Toward Resolving the Resveratrol Conundrum: Synthesis and in Vivo Pharmacokinetic Evaluation of BCP-Resveratrol

Article abstract of DOI:10.1021/acsmedchemlett.7b00018

Over the last few decades, resveratrol has gained significance due to its impressive array of biological activities; however, its true potential as a drug has been severely constrained by its poor bioavailability. Indeed, several studies have implicated this bioavailability trait as a major road-block to resveratrol’s potential clinical applications. To mitigate this pharmacokinetic issue, we envisioned a tactical bioisosteric modification of resveratrol to bicyclo[1.1.1]pentane (BCP) resveratrol. Relying on the beneficial bioisosteric potential demonstrated by the BCP-scaffold, we hypothesized that BCP-resveratrol would have an inherently better in vivo PK profile as compared to its natural counterpart. To validate such a hypothesis, it was necessary to secure a synthetic access to this novel structure. Herein we describe the first synthesis of BCP-resveratrol and disclose its PK properties.

Full text of DOI:10.1021/acsmedchemlett.7b00018

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Letter
Towards resolving the resveratrol conundrum: Synthesis
and in vivo pharmacokinetic evaluation of BCP-resveratrol
Yi Ling Goh, Yan Ting Cui, Vishal Pendharkar, and Vikrant Arun Adsool
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Towards resolving the resveratrol conundrum: Synthesis and in vivo
pharmacokinetic evaluation of BCP-resveratrol
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Yi Ling Goh,Ϫ Yan Ting Cui,Ϫ Vishal Pendharkar,Ψ and Vikrant A. Adsool*,Ϫ
ϪInstitute of Chemical and Engineering Sciences (ICES), Agency for Science Technology and Research (A*STAR), 8 Bi-
omedical Grove, Neuros, #07-01, Singapore 138665, Singapore; ΨExperimental Therapeutic Center (ETC), Agency for
Science Technology and Research (A*STAR), 31 Biopolis way, Nanos, #03-01, Singapore 138669, Singapore.
KEYWORDS: Bioisostere, bicyclo[1.1.1]pentane, BCP, resveratrol, pharmacokinetic studies.
ABSTRACT: Over the last few decades, resveratrol has gained significance due to its impressive array of biological activi-
ties; however, its true potential as a drug has been severely constrained by its poor bioavailability. Indeed, several studies
have implicated this bioavailability trait as a major road-block to resveratrol’s potential clinical applications. To mitigate
this pharmacokinetic issue, we envisioned a tactical bioisosteric modification of resveratrol to bicyclo[1.1.1]pentane (BCP)
resveratrol. Relying on the beneficial bioisosteric potential demonstrated by the BCP-scaffold, we hypothesized that BCP-
resveratrol would have an inherently better in vivo PK profile as compared to its natural counterpart. To validate such a
hypothesis, it was necessary to secure a synthetic access to this novel structure. Herein we describe the first synthesis of
BCP-resveratrol and disclose its PK properties.
Over the past two decades, resveratrol has become a topic
of intense research in fields such as biology, chemistry and
medicinal chemistry. Indeed, the compound has shown
many biological activities including antioxidant, anti-
cancer, antidiabetic, cardioprotective, and even antiaging
properties.1 Importantly, these modern findings are in line
with the traditional role of this compound, as an active
principle, in Japanese and Chinese folk medicine used to
treat ailments related to liver, skin, heart and lipid metabo-
lism.2 However, despite this impressive array of biological
and medicinal properties, poor bioavailability of resvera-
trol has severely restricted its application in human thera-
peutics. In fact, several studies on resveratrol, and its for-
mulations, in different rodent animal species and humans
have repeatedly emphasized on this fact.3 Clearly, a resolu-
tion to this pharmacokinetic (PK) issue may hold the key to
unlock the true medicinal potential of resveratrol and
thereby facilitate its clinical applications.3,4
keen on deploying bicyclo[1.1.1]pentane (BCP) scaffold, a
known bioisostere of 1,4-disubstituted aryl ring systems,
as a replacement of the phenolic ring A in resveratrol (see
Figure 1).10-12
OH
OH
4
1
3
1
.
.
HO
A
HO
.
OH
OH
Resveratrol (1)
BCP-resveratrol (2)
Figure 1. Resveratrol (1) and BCP-resveratrol (2).
Our hypothesis was supported by strong literature prece-
dents that allowed us to reasonably rationalize BCP-
resveratrol (2) as a potential contender of the parent com-
pound.10-12 On that premise, the broad range of biological
activities showcased by resveratrol makes 2 a strong can-
didate for biological evaluation against all the successful
targets reported for the natural product. However, we
opined that performing an in vivo PK study on 2 first, to
prove or disprove its in vivo PK advantage over 1, was es-
sential to justify such an extensive effort. Additionally, giv-
en our previous experience with the synthesis of BCP de-
rivatives, we were cognizant of the challenges offered by
the non-trivial synthetic behavior of this uniquely strained
scaffold.13-17 In this Letter, we now report the first synthe-
sis of BCP derivative 2, and also disclose its PK studies.
A closer analysis of the low bioavailability of resveratrol
reveals that its low plasma concentrations after oral ad-
ministration is an outcome of rapid first-pass metabolism
to glucuronide and sulfate conjugates.4 An obvious, and
reported, approach to optimize the absorption and metab-
olism properties of resveratrol can be seen in manipula-
tion of its phenolic functional groups.5-7 However, litera-
ture implication of the 4-OH group on the ring A of
resveratrol (1, see Figure 1) in inhibition and cell prolifera-
tion properties, warranted caution in designing of SAR
studies.8 Indeed, the task of retaining the 4-OH group while
eliminating the phenolic ring is challenging. To face this
daunting task we decided to mandate the deployment of
contemporary bioisostere tactics.9 Specifically, we were
Our retrosynthetic protocol for synthesis of BCP-
resveratrol is shown in Scheme 1. We first dissected the
target, 2, at the olefin to give us the aldehyde 4 as a rea-
sonable starting point. In a forward sense, a Wittig reaction
between the ylide 3 and 4 would generate the target com-
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sioned it to originate from 9 via the application of classical
reactions such as the Weinreb ketone synthesis, and the
Baeyer Villiger rearrangement. Thus, the onward synthesis
would commence with the formation of the Weinreb amide
from commercially available 9 to generate 8. The amide in
8 could then be subjected to a stoichiometric amount of
phenyl magnesium bromide to furnish the ketone 7. Bae-
yer Villiger oxidation of the latter would result in for-
mation of the bis ester 6 which in turn could be hydrolyzed
to furnish 5. Reduction of the carboxylic acid in the latter
would give the aldehyde 4.
9
12 resulted in decomposition. Fortunately however, we
could secure the tertiary alcohol in 13 by treating 12 with
MeLi.LiBr at a low temperature.
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Scheme 1. Retrosynthetic analysis of 2.
Equipped with a potential protocol to complete our
endgame, we then ventured into the synthesis of BCP-
resveratrol. Our sequence commenced with the reduction
of the carboxylic acid in 9 to give 14. Next, the primary
alcohol in 14 was concealed as a TBS ether, and the ester
In line with our retrosynthetic plan, we could access the
bis ester 6 in a straightforward fashion.18 However, despite
several attempts, hydrolysis of 6 proved to be difficult and
resulted in a complex mixture of decomposition products
(see Scheme 2). To test the viability of sequential hydroly-
sis, we also attempted hydrolysis of the carboxylic acid 10.
However, that attempt led to a similar outcome. It is possi-
ble that the hydroxide intermediate I, by the virtue of the
electron-withdrawing effect of the carbonyl function in 6
or 10, results in the ring-opening and subsequent disinte-
gration of the BCP scaffold.
was subjected to basic hydrolysis conditions to expose the
acid, and ultimately yield 15. The carboxylic acid in 15 was
transformed into the ketone, 16, by employing the
Weinreb protocol outlined above. Baeyer Villiger oxidation
of the ketone in 16, followed by TBAF promoted removal
of the TBS group gave the primary alcohol 17. The latter
could then be easily oxidized to the aldehyde 18. Notably,
this reaction sequence could be repeated on gram scale to
generate aldehyde 18 in an overall yield of 30%.18
Scheme 2a.Hydrolysis attempts on 6 and 10.
Above results indicated a need for a partial modification
of our original retrosynthetic plan. To that end, we planned
to postpone the liberation of the hydroxyl function to the
last step of our planned synthetic sequence. However, to
endorse this late-stage modification, especially in the light
of our failed hydrolysis attempts, we planned to study the
deprotection of alcohol on a substrate with a non-carbonyl
Scheme 4a. Synthesis of the key intermediate 18.
The endgame of the synthesis commenced with the Wit-
Scheme 3a. Synthesis of 13.
tig olefination of 18 with the phosphine salt to secure 19
functional group at the 3-position of the BCP ring. To that
end, the aryl-BCP-benzoate (12) was identified as an ap-
propriate model substrate. The aryl derivative was
promptly synthesized from 10 by first converting its car-
boxylic acid to perester 11, and then subjecting the latter
to the homolytic aromatic substitution conditions to afford
12 (see Scheme 3).18 Frustratingly, hydrolysis attempts on
1
as a mixture of predominantly E olefin (E:Z = >19:1 by H
NMR). Finally, by employing our conditions for removal of
the benzoyl function, we secured the BCP-resveratrol (2)
in a good yield of 80%.
Scheme 5a. Completion of the synthesis of 2.
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the reported values for resveratrol (for PK parameters see
1
2
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Table 2). Moreover, whereas the plasma levels of resvera-
trol seemed to deplete beyond the scope of reasonable
measurement after an hour in Asensi’s study,20 BCP-
resveratrol concentration could be easily measured up to 4
h with the mean plasma concentrations observed (in three
rats) to be 85 ng/mL at this time point.
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9
Having BCP-resveratrol (2) in hand, we could experi-
mentally determine, and compare, its key in vitro parame-
ters such as thermodynamic solubility and lipohilicity with
resveratrol (1). Thus, the thermodynamic solubility at pH
7.4 was found to be 619±64 µg/ml and 19±2 µg/ml for 2
and 1 respectively. Lipophilicity, measured as LogD (pH
7.4), was found to be 1.9 and 2.9 for 2 and 1 respectively.
Interestingly, the trend of higher solubility and lower lipo-
philicity of 2 as compared to 1, was in line with Stepan’s
seminal findings on the use of BCP motif.12 Encouraged by
these observations, we tested 1 and 2 against available
cancer cell lines; MDA-MB-231 (a metastatic breast cancer
cell line), MiaPaCa2 (Pancreatic cancer cell line), and
SUDHL10 (B cell lymphoma cell line) (see Table 1). We
were pleased to observe that both the compounds showed
similar activities in all three cases.
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Table 2: Comparison of PK parameters of BCP-resveratrol
with reported values of resveratrol.
BCP-
resveratrol
Resveratrol (estimated from
PK parameter
the published data20
)
Table 1: Biological activities of resveratrol and BCP-
resveratrol in selected cancer cell lines.
Cmax (ng/mL)
Tmax (h)
942
273
0.067
0.083
% inhibition of cell prolifera- CC50 (µM)
tion at 30µM18
AUC0-last
(ng.h/mL)
587
47.5
Resveratrol
BCP-
resveratrol
Puromycin
(reference
compound)
Cell Line
t1/2 (h)
2.6
0.19
409
CL/F (L/h/kg)
21.8
MDA-MB-231
Mia-PaCa2
20
30
46
22
30
41
0.48
0.20
0.11
Mean Cmax of BCP-resveratrol was 942 ng/mL, 5 minutes af-
ter oral administration of 20 mg/kg. Mean AUC0-last of BCP-
resveratrol was 587 ng.h/mL.
SU-DHL-10
Clearly, a comparison of the reported PK studies on
resveratrol with our finding on BCP-resveratrol (see Fig-
ure 2) suggests that the latter has an unambiguous PK ad-
vantage, in both absorption and metabolic stability, over
resveratrol.
Next, we dedicated our attention to determining the PK
properties of BCP-resveratrol. At that end, we were cogni-
zant of a few studies on resveratrol wherein a sensitive
bioanalytical method such as LC-MS/MS was employed.19
Based on this, we decided to perform in vivo PK studies of
BCP-resveratrol in rat and then attempt the bioanalysis
using LC-MS/MS. Our final task was to equate the outcome
of our studies with the reported PK data on resveratrol.
For this comparison, we identified the work reported by
Asensi and co-workers as most suitable.20 Thus, during the
course of their extensive investigations on the anti-cancer
and PK properties of resveratrol, the authors have report-
ed resveratrol to reach plasma levels of 273 ng/mL after
oral administration at 20 mg/kg, with Tmax at 5 min. Addi-
tionally, in a more recent study, Kapetanovic and co-
workers carried out similar experiments in rats, albeit
with a much higher dose of 50 mg/kg delivered every 24 h
for 14 days.21 Interestingly, they registered a Cmax of 76.7
ng/mL on day 1 and that of 176 ng/mL on day 14 prove
that the plasma levels of 1 do not increase significantly
despite repetitive dosing.
10
t-resveratrol (as reported by Asensi et al)20
BCP-resveratrol
1
0.1
0.01
0.0
0.2
0.4
0.6
0.8
1.0
Time (h)
Figure 2. Comparison of plasma levels of BCP-resveratrol
with reported plasma levels of resveratrol during a 1 h
timeframe.20
Additionally, we also performed in vitro metabolic stability
tests on both BCP-resveratrol and resveratrol (see Table
3). In human hepatocytes study we observed that the for-
mer had >3-fold higher metabolic stability. In accordance
with our in vivo studies, BCP-resveratrol was seen to have
significantly more metabolic stability than the natural
product in rat hepatocytes.
Pleasingly, our studies revealed that BCP-resveratrol
achieved Cmax of 942 ng/mL, a 3-fold increase over resvera-
trol; and an AUC0-4h of 587 ng.h/mL, a 10-fold increase over
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Table 3: Metabolic stability studies, of resveratrol and
BCP-resveratrol, in human and rat hepatocytes.
1
2
3
4
5
6
7
8
Compound
Human hepatocytes
Rat hepatocytes
t1/2
(min)
Mean ±
SD
CLint, app
(µl/min/1
06 cells)
t1/2
CLint, app
(µl/min/1
(min)
06 cells)
Mean ±
SD
Mean ± SD
Mean ± SD
BCP-
resveratrol
90.4±
11.7
7.7 ± 1.0
24.2 ±
0.5
<7.5+
57.4 ± 1.3
>184.8+
9
Resveratrol
23.2 ±
1.6
29.9 ± 2.1
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+half-life and intrinsic clearance of resveratrol would not be quanti-
fied owing to its very fast metabolism in rat hepatocytes
It is also worth reporting that formation of glucuronide
and sulfate conjugates in human hepatocyctes studies was
significantly higher for resveratrol compared to BCP-
resveratrol (Figure 3), thus confirming the efficiency of the
phenyl ring replacement.
To conclude, we have disclosed a tactical application of
the BCP motif to generate BCP-resveratrol (2), a potential
bioisostere of resveratrol, and established its superior in
vivo PK properties over the parent compound. In doing so,
we have provided an intriguing approach that may poten-
tially allow clinical exploitation of the beneficial activities
shown by resveratrol and thus resolve the longstanding
conundrum around its application. We have also demon-
strated the synthesis of BCP-tyrosine ester (23) and thus
opened the avenue for its applications in pharmaceutical
and other fields. It is also worth mentioning that, the stra-
tegic disposition of the BCP motif in 2 and 23 can render
these building-blocks, and the scaffolds employing them,
the cogency to mitigate intellectual property and com-
pound attrition related issues.24 Lastly, our in vivo PK stud-
ies on 2 strongly justify its biological testing in many of the
targets that have shown promise for resveratrol. We hope
that this report will initiate such enquiries.
Formation of glucuronide conjugates in human
hepatocytes
Formation of sulfate conjugates in human
hepatocytes
25000
250000
200000
150000
100000
50000
0
BCP-Res-Glucuronide
t-Res-Glucuronide
BCP-Res-Sulfate
t-Res-Sulfate
20000
15000
10000
5000
0
0
20
40 60
Time (min)
90
120
0
20
40
Time (min)
60
90
Figure 3. Formation of glucuronide and sulfate conjugates
of resveratrol and BCP-resveratrol in human hepatocytes.
While we were delighted by the pharmacokinetic profile of
2, we were aware of the significance of our synthetic ef-
forts in enabling this study; and were keen to facilitate
similar biological evaluation of novel and potentially ‘bi-
oisosteric natural products’. In line with this commitment,
we are actively pursuing synthetic development of such
compounds in our laboratories. One such synthetic study
that deserves to be introduced at this stage especially, giv-
en its synthetic relevance to 2, is a BCP-tyrosine derivative,
23. Thus, our synthesis (un-optimized) of this compound
originates from an advanced intermediate 18, used in the
synthesis of 2. The sequence commenced with a straight-
forward transformation of 18 to α,β-unsaturated ester 20
by employing Wittig reaction conditions (see Scheme 6).
Next, in the key-step of this protocol, the olefin in 20 was
subjected to Carriera hydrohydrazination conditions to
generate the diazo compound 21.22 Deprotection of the
Boc functionality with trifluoroacetic acid gave the hydra-
zine intermediate, which in turn could be converted to the
amine 22 with the help of samarium diiodide. Finally, acid
hydrolysis of 22 yielded the hydrolyzed product 23 to
complete our racemic synthesis of thetyrosine-BCP ethyl
ester. Given the aforementioned bioisoteric properties of
BCP motif, it would be interesting to compare 23 with its
tyrosine counterpart 24.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Synthesis details, characterization data for all new
compounds, and PK protocols (PDF)
AUTHOR INFORMATION
Corresponding Author
* Fax: +65 68745870; Tel: +65 67998503.
Email: vikrant_adsool@ices.a-star.edu.sg.
Author Contributions
The manuscript was written through contributions of all au-
thors. / All authors have given approval to the final version of
the manuscript. Project leader, V. A; Synthetic chemists Y. L., Y.
T., V. A; Biological studies V. P.
Scheme 6a. Synthesis of (±) BCP-tyrosine ethyl ester (23).
Notes
The authors declare no completing financial interest.
ACKNOWLEDGMENT
This work was performed in collaboration with GSK, Singa-
pore.
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clo[1.1.1]pentan-1-amine
iodobicyclo[1.1.1]pentane.
Org. Lett. 2014, 16, 1884-1887.
from
1-azido-3-
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