Synthesis of C11-desmethoxy soraphen A1α: A natural product analogue that inhibits acetyl-CoA carboxylase

Article abstract of DOI:10.1021/ml400377p

A synthesis of C11-desmethoxy soraphen A_1α is described that proceeds in just 14 steps from readily available starting materials. This natural product analogue was identified as a target of interest in a program aimed at identifying novel natural product-inspired inhibitors of acetyl-CoA carboxylase (ACC) as potential anticancer therapeutics. While describing the most efficient synthesis of a soraphen A_1α analogue (total syntheses of the natural product have been reported that proceed in 25 to ≥40 linear steps), we also present data supporting the conclusion that C11-heteroatom functionality is a beneficial but unnecessary structural characteristic of soraphen A_1α analogues for inhibiting ACC.

Full text of DOI:10.1021/ml400377p

Letter
pubs.acs.org/acsmedchemlett
Synthesis of C11-Desmethoxy Soraphen A1α: A Natural Product
Analogue That Inhibits Acetyl-CoA Carboxylase
Daniel P. Canterbury,† Kristen E. N. Scott,‡ Ozora Kubo,† Rolf Jansen,§ John L. Cleveland,‡
and Glenn C. Micalizio*,†,∥
†Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
‡Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida 33458, United States
§Department of Microbial Drugs, Helmholtz Centre for Infection Research, Braunschweig, Germany
S
* Supporting Information
ABSTRACT: A synthesis of C11-desmethoxy soraphen A1α is
described that proceeds in just 14 steps from readily available
starting materials. This natural product analogue was identified
as a target of interest in a program aimed at identifying novel
natural product-inspired inhibitors of acetyl-CoA carboxylase
(ACC) as potential anticancer therapeutics. While describing
the most efficient synthesis of a soraphen A1α analogue (total
syntheses of the natural product have been reported that
proceed in 25 to ≥40 linear steps), we also present data supporting the conclusion that C11-heteroatom functionality is a
beneficial but unnecessary structural characteristic of soraphen A1α analogues for inhibiting ACC.
KEYWORDS: Soraphen A, function-oriented synthesis, acetyl-CoA carboxylase (ACC), polyketide synthesis
oraphen A1α (1) is a natural product that was first isolated
from the soil bacterium Sorangium cellulosum (strain So
effect on normal cells.9−15 While soraphen A1α has been
described as a unique tool to study altered fatty acid
metabolism in cancer cells, its in vivo utility appears hampered
by its poor solubility and bioavailability.8,9 Over 30 natural
product family members have been isolated from Sorangium
cellulosum and numerous synthetic analogues have been
prepared, yet no analogues have been discovered with activity
akin to 1. Although the natural product is readily available from
fermentation (∼130 mg/L),16 the nature of structural changes
that are easily accessible from the fully functionalized natural
product are quite limited; such is often the case with natural
product derivatization.17−20 Soraphen A1α (1) has been pursued
as a target for total synthesis for ∼20 years, with two successful
syntheses being reported.21−23 Unfortunately, these accom-
plishments call for synthetic sequences of 25 to ≥40 steps
(longest linear sequence) and define a rather substantial barrier
to the use of chemical synthesis for the discovery of novel
soraphen analogues that may have better properties than 1.
Here, we report a concise synthesis of C11-desmethoxy
soraphen A1α (2), a natural product analogue that was targeted
in a function-oriented synthesis24 pursuit after analysis of the
ACC2−1 structure and an assessment of the challenges that
have plagued previous syntheses of 1. Our synthesis proceeds in
just 14 chemical steps from a readily available starting material
(longest linear sequence) and employs only eight chromato-
graphic purifications. Finally, we report that C11-desmethoxy
S
ce26) and recognized as a potent antimicrobial agent (Figure
1A).1−3 Early enthusiasm for commercial development of this
Figure 1. (A) Structure of soraphen A1α. (B) A structural motif within
soraphen A1α that impairs efficient synthesis of the natural product.
compound was centered on its use for the control of plant
disease due to the inhibitory activity of 1 against several
phytopathogenic fungi.3 Subsequent investigation led to
discovery that the biological target of soraphen A1α (1) is
acetyl coenzyme A carboxylase (ACC);4−7 ACCs play crucial
roles in fatty acid metabolism and, as such, have risen as
attractive therapeutic targets for diabetes.8 More recently,
ACCs have become of interest to those seeking novel targeted
cancer therapeutics,9 as several studies have established that
cancer cells have an intrinsic dependence on de novo fatty acid
synthesis and that inhibition of ACC, the rate-limiting step of
biosynthesis, triggers apoptosis of cancer cells with little to no
Received: September 26, 2013
Accepted: November 4, 2013
Published: November 6, 2013
© 2013 American Chemical Society
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soraphen A1α (2) has an ACC-inhibitory profile within 1 order
of magnitude of the natural product.
natural product. Further, this molecular deletion in the
otherwise challenging C8−C12 domain was reasoned to have
a substantial and beneficial impact on the efficiency of potential
routes for chemical synthesis.
While a cursory inspection of the structure of soraphen A1α
may lead one to suggest that the challenge associated with
preparing this target may lie in the stereochemically dense C1−
C7 domain, the region of soraphen A1α that has had the most
significant impact on efficiency associated with prior syntheses
is C8−C12 (Figure 1B). While many modern chemical
methods can be employed to establish this subunit, within
the broader problem of completing the total synthesis of 1,
successful solutions come with significant disadvantages; i.e.,
they require either multistep sequences to establish the
disubstituted alkene and the C11−C12 anti-diol, and/or dictate
the use of coupling partners that require numerous subsequent
chemical transformations to establish the functionalized
macrocyclic structure.21−23 Given these facts, we sought to
define a soraphen A1α analogue that would have similar activity
versus ACC but would harbor functionality in this C8−C12
region that would simplify efforts to accomplish de novo
chemical synthesis.
Our efforts began by adopting a retrosynthetic strategy for 2
based on late stage hemiketal formation (3 → 2; Figure 2B),
and two key C−C bond forming reactions: aldol between the
Li-enolate of 5 and aldehyde 4 (to forge the C2−C3 bond),
and ring-closing metathesis (RCM) to establish the macrocyclic
skeleton. Given the structure of the natural product and the
numerous examples of RCM en route to macrocyclic lactones,
this strategy for synthesis of 2 is not particularly surprising. In
fact, these very bond constructions were targeted by Ciufolini
in his studies directed toward a total synthesis of 1.26
Interestingly, these efforts were not successful as an entry to
the natural product, as the fully functionalized precursor 6 (that
bears the C11-methoxy group; Figure 3) could not be
With this goal in mind, we considered the structure of the
human ACC2−soraphen A1α complex (Figure 2A).7 While the
Figure 3. Aldol/RCM-based strategy of Ciufolini15 to generate the
macrocyclic framework of soraphen A1α.
efficiently converted to macrocycle 9. Here, ring-closing
metathesis required 30 mol % of the second generation
Hoveyda−Grubbs catalyst and delivered macrocycle 9 as a
minor product; the major product of this reaction sequence was
ethyl ketone 10 (derived from initial isomerization of the
alkene to the enol ether and subsequent hydrolysis). Despite a
number of attempts to optimize the ring-closing process, the
authors failed to find a substrate/catalyst combination that
provided better conversion to 9, and the study was concluded
without completing a synthesis of soraphen A1α.26
The challenges encountered by Ciufilini and co-workers were
undoubtedly due to the rate of competing reactions made
available by the C11-methyl ether, a functionality that is not
present in our designed analogue (2; Figure 2B). As such, we
moved forward with a plan to prepare C11-desmethoxy
soraphen A1α (2) by a synthetic pathway that embraced
sequential convergent aldol/ring-closing metathesis, despite the
established failure of this approach in efforts to target 1.
Synthesis of coupling partner 5 follows a simple sequence
from 1-phenyl cyclohexene26 as illustrated in Figure 4A. With
aldehyde 12 in hand, diastereoselective allylboration28 followed
by methylation delivered the propionate ester subunit 5 in 35%
yield over the 6-step sequence. Moving forward, synthesis of
the more stereochemically complex fragment began from the
readily available aldehyde 13 (Figure 4B).27 Diastereoselective
crotylboration,29 desilylation, and acid-mediated reaction with
the dimethyl acetal of p-anisaldehyde provided the cyclic acetal
14 in 46% yield. Regioselective opening of the PMP acetal,30,31
Figure 2. Targeting C11-desmethoxy soraphen A1α. (A) Structure of
soraphen A1α bound to human ACC2. (B) Retrosynthesis of C11-
desmethoxy soraphen A1α.
C11 and C12 methyl ethers of 1 have been proposed to
hydrogen bond to Arg277 of human ACC2, we speculated that
interaction with the C11 methyl ether may be less important in
the complex. In fact, it has been shown that a C11-ester-linked
BODIPY analogue of soraphen A1α potently binds to the BC
domain of ACC (<5 nM).25 Given that the ester functionality
at C11 of this BODIPY-conjugate effectively decreases electron
density at the C11 oxygen atom and diminishes its character as
a hydrogen bond acceptor, we speculated that C11-desmethoxy
soraphen A1α (2) may have anti-ACC properties similar to the
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treatment. Indeed, a 4 h treatment of two independent B-
lymphoma cell lines (SCR1163 and SCR1693; derived from
Eμ-Myc transgenic mice) with 2 resulted in a 59% and 48%
reduction in 14C-acetate incorporation into fatty acid (Figure
5A), reflecting a potency that is within an order of magnitude of
Figure 5. Biological activity of C11-desmethoxy soraphen A1α. (A)
Measurement of nascent fatty acid production by 14C-acetate
incorporation in SCR1163 and SCR1693 Eμ-Myc B-lymphoma cells.
(B) MTT proliferation assays in SCR1163 lymphoma cells treated
with C11-desmethoxy soraphen A1α (DMSA), soraphen A1α (SA), or
the ACC inhibitor, TOFA, at the indicated concentrations for 24, 48,
and 72 h. Values were expressed relative to control. All graphs
represent the mean of 3 independent experiments. Error bars
represent standard error of the mean. *p ≤ 0.05.
Figure 4. Synthesis of C11-desmethoxy soraphen A1α. (A) Synthesis of
the proponiate ester-containing coupling partner 5. (B) Completion of
the synthesis of 2.
followed by oxidation of the resulting primary alcohol to the
aldehyde,32 asymmetric Evans’ aldol reaction,33−35 silylation,
and reduction delivered the stereochemically dense primary
alcohol 16 in 38% yield over the five-step sequence. Conversion
to the β-ketoester 17 was then accomplished by a simple three-
step sequence: oxidation to the aldehyde (DMP, DCM), aldol
reaction with the Li-enolate of 5, and oxidation to the ketone
(DMP, DCM).
the natural product (1 μM vs 100 nM). Dose response
experiments with 2 also showed that it impaired lymphoma cell
proliferation at all concentrations and time points tested
(Figure 5B), albeit being ca. 10-fold less active than 1.
Gratifyingly, exposure of 17 to the Grubbs second-generation
catalyst resulted in efficient ring-closing metathesis to deliver
the macrocyclic lactone 18 as a mixture of isomeric products in
90% yield.36,37 At this juncture, we did not determine the
stereoselection of the RCM due to the inseparable nature of the
product mixture (C2-stereochemistry). Thus, we moved
forward with the planned sequence by oxidative deprotection
of the PMB ether (DDQ, DCM, pH 7 buffer) and subsequent
desilylation with TBAF. Remarkably, the C11-desmethoxy
soraphen A1α analogue 2 was produced as a single isomer in
46% yield over the final two-step sequence. Notably, the
absence of the C11 stereocenter apparently had a marked effect
on the efficiency of macrocyclization and enabled the
conclusion of a synthesis of C11-desmethoxy soraphen A1α
(2) in only 14 steps from a readily available starting material.
To test our hypothesis that the lack of C11-heteroatom
substitution has little effect on the ACC-inhibitory profile of 2,
we initiated biological evaluation of this analogue. The
inhibitory mechanism of action of 1 is to bind the biotin
carboxylase (BC) domain of ACC in the dimer/oligomer
interface and disrupt the protein−protein interactions critical
for the full-length (active) ACC oligomer to occur.38,39 In cells,
treatment with 1 results in significant reductions in de novo
fatty acid biosynthesis.9 If 2 has related activity to 1, then one
would predict a similar decrease in fatty acid synthesis following
It has been reported that mutations in yeast ACC near the
site where soraphen A1α’s C11−C12 bismethyl ether resides
(residues surrounding R76, including S77 and K73) abolish or
greatly reduce the binding of 1 to the modified enzyme.5
Similarly, Cho et al. demonstrated that R277 of the human
ACC2 BC domain participates in hydrogen bonding to both
the C11 and C12 methoxy groups of soraphen A1α.38 Given the
promising potency of 2 in comparison to the natural product,
our data suggest that the hydrogen bonding interaction of yeast
ACC R76 and of human ACC2 R277 to the C11 methoxy
group of 1 is not essential for the biological activity of soraphen
A1α. Given the increased potency of the natural product,
optimization of C11-desmethoxy soraphen A1α may be possible
by including functionality at C12 that can project electron
density into the position where the C11 methyl ether of the
natural product resides within ACC2, such that additional
opportunities for H-bonding with R277 of the human BC
domain can be achieved without the necessity of C11
oxygenation. The ease with which C11-desmethoxy soraphen
A1α (2) can now be synthesized40 and the promising activity
that has been identified for this natural product analogue
supports the growth of a program aimed at synthesizing natural
product-inspired agents based on soraphen A1α to fuel the
discovery of novel targeted cancer therapeutics. Results
associated with these pursuits will be reported in due course.
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regulation of human ACC2 through phosphorylation by AMPK.
Biochem. Biophys. Res. Commun. 2010, 391, 187−192.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and tabulated spectroscopic data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(8) Harwood, H. J., Jr. Treating the metabolic syndrome: acetyl-CoA
carboxylase inhibition. Expert Opin. Ther. Targets 2005, 9, 267−281.
(9) Beckers, A.; Organe, S.; Timmermans, L.; Scheys, K.; Peeters, A.;
Brusselmans, K.; Verhoeven, G.; Swinnen, J. V. Chemical inhibition of
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RNA interference-mediated silencing of the Acetyl-CoA-Carboxylase-α
gene induces growth inhibition and apoptosis of prostate cancer cells.
Cancer Res. 2005, 65, 6719−6725.
AUTHOR INFORMATION
Corresponding Author
*(G.C.M.) E-mail: glenn.c.micalizio@dartmouth.edu.
■
Present Address
∥Department of Chemistry, Dartmouth College, Hanover, New
Hampshire 03755, United States.
(11) Chajes, V.; Cambot, M.; Moreau, K.; Lenoir, G. M.; Joulin, V.
Acetyl-CoA carboxylase α is essential to breast cancer cell survival.
Cancer Res. 2006, 66, 5287−5294.
(12) Menendez, J. A.; Colomer, R.; Lupu, R. Why does tumor-
associated fatty acid synthase (oncogenic antigen-519) ignore dietary
fatty acids? Med. Hypotheses 2005, 64, 342−349.
(13) Menendez, J. A.; Mehmi, I.; Atlas, E.; Colomer, R.; Lupu, R.
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synthase-dependent breast cancer cell proliferation and survival: Role
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Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Funding
We gratefully acknowledge financial support of this work by the
Scripps Research Institute, the National Institutes of Health
(GM080266 to G.C.M.; CA076379 to J.L.C.), the Jane and
Leonard Korman Family Foundation (postdoctoral fellowship
to K.E.N.S.), the Japan Society for the Promotion of Science
(JSPS, postdoctoral fellowship to O.K.), and funds from the
State of Florida to Scripps Florida.
Notes
The authors declare no competing financial interest.
(16) The production of soraphen A1α reported in reference 2
proceeds on a 5500-L scale and delivers 700 g of the natural product
(determined by HPLC analysis; 300 g of 1 were obtained after
recrystallization).
ABBREVIATIONS
■
ACC, acetyl-CoA carboxylase; BODIPY, boron-dipyrrome-
thene; DCM, dichloromethane; DDQ, (2,3-dichloro-5,6-
dicyanobenzo-quinone); DMP, Dess−Martin periodinane;
DMSA, C11-desmethoxy soraphen A1α; PBM, p-methoxy-
benzyl ether; PMP, p-methoxyphenyl; RCM, ring-closing
metathesis; SA, soraphen A1α; TBAF, tetrabutylammonium
fluoride; TOFA, 5-(tetradecyloxy)-2-furoic acid
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the antifungal macrolide soraphen A(1 alpha): Deoxygenation in the
south-east ring segment. Liebigs Ann. Chem. 1997, 245−252.
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