Polar 3-alkylidene-5-pivaloyloxymethyl-5′-hydroxymethyl-γ-lactones as protein kinase C ligands and antitumor agents

Article abstract of DOI:10.1016/j.bmcl.2009.12.058

A series of DAG-lactones with polar 3-alkylidene substituents have been investigated as PKC-α ligands and antitumor agents. Extensive analysis of structure-activity relationships for the 3-alkylidene chain revealed that polar groups such as ether, hydroxy

Full text of DOI:10.1016/j.bmcl.2009.12.058

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1008–1012
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Polar 3-alkylidene-5-pivaloyloxymethyl-50-hydroxymethyl-
as protein kinase C ligands and antitumor agents
c-lactones
Ji-Hye Kang a, Yerim Kim a, Shin-Hye Won a, Song-Kyu Park b, Chang Woo Lee b, Hwan-Mook Kim b,
Nancy E. Lewin c, Nicholas A. Perry c, Larry V. Pearce c, Daniel J. Lundberg c, Robert J. Surawski c,
Peter M. Blumberg c, Jeewoo Lee a,
*
a Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea
b Korea Research Institute of Bioscience and Biotechnology, Bioevaluation Center, 685-1 Yangcheong-ri, Ochang-eup, Cheonewon-gun, Chungcheongbuk-do 363-883, Republic of Korea
c Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of DAG-lactones with polar 3-alkylidene substituents have been investigated as PKC-
a ligands
Received 21 October 2009
Revised 10 December 2009
Accepted 11 December 2009
Available online 21 December 2009
and antitumor agents. Extensive analysis of structure–activity relationships for the 3-alkylidene chain
revealed that polar groups such as ether, hydroxyl, aldehyde, ester, acyloxy, and amido were tolerated
with similar binding affinities and reduced lipophilicities compared to the corresponding unsubstituted
alkylidene chain. Among the derivatives, compounds 5, 6 and 8 with an ether type of side chain showed
high binding affinities in range of Ki = 3–5 nM and excellent antitumor profiles, particularly against the
colo205 colon cancer and the K562 leukemia cell lines.
Keywords:
Protein kinase C
Diacylglycerol
DAG-lactone
Ó 2010 Elsevier Ltd. All rights reserved.
Antitumor activity
The protein kinase C (PKC) family of serine/threonine kinases
plays a pivotal role in cellular signal transduction.1,2 These en-
zymes are activated by diacylglycerol (DAG) which can be gener-
ated either by phospholipase C (PLC) mediated hydrolysis of
phosphatidylinositol-4,5-bisphosphate (PIP2) or indirectly by
phospholipase D followed by phosphatidate phosphatase.3 DAG
binds to the C1 domains of both the calcium-dependent classical
PKC have also proven to have anticancer activity. Both bryostatin
18 and ingenol 3-angelate (PEP005)9 are in multiple clinical trials.
In addition, DPP (12-deoxyphorbol-13-phenylacetate) and pros-
tratin have been shown to be potent inhibitors of tumor promotion
in mice, contrasting with phorbol-12-myristate-13-acetate (PMA)
which is the paradigm for a tumor promoter.10,11 In addition, pros-
tratin (12-deoxyphorbol-13-acetate), gnidimacrin,12 and ingenol-
3-angelate9 have also demonstrated antitumor activities in se-
lected cell lines.
PKC isoforms
a, b, and
c and the novel or calcium-independent
PKC isoforms d,
e, g
and h. The binding activates these enzymes
and promotes their association with the membrane phospholipids,
inducing the translocation of cytosolic PKC to cellular membranes.4
In addition to the PKCs, other C1 domain-containing receptors,
including members of the RasGRP, chimaerin, MUNC13, PKD and
DAG kinase families, also function in DAG signaling and therefore
represent potential sites of action for DAG analogs.5
Changes in the level or activity of PKC in tumors, its role in sig-
naling pathways involved in cancer formation, and the effect of its
overexpression or knockout in animal models all emphasize its
important role in cancer.6 Reflecting this importance, a variety of
inhibitors of PKC have been tested in in vitro and in vivo cancer
models and developed clinically as a new class of antitumor
agents.7 It is important to emphasize, however, that activators of
Phorbol esters bind competitively to the DAG binding site on
the C1 domains with affinities several orders of magnitude greater
than those of DAGs and have provided powerful pharmacological
tools for studying PKC function.13,14 Phorbol esters function as po-
tent DAG surrogates because their conformationally rigid scaffold,
unlike the flexible glycerol backbone of DAG, is able to specifically
direct the hydrophilic pharmacophores of the ligand. In an attempt
to improve binding affinity of DAG through conformational restric-
tion, we had previously investigated a series of conformationally
constrained DAG analogues and finally obtained ‘ultrapotent’
DAG-lactone analogues built on a 5-[(acyloxy)methyl]-5-(hydroxy-
methyl)tetrahydro-2-furanone template.15 Depending on the type
of hydrophobic substitution, some of the compounds built with
this template displayed low-nanomolar binding affinities and a
variety of biological profiles (see Fig. 1).16
Branched DAG-lactones, for example HK-434, were shown to
* Corresponding author. Tel.: +82 2 880 7846; fax: +82 2 888 0649.
E-mail address: jeewoo@snu.ac.kr (J. Lee).
exhibit high binding affinities for PKC-
a and demonstrated a
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.058

J.-H. Kang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1008–1012
1009
mean-graph profile of DAG-lactones matched with that of pros-
tratin, the nontumor-promoting antitumor phorbol ester, indicat-
ing that the antitumor mechanism of DAG-lactone results from
PKC activation.17
The 3-alkylidene DAG-lactones such as compounds 1 and 2 are
highly lipophilic. In an effort to develop more drug-like DAG-lac-
tones, we have reduced the lipophilicity of the DAG-lactones by
incorporating a variety of polar groups into the 3-alkylidene chain.
In this Letter, we describe the structure–activity relationships for
PKC binding and for inhibition of growth of a variety of tumor
cell lines by these DAG-lactones possessing polar 3-alkylidene
chains.
R
R
O
O
O
O
O
O
O
13
O
H
9
HO
H
OH
OH
3
O
OH
20
HK-434
Phorbol ester
Figure 1.
The syntheses of DAG-lactones with polar 3-alkylidene chains
are described in Schemes 1–3. Basically, alkylation of the protected
5,5-disubstituted c-lactone, previously reported, with various po-
lar side chains followed by routine work-up provided the corre-
sponding final compounds.
selective and potent antitumor profile in the National Cancer
Institute (NCI) 60-cell line in vitro screen. The NCI’s computer-
ized, pattern-recognition program COMPARE showed that the
O
a, b
ArO
O
O
O
O
O
BnO
BnO
Ar=4-methoxyphenyl
c-e for 1-13
c-f for 14-17
(E)
(Z)
(E)
(E)
(E)
(Z)
(E)
(E)
(E)
(E)
(E)
(E)
(E)
(E)
(E)
(E)
(Z)
R=CH3
R=CH3
1
2
3
4
5
6
7
8
n=12
n=12
n=7
n=11
n=15
n=15
n=7
n=7
n=7
n=7
n=7
n=7
n=3
n=7
n=11
n=15
n=15
R=OCH3
R=OCH3
R=OCH3
R=OCH3
R=O(CH2)4CH3
R=O(CH2)8CH3
R=OCH2OCH3
R=OCH2O(CH2)2OCH3
R=O(CH2)2CH(CH3)2
R=Oc-C5H9
R=O(CH2)8CH3
R=OH
R=OH
R=OH
R=OH
O
O
O
O
HO
9
(CH2)n
R
10
11
12
13
14
15
16
17
Scheme 1. Syntheses of hydroxyl and ether analogues. Reagents and conditions: (a) CAN, CH3CN–H2O, 0 °C; (b) (CH3)3CCOCl, Et3N, DMAP, CH2Cl2; (c) LiHMDS,
CH3(CH2)12CHO for 1–2, RO(CH2)nCHO for 3–13, TrO(CH2)nCHO for 14–17, THF, ꢀ78 °C; (d) (i) MsCl, NEt3, CH2Cl2, (ii) DBU; (e) BCl3, CH2Cl2, ꢀ78 °C; (f) CF3CO2H, CH2Cl2, 0 °C.
a, e for 19-22
O
O
b, e for 23
O
O
O
O
b, c, e for 24-25
O
O
BnO
HO
(CH2)n
(CH2)n
R
OH
a, d, e
n=6
R=CHO
R=CHO
R=CHO
R=CHO
R=CO2H
R=CO2CH3
R=CO2CH3
(E)
19
n=10
n=14
n=14
n=14
n=6
(E)
(E)
(Z)
(E)
(E)
(E)
20
21
22
23
24
25
O
O
O
O
HO
n=14
(CH2)6
HO
(CH2)7CH3
18
Scheme 2. Syntheses of aldehyde and carboxylate analogues. Reagents and conditions: (a) PCC, 4 Å MS, CH2Cl2; (b) PDC, DMF; (c) TMS–diazomethane, MeOH; (d) C8H17MgBr,
ether, ꢀ10 °C; (e) BCl3, CH2Cl2, ꢀ78 °C.

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J.-H. Kang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1008–1012
O
O
O
O
O
O
a
O
O
BnO
BnO
(CH2)15OTr
(CH2)15
O
H
O
h for 26
e, f, h for 29
e-h for 30
b, c, h for 27
b, d, h for 28
e-g, c, h for 31
O
O
O
O
O
O
O
O
HO
HO
(CH2)15
O
R
(CH2)15
R
O
26 R=H
29 R=N3
27 R=CH3
30 R=NH2
28 R=C(CH3)3
31 R=NHCOCH3
Scheme 3. Syntheses of O-acylated and amino analogues. Reagents and conditions: (a) HCO2H, CH2Cl2, rt; (b) K2CO3, MeOH, rt; (c) Ac2O, NEt3, DMAP, CH2Cl2, rt; (d)
(CH3)3CCOCl, NEt3, CH2Cl2, rt; (e) CF3CO2H, CH2Cl2, 0 °C; (f) PPh3, DEAD, DPPA, THF, rt; (g) PPh3, H2O, THF, rt; (h) BCl3, CH2Cl2, ꢀ78 °C.
The interaction of the synthesized DAG-lactones with PKC was
assessed in terms of the ability of the ligand to displace bound
[20-3H]phorbol 12,13-dibutyrate (PDBu) from the recombinant
binding affinity than the Z-isomer (17) in contrast to the general
finding15 with aliphatic side chains. Positioning of the hydroxyl
PKC-a isoform in the presence of phosphatidylserine as previously
described.17 The IC50 values were determined by fitting the data
points to the theoretical competition curve, and the Ki values for
inhibition of binding were calculated from the corresponding IC50
values (Table 1). The antitumor activity of selected compounds
was evaluated against eight cancer lines, including leukemia
(K562, MOLT 4F, CCRF-CEM and HL-60), breast (HS 578T), colon
(Colo#205), melanoma (SK-MEL-5) and lung (NCI-H322) cell lines
and is expressed as GI50, the concentration that yields 50% inhibi-
tion of cell growth (Table 2).
Table 1
Binding affinities of DAG-lactones
O
O
O
O
HO
R
Compd #
Geo
R
Ki
(nM)
c Log P
The incorporation of a tetradecyl alkyl chain into the DAG-lac-
tone template provided reference compounds 1 (E-form) and 2
(Z-form). These compounds possessed a lipophilicity, expressed
in terms of a calculated c log P18 of 6.71 and yielded binding affin-
ities of Ki = 7.83 and 7.15 nM, respectively.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
E
Z
E
E
E
Z
E
E
E
E
E
E
E
E
E
E
Z
E
E
E
E
Z
E
E
E
E
E
E
E
E
E
(CH2)12CH3
(CH2)12CH3
(CH2)7OCH3
(CH2)11OCH3
(CH2)15OCH3
(CH2)15OCH3
(CH2)7O(CH2)4CH3
(CH2)7O(CH2)8CH3
(CH2)7OCH2OCH3
(CH2)7OCH2O(CH2)2OCH3
(CH2)7O(CH2)2CH(CH3)2
(CH2)7O-c-C5H9
(CH2)3O(CH2)8CH3
(CH2)7OH
(CH2)11OH
(CH2)15OH
(CH2)15OH
(CH2)6CH(OH)(CH2)7CH3
(CH2)6CHO
(CH2)10CHO
(CH2)14CHO
(CH2)14CHO
(CH2)14CO2H
(CH2)6CO2CH3
(CH2)14CO2CH3
(CH2)15OCOH
(CH2)15OCOCH3
(CH2)15OCOC(CH3)3
(CH2)15N3
7.83
7.15
191
8.2
4.4
5.0
8.1
3.2
198.4
323
7.74
10.2
7.44
378
14.5
6.4
8.24
118
39.3
30.3
6.38
11.4
29.7
533
6.83
8.0
9.3
10.5
15.6
36.4
( 0.55)
( 0.51)
( 8.5)
( 0.3)
( 0.1)
( 0.4)
( 0.8)
( 0.4)
( 4.8)
( 17)
6.71
6.71
3.01
4.98
6.93
6.93
4.97
6.94
2.75
2.78
4.84
4.33
4.97
2.71
4.68
6.64
6.64
6.57
2.28
4.25
6.21
6.21
6.46
2.82
6.75
6.69
7.24
8.60
7.67
6.23
6.17
DAG-lactones (3–13) were designed with oxygenated side
chains. Incorporation of an oxygen into compound 1 at three differ-
ent positions provided the compounds 4, 7 and 13. They were cal-
culated to be less lipophilic by 1.74 log units; nevertheless, they
possessed binding affinities similar to the parent. Compounds 5
and 8 showed similar behavior. Additional oxygens rendered the
DAG-lactone much less lipophilic, as shown for compounds 9 and
10; however, they reduced their binding affinities dramatically as
well. The pattern of the alkyl chain next to the oxygen did not af-
fect the binding affinities, as observed with compounds 7 (linear,
Ki = 8.1 nM), 11 (branched, Ki = 7.74 nM) and 12 (cyclic,
Ki = 10.2 nM). The result indicated that incorporation of an oxygen
into the 3-alkylidene chain of the DAG-lactone, regardless of posi-
tion, appears to be optimal for lowering lipophilicity without
affecting the binding affinity.
We next investigated the behavior of DAG-lactones with polar
groups, such as hydroxyl (14–18), aldehyde (19–22), carboxylate
(23–25), acyloxy (26–28), azido (29) and amino (30–31), at the ter-
minus of the side chain. The hydroxyl analogues (14–18) had sim-
ilar binding affinities compared to the corresponding alkyl
analogues (compound 1 vs 16 and 2 vs 17). Interestingly, for the
hydroxyl analogues, the E-isomer (16) showed modestly better
( 0.35)
( 1.3)
( 0.11)
( 15)
( 0.4)
( 1.4)
( 0.55)
( 6.8)
( 0.72)
( 2.5)
( 0.74)
( 0.79)
( 0.49)
( 19)
( 0.18)
( 1.1)
( 1.1)
( 0.58)
( 1.5)
( 3.1)
( 0.44)
(CH2)15NH2
(CH2)15NHCOCH3
8.25

J.-H. Kang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1008–1012
1011
Table 2
Antitumor activities of DAG-lactones (GI50
)
Compd #
PKCa
Leukemia
CCRF-CEM
Breast
Colon
Melanoma
SK-MEL-5
Lung
K562
MOLT 4F
HL-60
HS 578T
Colo #205
NCI-H322
Ki (nM)
GI50
(lg/ml)
ADR
HK-434
1
4
5
6
7
8
9
15
17
18
21
22
25
27
28
30
31
0.375
0.118
<0.1
0.277
1.098
0.227
2.384
0.498
1.639
1.029
2.139
1.842
1.343
1.374
7.910
>10
2.022
>10
1.546
0.605
3.167
6.352
0.181
<0.1
0.140
0.701
4.261
<0.1
0.877
0.304
>10
0.650
6.630
5.715
0.933
>10
0.413
3.469
2.398
5.217
4.653
3.967
2.960
4.525
>10
>10
6.389
>10
>10
>10
0.596
3.304
2.266
7.337
5.449
6.770
3.002
4.637
>10
>10
>10
>10
>10
0.523
0.138
0.253
0.541
0.118
0.178
0.491
0.264
2.008
2.487
2.337
8.908
>10
5.144
3.861
2.099
0.597
1.535
4.735
0.481
2.153
0.779
2.808
1.753
2.134
2.994
1.431
8.326
5.813
5.336
>10
0.615
4.236
>10
>10
>10
>10
9.520
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
8.428
>10
2.9
7.83
8.2
4.4
5.0
0.516
0.189
0.138
1.149
0.156
3.694
1.090
0.872
7.303
5.106
2.579
0.856
0.959
0.352
1.518
3.384
8.1
3.2
198
14.5
8.24
118
6.38
11.4
6.83
9.3
>10
>10
>10
>10
>10
5.238
>10
0.691
7.55
>10
2.820
1.076
>10
>10
7.783
>10
>10
7.796
5.618
3.456
5.104
>10
10.5
36.4
8.25
>10
group was critical. The hydroxyl in the middle of the side chain
caused a dramatic reduction in binding affinity (compound 16 vs
18). The aldehyde analogues (19–22) showed an SAR pattern sim-
ilar to that of the hydroxyl analogues. In particular, compound 21
exhibited better binding affinity despite of lower log P value com-
pared to compound 1. The carboxylic acid analogue (23) showed
moderately reduced binding affinity compared to the parent com-
pound; however, the ester analogue (25) had a similar affinity. The
acyloxy analogues (26–28) showed activities similar to those of the
other polar compounds. However, a higher log P rather caused a
lower binding affinity. Whereas the azide (29) and amino (30)
analogues showed moderate decreases in binding affinities, the
amide analogue (31) displayed binding affinity even better than
that of the corresponding ester (27).
We conclude that incorporation of polar groups at the terminus
of the linear alkyl chain had little effect on binding affinity in most
cases. However, charged polar groups, such as carboxylate and
amino, caused a moderate reduction in binding affinity. The posi-
tion of the polar groups is also critical. Whereas the polar groups
are tolerated at the terminus of the chain, there was a dramatic
reduction in binding affinity when they were present in the middle
of the chain. These results suggest that whereas the middle part of
side chain needs to be inserted into the hydrophobic interior of the
membrane, the terminus may be able to fold back to the region of
the hydrophilic lipid head groups.
affinities (Ki = 36–198 nM) displayed moderate to low activities.
The antitumor activity of the DAG-lactones was selective for the
colon cancer and several of the leukemia cell lines compared to
adriamycin. In particular, compounds 5, 6 and 8 demonstrated
excellent tumor inhibition against the colon cancer line which
was several times more potent than adriamycin.
Interestingly, although compounds 21 and 25 had similar PKC
binding affinities and lipophilicities compared to compound 5, they
showed weak cell growth inhibition. The role of intracellular local-
ization in determining functional activity is critical, and the ability
of PKCs to phosphorylate their substrates depends not only on
their intrinsic level of catalytic activity but also on their proximity
to their potential substrates. Typically, PKCs translocate to differ-
ent cellular compartments in response to ligand binding to the
C1 domains. Stability under the conditions of the cellular assays
may also be a factor.
In summary, in order to find less lipophilic DAG-lactones with
high affinity binding, a series of polar 3-alkylidene DAG-lactones
containing ether, hydroxyl, aldehyde, acid, ester, acyloxy, azido,
amino or amide functionalities have been synthesized and evalu-
ated as PKC-a ligands and as antitumor agents. Most polar groups
except the charged groups were tolerated and found to be compa-
rable to the corresponding linear alkyl ones in terms of binding
affinity. However, positioning of the polar groups and the overall
log P of the compounds were critical for binding to the enzyme.
The etheric DAG-lactones 5, 6 and 8 showed not only high binding
affinity but also significant antitumor activities, particularly
against the leukemia and colon cancer cell lines.
The comparison between c log P and binding affinity indicated
that the overall log P seems to be critical for binding affinity. The
binding affinity of DAG-lactones was correlated with the log P of
the compounds and a value of 6–7 appeared to be optimal for par-
titioning between enzyme and membrane. Importantly, the E-iso-
mer in this series was more potent than the Z-isomer, a result
different from our previous findings in the alkylidene series. It is
of substantial practical significance because the E-isomer is more
synthetically accessible and can be obtained exclusively during
the alkylation step in the DAG-lactone synthesis.
Acknowledgments
This work was supported by a Korea Research Foundation Grant
(KRF-2008-313-E00763), the ERC program of MOST/KOSEF (R11-
2007-107-02001-0) and by the Intramural Research Program of
the NIH, National Cancer Institute, Center for Cancer Research.
The antitumor activities of the PKC ligands were evaluated in
eight different cell lines and compared with adriamycin and HK-
434 as reference compounds. Compound 1 showed significant anti-
tumor activity in a broad range of cell lines with the exception of
the lung cancer cell line. In general, the DAG-lactones (compounds
5, 6, and 8) with high affinities (Ki = 3.2–5) showed significant anti-
tumor activities as expected whereas ligands (9, 18, 30) with low
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