Synthesis and structure-activity relationship study of 5a-carbasugar analogues of SL0101

Article abstract of DOI:10.1021/ml5004525

The Ser/Thr protein kinase, RSK, is associated with oncogenesis, and therefore, there are ongoing efforts to develop RSK inhibitors that are suitable for use in vivo. SL0101 is a natural product that demonstrates selectivity for RSK inhibition. However, SL0101 has a short biological half-life in vivo. To address this issue we designed a set of eight cyclitol analogues, which should be resistant to acid catalyzed anomeric bond hydrolysis. The analogues were synthesized and evaluated for their ability to selectively inhibit RSK in vitro and in cell-based assays. All the analogues were prepared using a stereodivergent palladium-catalyzed glycosylation/cyclitolization for installing the aglycon. The L-cyclitol analogues were found to inhibit RSK2 in in vitro kinase activity with a similar efficacy to that of SL0101, however, the analogues were not specific for RSK in cell-based assays. In contrast, the d-isomers showed no RSK inhibitory activity in in vitro kinase assay. (Chemical Equation Presented).

Full text of DOI:10.1021/ml5004525

Letter
pubs.acs.org/acsmedchemlett
Synthesis and Structure−Activity Relationship Study of 5a-
Carbasugar Analogues of SL0101
Mingzong Li, Yu Li, Roman M. Mrozowski, Zachary M. Sandusky, Mingde Shan,∥,∇
†
,∇
†,∇
‡,∇
§,∇
Xiwen Song,†,∇ Bulan Wu, Qi Zhang, Deborah A. Lannigan,* and George A. O’Doherty*
∥,∇
†,∇
,‡,§
,†
†
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States
‡
§
Departments of Pathology, Microbiology, and Immunology, and Cancer Biology, Vanderbilt University, Nashville, Tennessee
3
7232, United States
∥
Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506, United States
*
S Supporting Information
ABSTRACT: The Ser/Thr protein kinase, RSK, is associated
with oncogenesis, and therefore, there are ongoing efforts to
develop RSK inhibitors that are suitable for use in vivo. SL0101
is a natural product that demonstrates selectivity for RSK
inhibition. However, SL0101 has a short biological half-life in
vivo. To address this issue we designed a set of eight cyclitol
analogues, which should be resistant to acid catalyzed anomeric
bond hydrolysis. The analogues were synthesized and evaluated
for their ability to selectively inhibit RSK in vitro and in cell-
based assays. All the analogues were prepared using a
stereodivergent palladium-catalyzed glycosylation/cyclitoliza-
tion for installing the aglycon. The L-cyclitol analogues were found to inhibit RSK2 in in vitro kinase activity with a similar
efficacy to that of SL0101, however, the analogues were not specific for RSK in cell-based assays. In contrast, the D-isomers
showed no RSK inhibitory activity in in vitro kinase assay.
KEYWORDS: Ser/Thr protein kinase, cyclitol, RSK inhibition, SL0101, de novo synthesis
he Ser/Thr kinases, RSK, have emerged as a potential
1
T
drug target for numerous cancers. A number of RSK
2
−11
inhibitors have been identified
L-rhamnoside SL0101 (1a) is the only allosteric inhibitor of
7
and of these the kaempferol
1
0
RSK (Figure 1), which most likely accounts for its specificity.
Figure 2. Structure of D-/L-SL0101 analogues 1−4.
Figure 1. Structures of SL0101 (1a) and top analogue 2.
would serve as exact conformational mimics of the natural
sugar; whereas the enantiomeric analogues (ent)-3a−c serve as
control molecules. Finally, to further test the importance of the
C6″ alkyl group, we envisioned preparing and evaluating the
desmethyl cyclitol analogue 4.
RSK is unusual in that it contains two nonidentical kinase
1
2
domains. On the basis of the crystal structure of SL0101 in
complex with the RSK2 N-terminal kinase domain (NTKD) we
generated the derivative, C3″/C4″-diacetate with a C6″-n-
propyl substituent 2, which has a 50-fold higher affinity for RSK
1
3−15
than SL0101.
In an effort to further explore the structure−
Special Issue: New Frontiers in Kinases
activity relationship of SL0101 as it relates to RSK inhibition,
we targeted for synthesis cyclitol (aka, 5a-carbasugar) analogues
of SL0101 (e.g., 3 and 4, Figure 2).
Received: November 3, 2014
Accepted: November 26, 2014
1
6,17
We hypothesized that
the cyclitol analogues (3a−c) (i.e., sans-anomeric stabilization)
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ml5004525 | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
We have been developing practical and generalizable
16,17,27,28
Scheme 2. Enantiodivergent Cyclitolization of Aglycon 7
18−26
approaches to both pyranose
and 5a-carbasugar
and have reported synthetic approaches to SL0101 and its
derivatives. The general approach to these analogues is outlined
in Scheme 1. The technology that enables this approach was
Scheme 1. Enantiodivergent Synthesis of SL0101 Analogues
1
and 3
hydrolysis and acylation sequence (11 to 13). Using an Upjohn
3
5
dihydroxylation (1% OsO /NMO), the C2″/C3″-hydroxyl
4
groups were stereoselectively installed in 14. The required C3″
acetate was regioselectively installed by means of the Taylor
36−39
catalysis (14 to 15).
Finally hydrogenolysis was used for a
Scheme 3. Synthesis of SL0101 Cyclitol Analogue 4
2
7−31
the use of a Pd-catalyzed glycosylation
tion
or cyclitoliza-
1
6,17
and subsequent post-glycosylation transformations.
Using the Pd-catalyzed glycosylation, the desired pyranose
analogues 1a−c and (ent)-1a−c were produced in five to seven
steps from pyranones α-L-5 and α-D-5, respectively. Using the
related Pd-catalyzed cyclitolization and in the same number of
steps, the desired cyclitol analogues 3a−c and (ent)-3a−c were
produced from the corresponding enones α-L-6 and α-D-6.
The key to the success of this approach is the reliance of an
enantio-divergent (i.e., D/L) and highly stereocontrolled
synthesis of both glycosyl- and cyclitol-donors from readily
available intermediates (8 and 9, Scheme 1). For instance, the
pyranose glycosyl donors were readily prepared in three steps
from achiral acylfuran intermediate 8. In contrast, the
carbasugar cyclitol donor 6 was significantly more difficult to
prepare. Like the pyranones 5, the cyclitol 6 can also be
prepared from a single intermediate, D-quinic acid 9. Thus, in
11 steps, D-quinic acid was converted into α-D-enone α-D-6,
whereas in a related 12-step sequence quinic acid can be also
converted into its enantiomeric enone, α-L-6.
With access to the cyclitol analogues 3, we next pursued the
de novo asymmetric synthesis of the desmethyl cyclitol
analogues 4 and (ent)-4 (Schemes 3 and 4). Interestingly, the
removal of the C6″-methyl group greatly simplifies the
analogue synthesis. The simplicity of this approach is enabled
by the use of the Trost asymmetric allylation of 7 with meso-
global debenzylation of 15 to give the desired cyclitol analogue
4. Using an identical sequence, the enantiomer 11 was
converted into the enantiomeric analogue (ent)-4 (Scheme 4).
Using purified recombinant RSK2 enzyme in an in vitro
kinase assay, the analogues (ent)-1a, 3a−c, (ent)-3a−c, 4 and
(ent)-4 were evaluated for their ability to inhibit RSK2 kinase
activity. Nonlinear regression analysis was used to fit the data
(Table 1). Regardless of substitution, we found an absolute
requirement for the L-isoform, as none of the D-isoforms
displayed any RSK2 kinase inhibitory activity at concentrations
≤30 μM.
Interestingly, we found that replacing the ring oxygen in the
rhamnose ring with a methylene did not interfere with in vitro
RSK2 inhibitory activity (Table 1). In fact, the cyclitol analogue
3a was a slightly better inhibitor of RSK than SL0101, albeit the
difference is unlikely to be biologically meaningful. In contrast,
the cyclitols with varied acetate substitution (3b and 3c) had
40
1
1
,4-bis-benzoate 10 to form either enantiomer of cyclitol
3
2−34
1.
Thus, by appropriate choice of the chiral ligand,
cyclitol 11 (via (S,S)-DACH) or its enantiomer (ent)-11 (via
(
R,R)-DACH) was prepared in only one stereodivergent step.
The enantiomeric excess of 12 and (ent)-12 were determined
to be >96% ee by Mosher ester analysis. This was accomplished
by converting 12 and (ent)-12 into their corresponding Mosher
ester and integrating resolved diasteromeric vinyl protons in the
1
H NMR (see Supporting Information).
With the C1″/C4″ stereochemistry installed in 11, the C4″
benzoate was transformed into an acetate (Scheme 3), via a
B
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ACS Medicinal Chemistry Letters
Letter
Scheme 4. Synthesis of SL0101 Cyclitol Analogue (ent)-4
Figure 3. C3″,C4″ acetates are essential for preferential inhibition of
MCF-7 proliferation. The inhibitors were added at time 0, and ATP
content was measured after 48 h of treatment. Values are the fold
proliferation as a % of the control (n ≥ 2 in triplicate; mean, S.D.; *p <
0
.01 in a Student’s t test compared to the appropriate cell line in the
presence of vehicle).
a
Table 1. In Vitro Potency of SL0101 (1a) and Analogues
name
RSK2 IC50 (μM)
RSK2 IC50 p(1a)
SL0101 (1a)
0.37 ± 0.13
N.D.
(
ent)-1a
3
a
0.27 ± 0.15
N.D.
0.0404
(
ent)-3a
3
b
1.23 ± 0.62
N.D.
<0.0001
<0.0001
<0.0001
(
ent)-3b
3
c
1.60 ± 0.66
N.D.
(
ent)-3c
4
8.93 ± 1.02
N.D.
(
ent)-4a
a
RSK2 IC : concentration needed for 50% RSK2 inhibition (n > 2;
50
quadruplicate: mean; S.D., p(1a) Student’s t test compared to
SL0101(1a)). N.D.: no inhibition detected.
higher IC s. This trend was consistent to what was observed
50
41
for the related rhamnose sugar analogues (1b and 1c). The
C6″ methyl group proved to be important for activity, as the
desmethyl analogue 4 was a poor inhibitor. Even in the less
active desmethyl series, the importance of the sugar absolute
stereochemistry could be seen, as 4 was significantly more
active than its enantiomer (ent)-4. This result is consistent with
our crystal structure of the RSK2 NTKD/SL0101 complex.
Specifically, we observed SL0101 in a specific 3D orientation
with the C6″ methyl group residing in a key hydrophobic
Figure 4. Efficacy and specificity of analogues 3a and 3c for inhibition
of RSK. As described in Figure 3 (n ≥ 2 in triplicate; mean, S.D.; *p <
0
.01 in a Student’s t test compared to control).
1
0
pocket and that alkyl substitution of the C6″ alkyl group (Me
comparison, at 100 μM SL0101 (1a) inhibited MCF-7
proliferation by ∼60% but had no effect on MCF-10A
proliferation. Both analogues 3a and 3c were able to completely
inhibit proliferation of MCF-7 cells at ∼50 μM, but they also
significantly inhibited MCF-10A proliferation at that concen-
tration (Figure 4). For both 3a and 3c the dose response
differed by ∼3-fold between MCF-7 and MCF-10A cells. This
modest differential effect suggests that the inhibitors are not
specific for RSK, as we have found that MCF-10A proliferation
is not dependent on RSK.
13
to n-Pr) increased the affinity for RSK2.
The ability of the analogues to inhibit the proliferation of the
breast cancer cell line, MCF-7, was compared to that obtained
with the immortalized nontransformed human breast cell line,
MCF-10A. We have found that a preferential ability to inhibit
MCF-7 compared to MCF-10A proliferation correlates with
1
3,40−43
RSK inhibition.
The cyclitol analogue 3b inhibited both
cell lines to the same extent, which suggests that it does not
specifically inhibit RSK (Figure 3). In contrast, the enantiomer
(
ent)-3b showed no inhibition of either cell line. At 25 μM the
To further investigate the specificity of 3a and 3c for
inhibition of RSK we determined their ability to inhibit known
RSK substrates in comparison to SL0101. We tested the
analogue 3a inhibited MCF-7 proliferation by ∼60% but also
significantly inhibited MCF-10A proliferation (Figure 4A). For
C
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ACS Medicinal Chemistry Letters
Letter
compounds 3a and 3c at 50 μM, which is the cytostatic
concentration. Lysates were generated from MCF-7 cells that
had been treated with the mitogen, phorbol myristate acetate
phosphorylations generated by RSK, and therefore, observing
changes with SL0101 is expected. On the basis of our
immunoblot analysis, 3a and 3c do not inhibit kinases that
prefer an Arg at the -5 position but do inhibit kinases that
prefer an Arg at the -3 and -2 positions from the Ser or Thr
phosphorylation site. This information narrows down the
possible candidate kinases from within the AGC kinase family
that 3a and 3c target.
In conclusion, using a Pd-catalyzed glycosylation or
cyclitolization in combination with post-glycosylation trans-
formation, an enantiomerically diverse set of SL0101 analogues
were prepared and evaluated as RSK inhibitors. Replacement of
the L-rhamno-sugar with a L-rhamno-5a-carbasugar did not
substantially alter the ability of the analogues to inhibit RSK
kinase activity in vitro; however, the compounds demonstrated
off-target effects in cell-based assays. Further efforts aimed at
identifying cyclitol analogues that specifically target RSK
inhibition are ongoing and will be reported in due course.
(
PMA) after a pretreatment with inhibitor or vehicle. Inhibition
of RSK is known to result in an increase in the phosphorylation
of eukaryotic elongation factor 2 (p-eEF2) via release of the
44
RSK-induced repression of eEF2 kinase. As expected SL0101
dramatically enhanced p-eEF2 levels, but 3a and 3c induced
only a minor increase (Figure 5A). To further evaluate whether
ASSOCIATED CONTENT
Supporting Information
■
*
S
Experimental details for synthetic procedure and compound
characterization. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
E-mail: G.ODoherty@neu.edu.
E-mail: deborah.lannigan@vanderbilt.edu.
■
*
*
Author Contributions
∇
Co-first authors; the order is alphabetical.
Funding
This work was supported by NIH (GM09025901 to G.A.O.),
NSF (CHE-0749451 to G.A.O.), and Susan G. Komen Breast
Cancer Foundation (#IIR12223770 to D.A.L.).
Figure 5. Evaluation of 3a and 3c as RSK-specific inhibitors in MCF-7
cells. MCF-7 cells were treated with PMA after pretreatment with the
indicated inhibitors. Lysates of the cells were immunoblotted. The
arrows indicate bands whose intensity decreases upon treatment of
cells with SL0101 (1a).
Notes
The authors declare no competing financial interest.
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