Synthesis and Biological Evaluation of New (-)-Englerin Analogues

Article abstract of DOI:10.1002/cmdc.201600040

We report the synthesis and biological evaluation of a series of (-)-englerin A analogues obtained along our previously reported synthetic route based on a stereoselective gold(I) cycloaddition process. This synthetic route is a convenient platform to access analogues with broad structural diversity and has led us to the discovery of unprecedented and easier-to-synthesize derivatives with an unsaturation in the cyclopentyl ring between C4 and C5. We also introduce novel analogues in which the original isopropyl motif has been substituted with cyclohexyl, phenyl, and cyclopropyl moieties. The high selectivity and growth-inhibitory activity shown by these new derivatives in renal cancer cell lines opens new ways toward the final goal of finding effective drugs for the treatment of renal cell carcinoma (RCC).

Full text of DOI:10.1002/cmdc.201600040

DOI: 10.1002/cmdc.201600040
Full Papers
Synthesis and Biological Evaluation of New (À)-Englerin
Analogues
Laura López-Suµrez+,[a] Lorena Riesgo+,[a, d] Fernando Bravo,[a] Tanya T. Ransom,[c]
John A. Beutler,*[c] and Antonio M. Echavarren*[a, b]
We report the synthesis and biological evaluation of a series of
(À)-englerin A analogues obtained along our previously report-
ed synthetic route based on a stereoselective gold(I) cycloaddi-
tion process. This synthetic route is a convenient platform to
access analogues with broad structural diversity and has led us
to the discovery of unprecedented and easier-to-synthesize de-
rivatives with an unsaturation in the cyclopentyl ring between
C4 and C5. We also introduce novel analogues in which the
original isopropyl motif has been substituted with cyclohexyl,
phenyl, and cyclopropyl moieties. The high selectivity and
growth-inhibitory activity shown by these new derivatives in
renal cancer cell lines opens new ways toward the final goal of
finding effective drugs for the treatment of renal cell carcino-
ma (RCC).
Introduction
Since it was isolated from the stem bark of the east African
plant Phyllanthus engleri by scientists at the US National
Cancer Institute,[1,2] englerin A (1) (Scheme 1),
a complex
guaiane sesquiterpene, has attracted a lot of attention among
the scientific community due to its selective inhibition of renal
cancer cell line growth.[3] Several total syntheses of eng-
lerin A[4–17] and analogues[18–25] have been reported to date. Re-
cently, two distinct mechanisms for englerin A’s anticancer ac-
tivity have been proposed, agonism of protein kinase C theta
(PKCq)[26] and agonism of short transient receptor potential
channels 4 and 5 (TRPC4/5).[27]
We completed the enantioselective synthesis of (À)-eng-
lerin A (1) and B (2)[6] in 18 steps and 7% overall yield from in-
expensive geraniol (3) via a,b-unsaturated aldehyde
4
Scheme 1. Enantioselective synthesis of (À)-englerin A (1) based on a stereo-
selective gold(I)-catalyzed [2+2+2] alkyne/alkene/carbonyl cycloaddition.[6]
[a] Dr. L. López-Suµrez,+ Dr. L. Riesgo,+ Dr. F. Bravo, Prof. A. M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ), Av. Pa¨ısos Catalans 16,
43007 Tarragona (Spain)
E-mail: aechavarren@iciq.es
[b] Prof. A. M. Echavarren
(Scheme 1), following a similar approach to that used previous-
ly for the synthesis of (+)-orientalol F and pubinernoid B.[28]
Thus, the highly stereoselective intramolecular gold(I)-catalyzed
[2+2+2] alkyne/alkene/carbonyl cycloaddition[29] of 1,6-enyne
5a led to advanced intermediates 6a–c with two different OR
groups, which allow for the facile preparation of many deriva-
tives.
Departament de Química Analítica i Química Orgµnica, Universitat Rovira
i Virgili, C/Marcel·li Domingo s/n, 43007 Tarragona (Spain)
[c] T. T. Ransom, Dr. J. A. Beutler
Molecular Targets Laboratory, Molecular Discovery Program, Center for
Cancer Research, National Cancer Institute, Frederick, MD 21702 (USA)
E-mail: beutlerj@mail.nih.gov
[d] Dr. L. Riesgo+
Current affiliation: Institute of Polymer Science and Technology, ICTP-CSIC,
Herein we report the synthesis and biological evaluation of
a series of englerin A analogues prepared by following our syn-
thetic route which allowed us to identify very active com-
pounds with a double bond between C4 and C5. Interestingly,
as part of the optimization and scale-up, we found that only
1,6-enynes of type 5a with this specific relative configuration
react productively in the gold(I)-catalyzed cascade reaction to
form oxatricyclic compounds.
Juan de la Cierva 3, 28006 Madrid (Spain)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under http://dx.doi.org/10.1002/
cmdc.201600040.
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This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited and is not used for commercial purposes.
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Results and Discussion
The cinnamate and glycolate moieties are known to be key for
englerin’s activity.[18,19,21,30,31] Therefore, to take advantage of
the different advanced intermediates 6a–c generated through
our synthetic route, our strategy consisted of adding these
substituents to the oxatricyclic intermediates with various
levels of unsaturation. In this way, we could have direct access
to a set of analogues with great structural diversity.
The synthesis of an initial library of analogues started from
the tricyclic structure 6c (Scheme 2).[6] The free hydroxy group
at position C4 was esterified under standard conditions to give
cinnamate 7a, which could be further functionalized under Ya-
maguchi conditions[32] to give the glycolate product 7b in
moderate yield. Together with this, the lactate derivative 7c
was also synthesized. The lactate moiety has shown good ac-
tivities in other analogues.[21] Following the total synthesis
plan, 6c can be isomerized to 8a in two steps by an oxida-
tion/reduction protocol,[6,28] allowing the synthesis of engleri-
n A and B analogues with an extra unsaturation in the cyclo-
pentyl ring (between C4 and C5). The cinnamate substituent
was added by following the usual esterification method with
cinnamoyl chloride, and the C9 alcohol was deprotected to
give analogue 9a (45% yield, two steps). Esterification under
Yamaguchi conditions with the TBDPS-protected glycolic acid
followed by deprotection afforded analogue 9b (63%, two
steps).
Continuing with intermediate 8a, a hydrogenation of the
sterically hindered tetra-substituted alkene was performed
using Pfaltz’s Ir catalyst,[33] leading to a separable 1:1 mixture
of diastereomers 10a–b. Cinnamate derivatives 11 a–b, 12a–f
of both diastereomers were prepared under standard condi-
tions. For the diastereomer with the same configuration as the
naturally occurring englerin A, 11 a, we wanted to synthesize
a new derivative with an amine instead of a free hydroxy
group. Thus, esterification with commercially available d-Boc-
alanine led to 11 b. Unfortunately, removal of the Boc group
could not be achieved under the usual reaction conditions. For
the other diastereomer 10b, the glycolate residue was also in-
troduced to give 12b (60%). Other ester derivatives 12c–
e and carbonate 12 f were similarly prepared.
Scheme 2. Synthesis of (À)-englerin derivatives from 6c. Reagents and condi-
tions: a) 1. cinnamoyl chloride, DMAP, Et3N, CH2Cl2, 458C, 2. TBAF, THF, 238C,
6 h: 7a 85%, 9a, 45%, 12a 66%; b) 1. esterification conditions: RCOOH,
DMAP, NEt3, 2,4,6-trichlorobenzoyl chloride, toluene, 238C, 1 h, 2. deprotec-
tion TBDPS conditions (when needed): TBAF, AcOH, THF, 4 h, 238C: 7b 58%,
7c 76%, 9b 63%, 11 b, 72%, 12b 60%, 12c 39%, 12d 78%, 12e 58%, 12 f
50%; c) CrO3(2,5-dimethylpyrazole) (3 equiv), CH2Cl2, 238C, 73%; d) WCl6
(2 equiv), nBuLi (4 equiv), THF, 0!508C, 2 h, 82%; e) [Ir(py)(PCy3)(COD)][BArF]
(30 mol%), H2 (80 bar), CH2Cl2, 238C, 4 days, quant. (1:1 d.r.).
This first library of compounds was tested against renal
cancer cell lines A498 and UO-31. The results are summarized
in Table 1. The first compounds synthesized from 6c with the
Table 1. Biological activity of the first library of compounds.
Cell line
GI50 [mm][a]
7a
7b
7c
9b
9k
11 b
12a
12b
12c
12d
12e
12 f
A498
UO-31
>40
>40
32
31
33
32
<2.5
10
>40
>40
>40
>40
18
22
1.5
8.2
3.1
16
>40
>40
40
40
>40
>40
[a] Results of preliminary screening to identify any activity present in the structures. Values were obtained by NCI’s internal two-cell renal assays (see Sup-
porting Information) by interpolation; these are rough estimates using five concentration points and duplicate wells per point at each concentration. The
usual cutoff for cell growth inhibition in 48 h assays is 10 mm. Note that compound 9k (Scheme 3) was also tested using the internal two-cell renal assay.
The compounds with activity (9b, 12b, 12c) were then tested in the NCI 60 screen (Table 2).
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cinnamate moiety at C4 and a double bond between C5 and
C6 showed minimal cell growth inhibition of the two renal
cancer cell lines. As already observed with englerin B, new
compounds lacking the glycolate residue (R=H) showed much
lower activity than those containing this ester. Compounds 9b
and 12b showed interesting inhibition of growth against the
A498 cell line. Only lactate 12c has a similar IC50 value to that
of its glycolate counterpart, whereas the three other analogues
12d–f show much lower activity. The basic conclusion after
this initial screening was that the C4ÀC5 unsaturated series
and the cis ring fusion series are active and worthy of further
exploration, whereas the C5ÀC6 unsaturated series was of no
biological interest.
The good activity results observed with 9b are especially im-
portant, because early intermediates with this carbon skeleton
are readily available by our gold(I)-catalyzed synthetic route, in
contrast to those requiring the non-stereoselective hydrogena-
tion of 8a (Scheme 2). Therefore, we decided to focus our syn-
thetic efforts on a second library of compounds maintaining
the double bond between C4 and C5.
Scale-up of our original synthesis[6] to the multigram scale
(up to 50 g of geraniol) could be performed with minor
changes in the first steps and with minor loss in enantioselec-
tivity (Sharpless epoxidation 9:1 e.r., see Supporting Informa-
tion). To further simplify the synthesis and to access new dia-
stereomeric structures, a simple aldol reaction with 3-methyl-2-
butanone (instead of the stereoselective Denmark reaction)
was performed to obtain an approximate 1:1 mixture of diaste-
reomeric b-hydroxy ketones 5a/a’ (Scheme 3). This mixture
was directly submitted to the gold(I)-catalyzed cycloaddition
reaction. Surprisingly, instead of the expected 1:1 mixture of
diastereomers at C9, 6a was the only product that could be
isolated by column chromatography from the reaction mixture
(30% yield, 60% based on 5a with 5R,10S configuration). Pre-
sumably the gold(I)-catalyzed reaction 5a’ with 5S,10S configu-
ration is interrupted at one of the final cyclization reactions
and fails to form the tricyclic skeleton. Although not atom-eco-
nomical, this procedure opened the door for quick access to
derivatives of englerin with various substituents at the C7 posi-
tion by the use of readily available ketones in the aldol reac-
tion with aldehyde 4. Thus, aldols 5b–e with cyclohexyl,
phenyl, cyclopropyl, and tert-butyl substituents were obtained
as an approximate 1:1 mixture of diastereomers.
Scheme 3. Synthesis of derivatives 9c–s. Reagents and conditions: a) LDA,
RCOMe, THF, À788C, 15 h: 5a/a’ 78%, 5b/b’ 78%, 5c/c’ 70%, 5d/d’ 91%,
5e/e’ 80%; b) [iPrAuNCPh]SbF6 (3 mol%), CH2Cl2, 238C, 5 h: 6a 30%, 6d
32%, 6e 24%, 6 f 19%, 6g, 11%; c) TBAF, THF, 238C, 12 h, 30–82%;
d) DMAP, imidazole, TBDMSCl, 238C, 69–84%; e) 1. CrO3, pyridine, CH2Cl2,
238C, 1 h, 2. CeCl3(H2O)7, NaBH4, MeOH, 238C, 5 min, 43–70%; f) WCl6
(2 equiv), nBuLi (4 equiv), THF, 0!508C, 2 h: 8a 82%, 8b 74%, 8c and 8d
not isolated; g) 1. cinnamoyl chloride (or RCOCl), DMAP, Et3N, CH2Cl2, 458C,
4–12 h, 2. TBAF, THF, 238C, 12 h: 9n 48%, 9o 58% (3 steps), 9p 40% (3
steps), 9e 43%; h) 1. RCOOH, DMAP, NEt3, 2,4,6-trichlorobenzoyl chloride, tol-
uene, 238C, 1 h, and 2. TBAF, AcOH, THF, 4 h, 238C (deprotection of TBDPS
group), 9c 27%, 9d quant., 9 f 81%, 9g 80%, 9h 53%, 9i 41%, 9q 66%, 9r
38%, 9s 78%. With slight modifications (see Supporting Information): 9j
94%, 9k 95%, 9l 31%, 9m 26%. PhcPr=1,2-trans-cyclopropylphenyl.
C4 and C5, and isopropyl, cyclohexyl, phenyl, and cyclopropyl
substituents at position C7 (Scheme 3). Alcohol deprotection
and protection strategies followed by the oxidation/reduction
isomerization protocol[28] led to the key intermediates 8a–d,
which were converted into a second library of compounds 9c–
s by selective esterification reactions.
In all cases the gold(I)-catalyzed reaction gave a single dia-
stereomer, albeit in 11–32% yield. Interestingly, the mixture of
phenyl derivatives 5c/c’ could be separated by semi-prepara-
tive chiral chromatography (Supporting Information), and the
two main stereoisomers were independently submitted to the
gold(I)-catalyzed reaction using [iPrAuNCPh]SbF6 under the
standard reaction conditions. As predicted, only one of them
led to oxatricyclic 6e, whereas the other stereoisomer gave an
inseparable complex mixture of compounds from which no
other cyclic structure could be detected.
This second library of compounds was tested in the NCI 60
one-dose screen (except 9k (Table 1), 9e and 9o (not tested)),
along with compounds 9b, 12b, and 12c. Compounds with
apparent renal selectivity[34] were then tested in the NCI 60
five-dose protocol at the high concentration of 10À4
m
(Tables 2 and 3, see Supporting Information for complete
data). As expected, analogues with a free hydroxy group at po-
sition C9, namely englerin B derivatives 9c, 9d, 9n, and 9p dis-
played very low growth inhibitory activity. For the different
esters of the alcohol at C6, acetate 9h had no activity against
renal cancer cells, whereas the introduction of a longer chain
in 9 f resulted also in poor activity. On the other hand, the in-
troduction of the cyclopropyl ring in 9g resulted in moderate
With the oxatricyclic structures in hand (6g was not studied
in further detail because of the very low yield), the synthetic
route was followed to get the corresponding englerin ana-
logues with the unsaturation in the cyclopentyl ring, between
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Table 2. Activity results for compounds with apparent renal selectivity.
Cell line[a]
GI50 [mm][b]
1
9b
35
0.034
0.022
1.1
9g
15
0.24
3.0
11
0.041
9.3
9i
9j
85
2.2
4.5
13
8.9
10
93
20
9q
9r
9s
12b
12c
786-0
A498
1.1
3.2
1.5
5.2
0.095
0.045
13
0.039
1.1
3.2
0.10
0.034
11
0.022
0.74
37
35
2.2
6.6
23
29
28
0.010
0.017
0.39
0.059
1.0
0.23
0.14
6.2
0.011
1.5
0.021
0.033
5.9
0.029
0.32
0.74
1.4
13
35
19
ACHN
CAKI-1
RXF393
SN12C
TK-10
0.13
20
100
0.040
1.9
0.015
17
9.5
16
1.0
12
0.35
22
0.62
19
0.63
100
1.8
100
10
UO-31
[a] The eight cell lines in the renal cancer panel characterized at the outset of the NCI 60 screening project are distinct in molecular, cytological, and clinical
parameters, and are intended to be representative of different kidney cancers.[35] [b] Positive control standard adriamycin (NSC #123127; see Supporting In-
formation). Data are the average values of n=2 assays except 9j (n=1) and 1 (n=3); (À)-englerin A as reference.
Table 3. Matrix COMPARE at the GI50 level of response between selected englerin A analogues and englerin A (1).[a]
[a] Heat map colors indicate increments of 0.1 in the Pearson correlation; in the NCI 60 data, the statistical significance of differences in patterns has gener-
ally been drawn at a coefficient of 0.5.
GI50 values for the renal cancer cell lines, although an interest-
ing selectivity for the RXF393 line could be observed.
potency and selectivity against the growth of renal cancer cell
lines.
Substitution of the glycolate appendix by the alanine and
glycine derivatives 9k–m did not give good inhibition results.
Poor potency and activity was observed in these three cases.
The acetyl derivative 9j displayed better results, as it showed
good selectivity for renal cancer cell lines, but with moderate
GI50 values. The lactate analogue 9i gave an interesting selec-
tivity profile and very good growth inhibition potency in some
of the lines.
The selectivity of the compounds listed in Table 2 was exam-
ined by using the COMPARE algorithm.[36] All of the com-
pounds had meaningful Pearson correlation coefficients at the
GI50 level of response with each other and with englerin A
(Table 3). Although 9j had somewhat lower coefficients than
the rest, this can be attributed to its low potency. In fact, the
correlation for NCI 60 tests of englerin A and englerin B acetate
at the GI50 level, previously reported, is only 0.491, with engler-
in B acetate being 400-fold weaker than englerin A.[1]
Englerin analogues with substitution of the isopropyl motif
at C7 are rare. Previous analogues in which the isopropyl
group is substituted by ethyl or methyl groups have been de-
scribed by Christmann and co-workers[18] and showed lower
growth inhibition. Here, in the guaiane structure with a double
bond in the cyclopentyl ring, we found that substituting the
isopropyl group with a bulkier cyclohexyl in 9q was beneficial
for the selectivity and growth inhibitory activity for most of
the lines, relative to 9b. Adding the phenyl group at C7 in 9r
also shows similar benefits and even lower GI50 values in some
cases. In addition, the cyclopropyl analogue 9s shows good
Conclusions
In summary, we synthesized new englerin analogues by follow-
ing our previously reported enantioselective synthesis of (À)-
englerin A. We found that our synthetic route is a good plat-
form to access varied analogues, which allowed us to discover
an unprecedented and easier way to synthesize a family of de-
rivatives with a cyclopentene ring. In addition, novel analogues
with substituents distinct from isopropyl could be prepared by
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Acknowledgements
We thank MINECO Severo Ochoa Excellence Accreditation 2014–
2018 (SEV-2013-0319), project (CTQ2013-42106-P), the European
Research Council (Advanced Grant No. 321066), the AGAUR (proj-
ects 2014 SGR 818 and 2010 VALOR 00015), and the ICIQ Foun-
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matography unit ICIQ for technical support. This research was
supported in part with funds from the Intramural Research Pro-
gram, National Cancer Institute (project 1 ZIA BC01147 003, to
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Keywords: enantioselective synthesis
catalysis · natural products · renal cancer · tumor growth
inhibition
· englerin A · gold
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Published online on March 23, 2016
ChemMedChem 2016, 11, 1003 – 1007
www.chemmedchem.org
1007 ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim