Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics

Article abstract of DOI:10.1002/anie.202010090

Hemiasterlin is an antimitotic marine natural product with reported sub-nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four-component Ugi reaction (Ugi-4CR) as the key st

Full text of DOI:10.1002/anie.202010090

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Accepted Article
Title: Expeditious Total Synthesis of Hemiasterlin via a Convergent
Multi-component Strategy and Its Use in Targeted Cancer
Therapeutics
Authors: Jiraborrirak Charoenpattarapreeda, Stephen J. Walsh, Jason
S. Carroll, and David R. Spring
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202010090
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COMMUNICATION
Expeditious Total Synthesis of Hemiasterlin via a Convergent
Multi-component Strategy and Its Use in Targeted Cancer
Therapeutics
[a]
[a,b]
[b]
[a]
Jiraborrirak Charoenpattarapreeda, Stephen J. Walsh,
Jason S. Carroll, and David R. Spring*
[
a]
J. Charoenpattarapreeda, Dr. S. J. Walsh, Prof. Dr. D. R. Spring*
Department of Chemistry
University of Cambridge
Lensfield Rd, Cambridge, CB2 1EW, UK
E-mail: spring@ch.cam.ac.uk
Website: https://www-spring.ch.cam.ac.uk
Dr. S. J. Walsh, Prof. Dr. J. S. Carroll
Cancer Research UK Cambridge Institute
University of Cambridge
[
b]
Robinson Way, Cambridge, CB2 0RE, UK
Supporting information for this article is given via a link at the end of the document.
Abstract: Hemiasterlin is an anti-mitotic marine natural product with
reported sub-nanomolar potency against several cancer cell lines.
Herein, we describe an expeditious total synthesis of hemiasterlin
featuring a four-component Ugi reaction (Ugi-4CR) as the key step.
The convergent synthetic strategy enabled rapid access to taltobulin
(HTI-286), a similarly potent synthetic analogue. This short synthetic
sequence enabled investigation of both hemiasterlin and taltobulin as
cytotoxic payloads in antibody-drug conjugates (ADCs). These novel
ADCs displayed sub-nanomolar cytotoxicity against HER2-
expressing cancer cells, while showing no activity against antigen-
negative cells. This study demonstrates an improved synthetic route
to a highly valuable natural product, facilitating further investigation of
hemiasterlin and its analogues as a potential payload in targeted
therapeutics.
Figure 1 Hemiasterlin (1), its family of marine natural products, and a synthetic
analogue taltobulin (HTI-286, 8)
Three synthetic strategies for the total synthesis of
hemiasterlin have been reported. Andersen et al. used Evans’
oxazolidinone
to
produce
an
enantiomerically
pure
tetramethyltryptophan unit and the route was highly linear with a
longest linear sequence (LLS) of 17 steps (total 23 steps).[
Vedejs and Kongkittingam utilised N-benzothiazole-2-sulfonyl
Hemiasterlins (1-4),[1–4] milnamide A (5),[5] and criamides (6-
16]
7
)[2] are a family of cytotoxic tripeptide natural products isolated
from marine sponges (Figure 1). Hemiasterlin (1), the most toxic
of the family, acts as an anti-mitotic agent by disrupting
microtubule dynamics causing mitotic arrest and cell deaths with
low- to sub-nanomolar potencies against several cancer cell
lines.[6–9] Several studies have detailed investigations into
discerning the pharmacophore of hemiasterlin with the aim of
generating efficacious anti-cancer agents. These efforts lead to
(
Bts) protecting group for peptide bond formation and (R)-2-
phenylglycinol chiral auxiliary for synthesising the
tetramethyltryptophan subunit with an LLS of 13 steps (total 20
steps).[17]
Finally, Lindel and co-workers employed
organocatalytic α-hydrazination using a proline-based tetrazole
catalyst in their total synthesis with a 15-step LLS (total 21
steps).[18]
the development of taltobulin (also known as HTI-286, 8),[8,10]
synthetic analogue of hemiasterlin, which was also shown to bind
a
The highly cytotoxic properties of hemiasterlin and its reported
analogues make them attractive candidates for use in targeted
therapeutics, such as antibody-drug conjugates (ADCs). ADCs
utilise the exquisite targeting ability of antibodies to deliver
[11–
at the vinca domain between the α- and β-subunits of tubulin.
1
3]
In the early 2000s, HTI-286 advanced to Phase II clinical trials
for the treatment of non-small cell lung cancer (NSCLC).[14] Its
development was halted by Wyeth for business reasons.[15]
[19,20]
cytotoxic payloads to specific cell types, such as cancer cells.
This strategy has witnessed renewed clinical success and interest
in recent years, with nine ADCs now approved by the US Food
and Drug Administration and more than 80 others undergoing
clinical evaluation.[21–23] Key to the success of any ADC is the
potency of the drug payload; only a tiny fraction of the
administered ADC reaches and is internalised by its target
cells.[
19]
Therefore, the limited number of intracellular drug
molecules must be sufficiently potent (typically sub-nanomolar in
vitro IC50) to affect the desired cell death. This requirement means
1
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that most ADC payloads are large, lipophilic species with difficult
and laborious synthetic routes, increasing the cost of an already
expensive development process. We hypothesised that if
synthetic access to hemiasterlin could be improved, it could
potentially serve as a useful payload for the ADC field due to its
high potency, relatively small size and hydrophilic zwitterionic
structure. Indeed, STRO-002, an ADC developed by Sutro
Biopharm, uses the hemiasterlin analogue 3-aminophenyl
hemiasterlin as the payload. This ADC is currently undergoing a
Phase I clinical trial for the treatment of ovarian and endometrial
cancer (clinical trial number: NCT03748186).[24]
methods.[29,30] It was found that the use of 3 Å molecular sieves
were critical to reaction progression; alternative drying reagents
resulted in the formation of undesired side-products (Scheme S1).
Amide coupling of the two fragments, dipeptide (9a or 9b) with
[8]
amino ester 14 (see SI for synthesis ) was then attempted. While
Lesma and co-workers could perform the fragment coupling to
generate their tripeptide library with the use of HBTU as the
coupling agent,[ unfortunately, our screening of various amide
coupling agents did not afford formation of the desired product 15
(Table S1). Complex reaction mixtures or apparent intramolecular
cyclisation of dipeptide 9a or 9b to form an undesired oxazolone
were observed under all conditions tested. Given the success of
the Ugi reaction to generate fragment 9, it was hypothesised that
an analogous Ugi reaction could facilitate fragment coupling to
complete the natural product synthesis. Favourably, isonitrile 17
was identified as the key intermediate for this strategy, which
could be accessed from common intermediates synthesised in
the initial route.
25]
To commence investigations, we envisaged that the synthetic
route to hemiasterlin could be simplified via a convergent, multi-
component approach (Scheme 1). Previously Lesma et al. has
reported the use of four-component Ugi reaction (Ugi-4CR) to
generate analogues of hemiasterlin with the L-tert-leucine central
amino acid replaced by L-valine.[25] In this vein, it was
hypothesised that a similar Ugi-4CR could be used to generate
dipeptide 9 from simple starting materials. Coupling of this
dipeptide to unsaturated γ-amino ester 10, accessible from N-
Boc-N-methylvaline via a reported procedure,[8] would then
complete the synthesis of the desired natural product.
Scheme 2 a) Synthesis of isonitrile 11 b) The four-component Ugi reaction and
the subsequent failed fragment amide coupling. NMM = N-methylmorpholine,
MS = molecular sieves, THF = tetrahydrofuran, DMF = N,N-dimethylformamide
Scheme 1 Retrosynthetic analysis of hemiasterlin (1)
The synthesis of isonitrile 17 began by Boc-deprotection of 10
and amide coupling of the free amine with Boc-Tle-OH, affording
dipeptide 16 in excellent yield (Scheme 3a). Subsequent Boc-
deprotection, formamide formation, and triphosgene-mediated
dehydration[ produced the required isonitrile 17 (65% yield over
five steps). Next, the Ugi-4CR to complete the synthesis was
attempted, which resulted in only total 20% yield of the desired
product (Table S4). A significant amount of an oxazole by-product
was observed by LCMS analysis of the reaction mixture.
Isonitrileacetamides have been used in three-component Ugi-
type reactions for synthesis of oxazoles due to the higher basicity
Accordingly, our synthesis of fragment 11 commenced with
the conversion of ethyl ester of L-tert-leucine to formamide 13 by
heating to reflux in ethyl formate (Scheme 2a).[26] Triphosgene-
mediated dehydration proceeded smoothly to produce isonitrile
27]
1
1 in excellent yield (91% over two steps).[27] The aldehyde
fragment 12 was synthesised in four steps according to the
procedure from Nieman et al. (see SI for synthesis).[8] Briefly,
starting from methyl (1H-indol-3-yl)acetate, trimethylation in two
steps, followed by a reduction by DIBAL-H gave homobenzylic
alcohol S4. Subsequent Ley-Griffith oxidation produced aldehyde
1
2 (70% over four steps).[28] With isonitrile 11 and aldehyde 12 in
of the amide oxygen, which promotes intramolecular cyclisation
hand, the Ugi-4CR was undertaken via their reaction with
methylamine and trifluoroacetic acid in the presence of 3 Å
molecular sieves, a procedure adapted from Lesma et al.
31]
(
Scheme S2).[
We hypothesised that by increasing the
concentration of trifluoroacetate anion in the reaction, we may be
able to outcompete this intramolecular process. Pleasingly,
(
Scheme 2b).[25] A separable mixture of diastereomers 9a and 9b
addition of CF
to 73% (dr 1:1.4, Scheme 3a). X-ray crystallography analysis of
5a was used to determine its absolute stereochemistry, which
corresponded to the stereochemistry of hemiasterlin (Scheme
b).[50]
3
COONa increased the overall yield of the Ugi-4CR
were obtained in good yield (70%, dr 1:1.3), which we identified
the absolute stereochemistry by X-ray crystallography analysis.[50]
Trifluoroacetic acid was used as the resulting N-
trifluoroacetamide is stable under mild ester hydrolysis condition
and can also be removed orthogonally using reductive
1
3
2
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COMMUNICATION
via reaction with bis(4-nitrophenyl)carbonate to generate mixed
carbonate 22 (56% yield over three steps). It was then found that
the presence of a free carboxylic acid on hemiasterlin or taltobulin
hindered carbamate formation. Thus, selective removal of the
trifluoroacetamide from 15a and 19a was achieved using NaBH
4
reduction (59% for 20 and 99% for 21, Scheme 4a). The free
amines were then reacted with activated carbonate 22 to form the
corresponding carbamates 23 and 24. It was then hypothesised
that an alkynyl DVP could be prepared via a strategy resembling
solid-phase peptide synthesis. Introduction of a reactive alkyne
could be achieved through propargyl glycine (propargylGly) while
incorporation of polyethylene glycol (PEG) chains and glutamic
acid residues would improve the aqueous solubility of the linker-
drug and decrease the hydrophobicity and aggregation propensity
2 3 2
of the resultant ADCs. Thus, peptidomimetic H-PEG -Glu -PEG -
propargylGly-NH ∙TFA (S11) was synthesised using a standard
2
Fmoc-protecting group protocol. Following cleavage from the
resin and purification, amide coupling of amine S11 with DVP-
carboxylic acid S12 produced the desired linker 25 (Scheme S4).
CuAAC reaction of DVP-alkyne 25 with azides 23 and 24 was
followed by ester hydrolysis to give the final linker-drug
compounds 26 and 27 after reverse-phase chromatography
purification (Scheme 4a).
Scheme 3 a) Final route to the synthesis of hemiasterlin (1) and taltobulin (8).
b) X-ray crystal structure of intermediate 15a.[50] HATU = hexafluorophosphate
azabenzotriazole tetramethyl uronium, DIPEA = diisopropylethylamine, TFA =
trifluoroacetic acid
The low diastereoselectivity observed in the Ugi-4CR step
was similarly experienced in many previous total syntheses which
[
32–
utilised isocyanide-based multicomponent reactions (IMCRs),
3
6]
where notable exceptions were when cyclic imines were
used.[37,38] Consequently, several groups have reported the use of
chiral phosphoric acids (CPAs) to induce enantioselectivity for
IMCRs.[39–42] Thus, we have attempted the screen of CPAs to
improve the diastereoselectivity, but no improvement was
observed (Table S2).
Lastly, the Ugi products 15 were hydrolysed to give
hemiasterlin 1 and its epimer 1b in 86% and 78% yield,
respectively. Taltobulin 8 and its epimer 8b were also synthesised
via the same synthetic route (Scheme 3a), demonstrating the
amenability of the route for analogue synthesis. Hemiasterlin and
taltobulin were each synthesised in 14 and 12 total steps,
respectively (both with an LLS of 10), in good overall yield.
Having successfully developed a superior synthetic route to
both hemiasterlin and taltobulin, we next wanted to investigate the
utility of these natural products in ADCs. First, it was necessary to
modify these warheads with bioconjugation linkers, to facilitate
attachment to an antibody. We have recently reported the
development of divinylpyrimidine (DVP) linkers as efficient
reagents for the selective and stable modification of antibodies via
disulfide rebridging.[43,44] The cathepsin-cleavable Val-Ala-PABC
was incorporated in the linker design as it was deemed essential
to release an unmodified drug from the antibody.[45] Finally, to
enable
a convergent synthesis, it was hypothesised that
modification of the warhead moiety with an azide and the DVP
linker with an alkyne would allow the use of a copper-catalysed
azide-alkyne cycloaddition (CuAAC) to complete the synthesis of
the desired linker-drugs.
Scheme 4 a) Synthesis of linker-drug compounds 26 and 27. b) Structures of
2
2 and 25 (see SI for the syntheses). PABC = p-aminobenzyloxycarbonyl, HOAt
1-hydroxy-7-benzotriazole, THPTA tris(3-
hydroxypropyltriazolylmethyl)amine
=
=
Accordingly, deprotection of Alloc-Val-Ala-PABA (S8) was
achieved via treatment with Pd(PPh
coupling of the free amine with N -PEG
S10 (Scheme S3). Activation of the benzyl alcohol was achieved
3
)
4
, followed by amide
-COOH, yielding azide
3
4
Trastuzumab is an FDA-approved monoclonal antibody
targeting HER2, a transmembrane receptor that is overexpressed
3
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COMMUNICATION
in 20-30% breast cancers. Trastuzumab also constitutes the
antibody component in two of the marketed ADCs (Kadcyla and
Enhertu).[21,46–48] Trastuzumab was chosen for this study to
enable comparison of hemiasterlin-based ADCs with other
reported trastuzumab ADCs loaded with alternative payloads. To
commence ADC synthesis, the four interchain disulfides in
trastuzumab were reduced via treatment with tris(2-
carboxyethyl)phosphine hydrochloride (TCEP) for 1 hour at 37 C,
revealing eight reactive thiols. The reduced antibody was then
reacted with the DVP linker-drug compounds 26 and 27 for 4
hours at 37 C. Pleasingly, LCMS and SDS-PAGE analysis
revealed >95% conversion to the re-bridged antibody species
ADC 1 and ADC 2 with a loading of four drug molecules per
antibody (Scheme 5). The SDS-PAGE analysis also showed
significant formation of the half-antibody species whereby the
hinge disulfides did not undergo interchain rebridging; instead,
non-native intrachain cross-linking of the reduced heavy chain
cysteines occurred (Scheme 5b). This is in line with the usage of
To investigate the biological activity of hemiasterlin, taltobulin
and their corresponding ADCs, their effect on the cell viability of
both HER2-positive (SKBR3, BT474) and HER2-negative (MCF7)
cell lines was determined (Figure 2 / Table 1). Hemiasterlin
exhibited sub-nanomolar cytotoxicity against all cell lines, whilst
the potency of taltobulin was approximately one order of
magnitude lower.[9] Pleasingly, both ADC 1 and ADC 2 displayed
exquisite cytotoxicity against SKBR3 and BT474 cells,
comparable to that reported for an analogous cathepsin-cleavable
trastuzumab-MMAE ADC (Table S5).[44,49] Furthermore, both
ADCs had negligible activity against MCF7 cells at the
concentrations tested. These combined data suggest that both
hemiasterlin and taltobulin have the potential to serve as cytotoxic
payloads in the development of targeted therapeutics and that
they can generate equivalent potency as clinically validated
payloads.
Table 1 In vitro cellular evaluation of 1, 8, ADC 1 and ADC 2.
DVP as
chromatography analysis demonstrated that both ADCs had
99.5% monomeric content, confirming minimal aggregation
a
rebridging linker.[43] In addition, size-exclusion
SKBR3
(HER2+)
BT474
(HER2+)
MCF7
(HER2-)
IC50 (nM)†
≥
Hemiasterlin (1)
Taltobulin (8)
ADC 1
0.18
1.12
0.15
1.40
0.27
0.45
0.37
3.00
>50
>50
propensity with this linker-payload (Figure S4, Table S3).
0.086
0.25
ADC 2
†Each data point is an average of independent triplicates.
In conclusion, the total synthesis of hemiasterlin has been
accomplished via a four-component Ugi reaction with a longest
linear sequence of 10 steps, in 11% overall yield. Our improved
synthetic approach allows for simple analogue exploration on the
N-terminus of the molecule, which was demonstrated by the
synthesis of taltobulin, a synthetic analogue of hemiasterlin.
ADCs synthesised from the two compounds showed
exceptionally potent and selective bioactivity, similar to that of an
analogous MMAE ADC. With its routine synthesis and high
cytotoxicity, this study paves the way for the future use of
hemiasterlin and its analogues as payloads in ADC therapeutics.
Furthermore, this represents the first documented use of
hemiasterlin and its ADC in the treatment of breast cancer,
showcasing its potential in the treatment of this disease.
Scheme 5 a) Synthesis of ADC 1 and ADC 2. b) SDS-PAGE analysis of the two
ADCs; lane 1 is non-reducing, lanes 2-4 are reducing; lanes: MW = molecular
weight marker, (1) trastuzumab, (2) reduced trastuzumab, (3) ADC 1, (4) ADC
2. TCEP = tris(2-carboxyethyl)phosphine. TBS = Tris-buffered saline (TrisHCl
25 mM, NaCl, 25 mM, EDTA 0.5 mM pH 8).
4
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Figure 2 Cellular viability assays of 1, 8, ADC1, and ADC2 in a), b) HER2-positive SKBR3 cells, c), d) HER2-positive BT474 cells, and e), f) HER2-negative MCF7
cells.
[
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Acknowledgements
1
We acknowledge Hikaru Seki for valuable discussions and the
provision of compound S12, Guillermo Caballero-Garcia for
supplying CPA1-4, Teodors Pantelejevs and Dr Marko Hyvönen
for their help with the size-exclusion chromatography experiment,
and Dr Andrew Bond for his assistance in X-ray crystallography
analysis. JC acknowledges Trinity College, Cambridge and DPST,
Royal Thai Government for support. The Spring lab
acknowledges general lab support from the EPSRC, BBSRC,
MRC and Royal Society.
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Keywords: hemiasterlin ∙ total synthesis ∙ multicomponent
reactions ∙ targeted therapeutic ∙ antibody-drug conjugates
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Angewandte Chemie International Edition
10.1002/anie.202010090
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Target and kill: We report a novel synthesis of hemiasterlin, a highly cytotoxic marine natural product, via a multi-component
approach with LLS of 10 steps. Its use in a targeted therapeutic was demonstrated as a payload in an antibody-drug conjugate (ADC)
showing mid-picomolar cytotoxicity against HER2-expressing cancer cell lines.
Institute and/or researcher Twitter usernames: @SpringGroupChem
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