afforded tetrahydro-agialomycin D (20). Attempted
methylation of the 2,4-phenolic groups of 1 using excess Me2SO4
in acetone did not provide either the mono- or the dimethylated
product. Unexpectedly, the acetonide 21 was obtained as the sole
product in high yield (94%). Alternative methylation of the
phenolic groups in compound 1 using trimethylsilyldiazomethane
in the presence of methanol and N,N-diisopropylethylamine32 pro-
vided a mixture of mono- (at C-4) and dimethylated products (22
From the key intermediate 6a, a number of analogues were
also accessed (Scheme 2). Deprotection of 6a provided 14,
which was further hydrogenated to give 15. Reduction of the
carbonyl group in 6a using NaBH4 followed by deprotection
yielded 16 as a C-20 epimeric mixture, which was further
hydrogenated to give 17. The N-oxime analogue (18) was
obtained by treating 14 with hydroxylamine hydrochloride to
give 18 as a cis- and trans-mixture. 70,80-Dihydro aigialomycin D
(19) was prepared from 6a by reduction of the carbonyl group
followed by saturation of 70,80-double bond, elimination and
deprotection. Taking advantage of the pivotal intermediate 6a,
1
and 23) in a ratio of 1:1 (by H NMR spectroscopy). The two
compounds 22 and 23 were separable by HPLC.
With aigialomycin D and its analogues in hand, the competi-
tive inhibition of these compounds to the ATP-binding site of
CDK2/cyclin A was initially screened using an immobilized,
metal ion, affinity-based fluorescence polarization (IMAP) en-
zyme assay.33 In this assay, purvalanol A (a highly potent CDK
inhibitor) was used as the positive control, and percentage
inhibitions by aigialomycin D and analogues were measured.
From this screen, compounds 1, 11, and 23 were identified as the
three most active ones at a 10 μM concentration (Table 1). The
IC50 values of these three compounds were determined and
found to be at ca. 20 μM (Table 1), indicating that they were only
moderate CDK2/cyclin A inhibitors. These results, however,
Figure 1. Representative RALs and their biological activities.
Scheme 1. Synthesis of Aigialomycin D 1 and Its Analogues 11ꢀ13a
a Reagents and conditions: (a) Diisopropylazodicarboxylate (DIAD), PPh3, THF, room temperature, 3 days, >90%. (b) LDA, THF, ꢀ78 °C, then 9 or
10, 15 min, 19ꢀ65%. (c) HoveydaꢀGrubbs II (5ꢀ10 mol %), 1,2-dichloroethane, reflux, 1 h, 76ꢀ99%. (d) NaBH4/MeOH, 0 °C, 30 min, 77ꢀ99%. (e)
(i) MsCl, Et3N, 4-dimethylaminopyridine (DMAP), CH2Cl2, 0 °C to room temperature, 3 h; (ii) diaza(1,3)bicyclo[5.4.0]undecane (DBU), toluene,
reflux, 16 h, 32ꢀ65%. (f) 2 N HCl, MeOH, 40 °C, 6 h, quantitative.
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Scheme 2. Synthesis of Aigialomycin D Analogues 14ꢀ19, 24, and 27a
a Reagents and conditions: (a) 2 N HCl, MeOH, 40 °C, 6 h. (b) H2, 10%Pd/C, EtOH, room temperature, 20 h. (c) NH2OH HCl, NaOAc, dioxane,
3
100 °C, 3 h, quantitative. (d) NaBH4/MeOH, 0 °C, 30 min. (e) (i) MsCl, Et3N, DMAP, CH2Cl2, 0 °C to room temperature, 3 h; (ii) DBU, toluene,
i
refluxing, 16 h. (f) 0.2 M trifluoroacetic acid, MeOH, room temperature, 3 h. (g) Me3SiCHN2 (2 equiv), Pr2NEt, MeOH/MeCN (2:3), room
temperature, 18 h.
Scheme 3. Synthesis of Aigialomycin D Analogues 20ꢀ23a
Table 1. Percentage Inhibition of CDK2/Cyclin A by 1 and
Its Analogues at 10 μM and IC50 Values of Selected
Compounds
IC50
IC50
compound % inhibitiona (μM)b compound % inhibitiona (μM)b
1
55 ( 8
64 ( 5
38 ( 2
17 ( 11
21 ( 4
17 ( 4
8 ( 15
6 ( 0
21 ( 5 19
19 ( 2 20
25 ( 3
16 ( 1
19 ( 5
13 ( 7
49 ( 12
17 ( 8
10 ( 3
94 ( 1
ND
ND
ND
ND
19
11
12
13
14
15
16
17
18
ND
ND
ND
ND
ND
ND
ND
21
22
23
24
ND
ND
ND
27
purvalanol A
19 ( 5
a Experiments were carried out at 10 μM with purvalanol A (1 μM) as a
reference compound. Percentage inhibition values were the averages (
SDs of three independent experiments except for 17, 19, 20, 21, and 27,
which were given as the means of two experiments. b Data are expressed
as averages ( SDs from doseꢀresponse curves of three independent
experiments, except for 23, which is the mean value of two experiments.
ND = not determined.
a Reagents and conditions: (a) Me3SiCHN2 (3 equiv), iPr2NEt, MeOH/
MeCN (2:3), room temperature, 18 h. (b) H2, 10%Pd/C, EtOH, room
temperature, 20 h. (c) Me2SO4, K2CO3, acetone, room temperature, 1 h.
bridged the gap of aigialomycin D against CDK2, which has not
been disclosed previously.
To identify better kinase targets, aigialomycin D (1) was
screened against a panel of 96 kinases at 10 μM (see the Sup-
porting Information). Five most inhibited kinases with an
inhibition of <10% of negative control are listed in Table 2.
Among these, UFO/ARK/Tyro7 (AXL),34 FMS-like tyrosine
kinase 3 (FLT3),35,36 mitogen-activated protein kinases inter-
acting kinases (MKNK, or MNK),37ꢀ39 and multifaceted polo-
like kinase 4 (PLK4)40ꢀ42 are validated targets for oncology drug
development. The Kd values of these kinases against 1 showed
that MKNK2 (also named MNK2 and referred to hereafter) was
the most inhibited with a Kd value of 0.16 μM. This high activity
is very attractive as MNKs are known to phosphorylate and
regulate oncogene eIF4E,43,44 which is an emerging target
for cancer drug development.37ꢀ39 In addition, the biological
implication of the great selectivity of MNK2 over MNK1 (Kd =
40 μM, not shown in Table 2) could be worth exploring.
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LETTER
Table 2. Kinases with Inhibition <10% Control by 1 and
’ AUTHOR INFORMATION
Their Kd Values
Corresponding Author
kinase
AXL
FLT3
MNK2
PLK4
PRKCE
*Fax: +65-64642102. E-mail: chen_anqi@ices.a-star.edu.sg@
ices.a-star.edu.sg (A.C.) or christina_chai@ices.a-star.edu.sg
(C.L.L.C.).
% controla
4.7
1.0
7.1
0.15
0.16
9.6
7.2
12
Kd (μM)
0.30
0.26
a Determined at 10 μM with DMSO as a negative control. A lower value
Funding Sources
This work is funded by the Agency for Science, Technology and
Research (A*STAR), Singapore.
indicates a stronger inhibition.
Table 3. IC50 Values of Compounds against MNK2
IC50 (μM)a
compound
IC50 (μM)a
’ ACKNOWLEDGMENT
compound
We are grateful to Dr. Jeffrey Hill (Experimental Therapeutic
Centre, Agency for Science, Technology and Research) for the
support on the MNK2 assay, Dr. Paul H. Bernardo [Institute of
Chemical and Engineering Sciences (ICES), Agency for Science,
Technology and Research] for the help on molecular modelling,
and Wee Xi Kai (Department of Pharmacy, National University
of Singapore) for the assistance on the CDK2 assay.
1
11
12
13
14
15
16
17
0.45 ( 0.2
18
19
20
21
22
23
24
27
>10
1.35 ( 0.07
>10
0.58 ( 0.36
>10
>10
>10
1.61 ( 0.81
>10
>10
>10
>10
>10
>10
>10
a Data are expressed as averages ( SD from dose response curves of 2
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Supporting Information. Experimental procedures and
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characterization data for all new compounds and protocol for
IMAP assays for CDK2 and MNK2. This material is available free
of charge via the Internet at http://pubs.acs.org.
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