Importance of a 4-Alkyl Substituent for Activity in the Englerin Series

Article abstract of DOI:10.1021/acsmedchemlett.7b00161

The ring closing metathesis/transannular etherification approach to the englerin nucleus was adapted to provide two key intermediates for analogue synthesis: the 4-desmethyl Δ^5,6 tricycle and the 4-oxo Δ^5,6 tricycle. The former was elaborated to 4-desmethyl englerin A and the latter served as a common precursor for englerin A, 4-ethyl englerin A, and 4-isopropyl englerin A. 4-Desmethyl englerin A was less active than the natural product by an order of magnitude, but the 4-ethyl and 4-isopropyl analogues were comparable in activity to englerin A. These results are consistent with the premise that the 4-alkyl group enforces the binding conformation of the cinnamoyl ester substituent. Furthermore, they suggest that 4-alkyl englerin structures may prove to be useful tool compounds.

Full text of DOI:10.1021/acsmedchemlett.7b00161

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Letter
The Importance of a 4-Alkyl Substituent for Activity in the Englerin Series
Daniel Craig Elliott, John A. Beutler, and Kathlyn A. Parker
ACS Med. Chem. Lett., Just Accepted Manuscript • Publication Date (Web): 06 Jun 2017
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The Importance of a 4-Alkyl Substituent for Activity in the Englerin
Series
Daniel C. Elliott,† John A. Beutler,‡ and Kathlyn A. Parker†*
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†Department of Chemistry, Stony Brook University, Stony Brook, NY 11794ꢀ3400
‡Molecular Targets Laboratory, National Cancer Institute, Frederick, MD 21702
Supporting Information Placeholder
ABSTRACT: The ring closing metathesis/transannular etherification approach to the englerin nucleus was adapted to provide two
key intermediates for analog synthesis: the 4ꢀdesmethyl ꢁ5,6 tricycle and the 4ꢀoxo ꢁ5,6 tricycle. The former was elaborated to 4ꢀ
desmethyl englerin A and the latter served as a common precursor for englerin A, 4ꢀethyl englerin A, and 4ꢀisopropyl englerin A.
4ꢀDesmethyl englerin A was less active than the natural product by an order of magnitude but the 4ꢀethyl and 4ꢀisopropyl analogs
were comparable in activity to englerin A. These results are consistent with the premise that the 4ꢀalkyl group enforces the binding
conformation of the cinnamoyl ester substituent. Furthermore, they suggest that 4ꢀalkyl englerin structures may prove to be useful
tool compounds.
Engerlin A (1a), a sesquiterpene diester isolated from an East
African Phyllanthus species, exhibits potent and impressively
selective inhibition of kidney tumor cell growth. This was first
demonstrated by the isolation team in the NCI 60 screen.1 In
an independent study, englerin A was shown to reduce the
viability of renal cancer cells (UOꢀ31 and Aꢀ498) with IC50
values in the mid nanomolar range while its effect on the viaꢀ
bility of two nonꢀcancerous cell lines (immortalized HEK 293
cells, derived from human embryonic kidney cells and renal
proximal tubule cells) was barely detectable at much higher
concentrations (low micromolar and molar respectively).2
In vivo experiments show the potential of englerin A as a drug
lead and the difficulties associated with drug delivery. When
administered to mice bearing the renal cancer xenograft 786ꢀ0,
Figure 1. Englerins and C-4 Synthetic Analogs
Englerin A could be detected in mouse serum following ip
dosing; however, it could not be detected in serum when the
maximum tolerated dose was administered orally (by gavage).
It has been shown to be unstable over time in rodent serum,
being converted to the inactive englerin B (2).4 The picture
that emerges is one in which the glycolate ester of englerin A
is cleaved by gastric acid or, more slowly, by serum esterases.
an intraperitoneal (ip) dosage protocol led to reduced tumor
growth along with effects on phosphorylation of two kinase
targets in tumor tissue.3 On the other hand, rats and nude
mice, subjected to a different ip dosing protocol, did not tolerꢀ
ate the compound.4 Intravenous injection of englerin A has
generally proven to be rapidly lethal and oral administration
ineffective.5
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Nonetheless, in the mere eight years since its discovery, the
Page 2 of 5
As expected,12 hydrogenation with the iridium Crabtree cataꢀ
lyst22 gave us the trans hydroazulene 3 (Scheme 3). Applicaꢀ
tion of Echavarren’s 4ꢀstep sequence for englerin A (Oꢀ6 esꢀ
terification, Oꢀ9 deprotection and esterification, glycolate
deprotection)23gave the 4ꢀdesmethyl analog (1b).
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englerin series has reached important milestones on the path to
drug development and remains an area of active research.5ꢀ11
Total syntheses based on several different strategies have been
reported. These and more classical medicinal chemistry have
yielded active analogs and contributed to the development of a
structure activity relationship (SAR). The issue of in vivo
hydrolysis was addressed with the preparation of a moderately
active, orally available aza analog which has improved serum
stability. Studies of the mechanism of action of englerin A
have implicated several protein targets and are now leading to
proposals for drug combination studies and applications in
diseases other than cancer. Much of this progress is summaꢀ
rized in the recent review on englerins.5
Although we preferred that the oxidative demercuration of
mercurial 4 give alcohol 18 directly, we noted the potential of
the alcohol mixture 14a,b as the synthetic equivalent of ketone
19 (Scheme 4), an attractive common precursor for 4ꢀalkyl
englerin systems. Indeed addition of MeMgBr to ketone 19
gave a mixture of alcohols 20; a similar mixture of alcohols 20
has been separated by the Echavarren group who then conꢀ
verted alcohol 20a to englerin A.23 Therefore this variant of
the our approach also affords a formal total synthesis of the
natural product.
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Seeking to contribute to the developing structure activity reꢀ
lationship (SAR) for englerin A and also to devise potent and
selective “tool compounds” for mechanism studies, we conꢀ
templated the requirements for the cinnamic acid and glycolic
acid ester substituents at Cꢀ6 and Cꢀ9.12ꢀ15 We postulated that
the methyl groups adjacent to these appendages might be imꢀ
portant for maintaining sidechain conformations that are reꢀ
quired for binding to the target protein; indeed we note that
truncation of the Cꢀ7 isopropyl group to an ethyl or methyl
group results in reduced activities.14 We assumed that larger
alkyl groups at Cꢀ4 would not be detrimental to activity and
that, if functionalized, they would prove useful for affinity
binding studies. Here we describe the synthesis and activity
profiles in the NCI 60 panel of 4ꢀdesmethyl englerin A16 and
two analogs that bear extended alkyl groups at Cꢀ4. We note
that a recent total synthesis paper includes reports of three Cꢀ4
alkyl extended englerins; however, no biological testing was
disclosed.6
Scheme 1. Retrosynthetic Analysis of 4-Desmethyl EA
Scheme 2. Synthesis of RCM Substrate for 4-Desmethyl
Englerin A
Initially it appeared that the synthesis of the 4ꢀdesmethyl
englerin (1b) would be simpler than that of EA or another 4ꢀ
alkyl structure by our ring closing metathesis/transannular
etherification approach.17 Thus we imagined that the
desmethyl englerin core 3 would be obtained from the metathꢀ
esis product 5 (Scheme 1) by modifying the oxymercuration
product 4 and that the carbonate 6 would be obtained from the
readily available 7. Therefore, we began our SAR study with
the preparation of analog 1b.
Our synthesis of the metathesis substrate 6 from known alꢀ
cohol 718 through the chiral epoxide 819 (Scheme 2) followed
our prior art as described in our formal synthesis of englerin
A.17 Regioselective opening of the epoxide ring gave the 1, 2ꢀ
diol 9 and oxidation gave the expected aldehyde 10. We were
able to favor the desired homoallylic alcohol 11 by employing
the Bꢀallyldiisopinocampheylborane reagent prepared accordꢀ
ing to Singaram.20 Treatment with carbonyl diimidazole then
gave the metathesis substrate.
Continuation of the synthesis paralleled our ring closing meꢀ
tathesis/transannular etherification englerin approach. Double
ring closure gave bicyclic 12 and functional group modificaꢀ
tion gave the key intermediate 5. Oxymercuration allowed
isolation of the mercurial 4 and oxidative demercuration led to
a mixture of alcohols 14 and olefin 15. On the other hand,
reductive demercuration converted mercurial 4 cleanly to oleꢀ
fin 15.
We were able to adapt Ma’s 4ꢀstep net hydroxylation seꢀ
quence21 to this intermediate to obtain the allylic alcohol 18.
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Scheme 3. Desmethyl Englerin A by a Modified RCM
Transannular Etherification Sequence
4 substituents would be tolerated, we set out to prepare both 4ꢀ
ethyl and 4ꢀisopropyl englerin A (Scheme 5).
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Scheme 5. Synthesis of C4-Englerin Analogs 1c and 1d
Stewart-
Grubbs
catalyst
TBSOTf,
CH2Cl2
2,6-lutidine,
toluene
80 oC, 20 h
O
H
OR'
-78 o
C
O
OR
12 R, R' = CO (83%)
6
O
2N NaOH
EtOH, RT
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13 R, R' = H, H (74%)
ClHg
1) Hg(OTFA)2
CH2Cl2/ MeOH
- 78 oC to - 5 oC
O
H
OTBS
H
OTBS
OH
2) aq NaCl,
4 (71%)
5 (78%)
NaHCO3, 1 h
NaBH4
O2
OH
NaBH4
DMF
0 oC
mCPBA
O
O
CH2Cl2
0 oC
H
OTBS
H
OTBS
14 (68%)
15 (52%)
1) TPAP/ NMO
CH2Cl2/MeCN
71% (10:1)
HO
O
O
CSA
O
2) NaBH4
CDCl3
0 o
C
H
CeCl3•7H2O
H
OTBS
OTBS
MeOH, 0 o
C
16 (68%)
17 (55%)
74%
1) PhCH=CHCOCl,
DMAP, CH2Cl2,
rt (85%)
HO
HO
2) TBAF, THF,
0 oC to rt (89%)
H
H2
[Ir]
Some exploration of reactions and conditions proved necesꢀ
sary but ultimately successful. Treatment of ketone 19 with
EtMgBr gave the 1,2ꢀaddition product 21 exclusively. Howꢀ
ever, the isopropyl alcohol mixture (22a,b) was obtained in
useful yields only when iꢀPrMgCl was accompanied by a lanꢀ
thanum salt additive.25 From this point the completion of the
synthesis of the C4 substituted nuclei required transposition of
the allylic alcohol functionality. To accomplish this in their
englerin synthesis, Echavarren and coworkers had treated alꢀ
O
O
1b
3) TIPSOCH2COCl,
DMAP, CH2Cl2
H
OTBS
H
OTBS
4) HF-TEA, THF
(39%, 2 steps)
3 (92%)
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Scheme 4. New Formal Synthesis of Englerin A
lylic alcohol 20a with Collins reagent (CrO3•py2) or CrO3 /
2,5ꢀdimethylpyrazole and then deoxygenated the resulting
epoxy alcohol with Sharpless’s low valent tungsten reagent
26, 27
(from WCl6/2 n-BuLi).23,
Following this protocol, we
oxidized alcohol 21 with Collins reagent, obtaining epoxy
alcohol 23a in 62% yield. However, attempts to apply the
deoxygenation protocol to epoxide 23a gave us a complex
mixture that did not appear to contain the desired 25a.
We noted that if this chemistry were to prove general, it
would provide access to englerin analogs that bear Cꢀ4 “meꢀ
thyl extensions.”24 Such compounds are attractive targets, not
only because they would provide data for SAR construction,
but because appropriately functionalized, active derivatives
could be employed in protein labeling and imaging studies. In
order to test the premise that extended and/or locally bulky Cꢀ
On the other hand, treatment of alcohol 21 with PDC gave
enone 24a along with epoxide 23a. Borohydride reduction of
the enone followed by Nicolaou’s Crabtree hydrogenation12
gave the expected 26a. Application of the 4ꢀstep sidechain
introduction sequence gave 4ꢀethyl englerin A (1c). A parallel
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set of procedures applied to alcohol 22a gave 4ꢀisopropyl engꢀ
lerin A (1d).
tional Institutes of Health (GM 74776), with funds from the
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Targeted Research Opportunity (TRO) Program of the Carol M.
Baldwin Breast Cancer Fund (Stony Brook University), and
with funds from the Intramural Research Program, National
Cancer Institute (project # 1 ZIA BC01147 003 [JAB]. We
thank the Developmental Therapeutics Program of NCI for NCI
60 testing. We are grateful to Joshua D. Seitz for a gift of TIPSꢀ
protected glycolic acid.
Compounds 1b, 1c, and 1d were tested in the NCI 60 human
tumor cell line screen (Table 1). The data from all three comꢀ
pounds were highly correlated with those for englerin A (Taꢀ
ble Sꢀ1, Supporting Information). While the 4ꢀdesmethyl
compound 1b was notably less potent than englerin A in nearꢀ
ly all sensitive cell lines, extension of the 4ꢀsubstituent to ethyl
and isopropyl groups yielded analogs that were approximately
as potent as the parent.
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8.1
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3.2
a
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values
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AUTHOR INFORMATION
Corresponding Author
kathlyn.parker@stonybrook.edu
Present Address
Daniel C. Elliott, University of Basel, Chemistry Department,
Organic Chemistry, St. JohannsꢀRing 19, CHꢀ4056 Basel, Switꢀ
zerland
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manuꢀ
script.
ACKNOWLEDGMENT
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V.; Freichel, M.; Boehm, U. Functional characterization of
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For part of his graduate career, DCE was supported with a felꢀ
lowship from the Graduate Assistance in Areas of National
Need (GAANN) Program of the US Department of Education.
In addition, this research was supported with a grant (KAP)
from the National Institute of General Medical Sciences, Naꢀ
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