A Scaffold-Diversity Synthesis of Biologically Intriguing Cyclic Sulfonamides

Article abstract of DOI:10.1002/chem.201904175

A “branching–folding” synthetic strategy that affords a range of diverse cyclic benzo-sulfonamide scaffolds is presented. Whereas different annulation reactions on common ketimine substrates build the branching phase of the scaffold synthesis, a common hydrogenative ring-expansion method, facilitated by an increase of the ring-strain during the branching phase, led to sulfonamides bearing medium-sized rings in a folding pathway. Cell painting assay was successfully employed to identify tubulin targeting sulfonamides as novel mitotic inhibitors.

Full text of DOI:10.1002/chem.201904175

A Journal of
Accepted Article
Title: A Scaffold Diversity Synthesis of Biologically Intriguing Cyclic
Sulfonamides
Authors: Kamal Kumar, Stefan Zimmermann, Mohammad Akbarzadeh,
Felix Otte, Carsten Strohmann, Muthukumar Gomathi Sankar,
Slava Ziegler, Axel Pahl, and Sonja Sievers
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201904175
Link to VoR: http://dx.doi.org/10.1002/chem.201904175
Supported by

10.1002/chem.201904175
Chemistry - A European Journal
RESEARCH ARTICLE
A Scaffold Diversity Synthesis of Biologically Intriguing Cyclic
Sulfonamides
Stefan Zimmermann,[a,b] Mohammad Akbarzadeh[a], Felix Otte,[b] Carsten Strohmann,[b] Muthukumar
Gomathi Sankar,[a] Slava Ziegler,[a] Axel Pahl,[a] Sonja Sievers,[a] and Kamal Kumar*[a]
Dedication ((optional))
Abstract: A branching-folding synthesis strategy is presented that
affords a range of diverse cyclic benzosulfonamide scaffolds. While
different annulation reactions on common ketimine substrates build
the branching phase of scaffold synthesis; a common hydrogenative
ring-expansion method, facilitated by ring-strain in scaffolds formed in
branching phase, led to sulfonamides bearing medium-sized rings in
a folding pathway. Cell painting assay was successfully employed to
identify tubulin-targeting sulfonamides as novel mitotic inhibitors.
more sp3 character and decorated with stereogenic centers. The
next folding ring-expansion strategy driven by the ring-strain in the
scaffolds formed in branching phase leads to medium ring-sized
benzosulfonamides.
The ability of small molecules to perturb biological systems in a
temporal and dose controlled-manner endows them uniqueness
to reveal insights of different biological functions. Advancement of
chemical biology and drug discovery demands a regular supply of
novel bioactive small molecules. The unmet medical needs and
limited understanding of life at molecular level urgently call to
interrogate biologically intriguing yet least explored areas of
chemical space to deliver small molecules as probe and drug
candidates.[1] Unfortunately, organic synthesis had remained
focused on a narrow range of molecular scaffolds despite the
emergence of strategies such as diversity-oriented synthesis
which precisely aimed to deliver a range of diverse chemotypes.[2]
Sulfonamides, cyclic and acyclic, are a well-known class of
small molecules that represents a number of FDA-approved
drugs and developmental candidates for a range of molecular
targets and indications. Intriguingly, no natural product is yet
known to embody a cyclic sulfonamide moiety. The primary
sulfonamide and sulfamate groups too are rarely found in natural
product structures (Scheme 1a). While introduction of
a
sulfonamide moiety on small molecules is relatively easy and well
established,[3] development of synthetic approaches affording a
range of diverse biologically relevant cyclic sulfonamides remain
underexplored.[4] Here we disclose a scaffold diversity synthesis
Scheme 1. a) Some natural products with acyclic sulfonamides; b) synthetic
bioactive cyclic sulfonamides; c) a branching-folding synthesis planning to form
diverse, complex and medium ring-sized cyclic sulfonamides.
of cyclic benzosulfonamides by employing
a
sequential
branching-folding synthesis approach and using easily accessible
Saccharin-derived cyclic N-sulfonyl ketimines 1 as the precursors
(Scheme 1c).[5] In this approach, the first branching pathway
exploits different annulation and nucleophilic addition reactions on
common substrates to form complex and cyclic sulfonamides with
A branching synthesis pathway transforms a common substrate
into structurally distinct scaffolds. The plan to employ saccharin-
derived ketimine 1 as the substrate for the sequential scaffold
generating approach stemmed from both the reported as well as
potential and unexplored reactivity of these cyclic ketimines in
annulation and addition reactions. In particular, we focused on
developing a range of different ring-fusions to the imine moiety i.e.
from three-membered aziridine to a six-membered piperidine ring.
This would offer possibilities for a subsequent and more
challenging folding pathway wherein common reaction conditions
may induce ring-expansion of different scaffolds formed in the first
branching phase and delivering another set of cyclic sulfonamides
(Scheme 1c).
[a] S. Zimmermann, Dr. M. Akbarzadeh, Dr. M. G. Sankar, Dr. A.
Pahl, Dr. S. Sievers, Dr. S. Ziegler, Dr. K. Kumar
Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische
Biologie, Otto-Hahn-Straße 11, 44227 Dortmund (Germany)
E-mail: kamal.kumar@mpi-dortmund.mpg.de
[b] S. Zimmermann, F. Otte, Prof. Dr. C. Strohmann
Fakultät Chemie und Chemische Biologie, Technische Universität
Dortmund, Otto-Hahn Str. 6, 44227 Dortmund (Germany)
Supporting information for this article is given via a link at the end of the
document
In our first reaction design in branching phase, we planned
to make annulation reactions with imine moiety of common
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Scheme 2. A branching pathway to cyclic sulfonamides via annulation and addition reactions of N-sulfonyl ketimines.
substrate 1 employing 1- to 4-carbon annulation partners to afford
three to six-membered aza-heterocycle fused sulfonamides. To
this end, the first scaffold target was the smallest stable aza-ring
system i.e. aziridines.[6] Among different possible synthetic
strategies to aziridines,[7] the carbenium transfer approach via
sulfonium ylides was employed affording different aziridine-fused
sulfonamides (2a-h) with two diversity sites in acceptable to good
yields (Scheme 2). Intriguingly, reactions of sulfonium ylides with
N-sulfonyl-aldimine 1-H (R1 = H) did not afford the corresponding
aziridines. Except for 2c and 2h that bear two neighbouring aryl
groups, and formed in equimolar ratio of syn- and anti- isomers in
high yields, aziridines were formed mostly as single syn-
diastereomers (2b, 2d-g) or as major isomer (2a, d.r. 7:1).
However, for ketimines with carboethoxy moiety, in particular, 2e-
2f, formation of uncharacterizable by-products (low molecular
weight) was observed that led to lower yields of desired products
(Scheme 2).
DABCO as nucleophilic catalyst in the above methodology
affording 5a and 5b in high yields (Scheme 2). The latter features
two orthogonal esters for further selective functional group
transformations.
Towards six-membered ring-fused benzosulfonamides, we
resorted to the Diels-Alder reaction.[9] After some reaction
conditions optimization, reaction of 1 with Danishefsky’s diene
under microwave irradiation in toluene furnished 1,4-dihydro--
pyridones 6a-d in good to excellent yields (Scheme 2). However,
under the optimized microwave heating condition, reaction of
relatively electron-rich ketimine 1-Me, could afford only low yield
of adduct 6e.[10]
In order to introduce more heteroatoms as well as
quaternary centers in more diverse and complex benzo-
sulfonamides, we employed two different azomethine ylides
derived from 7[11] and -silyl imines 9 with ketimines 1 in dipolar
annulation reactions and yielding imidazolidine based
benzosulfonamides 8a-e and 10 in moderate to high yields (37-
83%).[12] Interestingly, reactions of 7 derived dipole performed
better with aryl or alkyl ketimine 1 than with aldimine (1, R1 = H)
or iminoester (1, R1 = CO2Et, Scheme 2). Notably, -silyl imines
(9) have only rarely been explored in cycloaddition chemistry and
are interesting substrates for generating small molecules
embodying quaternary centers and thereby complex
stereochemical frameworks.[13] Another reaction screening
revealed that catalytic AgOAc and phosphine complex in
acetonitrile could transform 1-CO2Et with 9 into syn-imidazolidine
10 (d.r. = 87:13) as major adduct that bear two consecutive
quaternary stereocenters (Table S1 in Supporting information).
Towards 4- and 5-membered ring-fused benzosulfon-
amides, Ye and co-workers´ approach[8] of nucleophilic base-
catalyzed annulation reactions was exploited. Thus, zwitterionic
intermediate formed by addition of DABCO (cat.) and allenoates
(3) added regioselectively from terminal position of allene to
effectively result in a [2+2]-annulation and formed benzosultam-
fused (E)-azetidines (4a-f). We observed that
a reduced
electrophilicity of imine moiety in 1 (R1 = Me) negatively influenced
the reaction progression and product yield for 4d. Interestingly,
aldimine 1-H did not react with allene-derived zwitterions at all.
Furthermore, five-membered pyrroline based benzosulfonamides
were easily synthesized employing triphenylphosphine instead of
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RESEARCH ARTICLE
Scheme 3. A ring-expansion and -modulation reactions via palladium mediated heterogeneous hydrogenation/hydrogenolysis.
In the last reaction of branching pathway, a Mannich-type
addition of α-angelica lactone[14] as nucleophile to ketimine moiety
in 1 was explored.[15] By this way, we targeted molecular
complexity both in terms of consecutive quaternary
stereocenters[16] in the product, as well as having a natural
product fragment – the lactone ring - with a free rotation around
newly constructed bond. In our hands, silyl enol ether 11 worked
far better in the desired addition reaction than lactone itself.
Variation of reaction temperature and Lewis acids identified
AgOAc (Table S2) as the best catalyst for vinylogous addition
reaction exhibiting high reactivity (quick reaction within 10 min) at
-78 °C to form lactone 12a in good yield (89%) and diastereomeric
ratio (25:2) in favor of syn-diastereomer (based on nOe
experiments). Hydrogenation of 12a using 10 mol% Pd/C
furnished a saturated γ-lactone 12b in 63%.
key to success in approach was the selective cleavage of carbon-
nitrogen bond in the annulation adducts in branching phase.
Although C−N bond cleavage does occur in the course of
coupling[19] and aziridine-opening reactions,[20] but has not been
thoroughly utilized as a strategy to build larger cyclic systems.[21]
We hypothesized that, palladium on carbon can be used to cleave
N−C bond in adducts from branching phase in analogy to N-
debenzylation, but in intramolecular and stereoselective[22]
fashion to offer an additional set of novel cyclic sulfonamide
scaffolds (Scheme 1). Interestingly, aziridines 2a−h supporting
one benzylic N−C bond (R2 = CO2Et) under hydrogenation
conditions (10 mol% Pd/C, H2), cleaved from benzylic quat. C−N
bond to deliver sultams 13a−d (30-99% yield) exclusively in syn-
configuration. However, aziridines bearing two benzylic N−C
bonds (R1 and R2 = Ar) preferred cleavage at benzylic tert-C−N
bond to provide sulfonamides 14a−d (30-69% yield). It appears
that ring-strain in aziridines with quaternary benzylic carbon
indeed could drive the formation of sulfonamides 13 (for details
With tricyclic scaffolds (2, 4−6, 8 and 10) in hand, we were
curious to realize a common ring-expansion approach in a ´folding
pathway´ that could expand the range of distinct sulfonamides,[17]
in particular supporting medium-ring-sized frameworks.[18] The
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10.1002/chem.201904175
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RESEARCH ARTICLE
see Supporting info). However, when available, a tertiary benzylic
C−N cleavage was preferred to form 14a−d (Scheme 3).
Encouraged by above ring-expansion, other substrates
were also subjected to Pd-mediated hydrogenation conditions. In
particular, we expected to get medicinally important[3g, 23] seven-
membered sulfonamides from azetidines (4). To our delight,
under same hydrogenative conditions, 4a-b afforded syn-
diastereomer of corresponding seven-membered benzo-
sulfonamides 15a-b in moderate yields (Scheme 3). Isolation of a
ring-expanded intermediate
15a´
(49%
yield, Supp.
information)[12] suggests that hydrogenolysis of C−N bond
precedes hydrogenation of exocyclic double bond (Scheme 2).
We observed that a double benzylic substitution (R1 = Ph) in
azetidine 4 is a requisite for ring expansion to happen. For
instance, all our efforts for the desired ring expansion of ester
substituted azetidine 4e to seven–membered sulfonamide failed.
Infact, the reaction led to extra-cyclic opening of azetidine 4e
yielding 16 in 96% yield. Nevertheless, ester hydrolysis and amide
synthesis in 15a and 15b was performed to afford amides 18a-c
via carboxylic acid 17 (Scheme 3).
Pyrrolinyl sulfonamides 5 did not follow ring-expansion that we
assume owes to its lower ring-strain as compared to aziridines or
azetidine rings. Instead, hydrogenation of double bond occurred
to give pyrrolidine syn-19 in 95% yield. Hydrogenation of aminal
8a cleaved the ring at the expected aminal carbon to furnish a
relatively unstable benzosulfonamide 20 (87% yield). The latter
was quickly transformed into a stable tricyclic sulfonyl urea 21 that
features
a
key motif of herbicidal[24] and anti-diabetic
sulfonamides,[25] by treating with carbonyl diimidazole in presence
of base.
Likewise, six-membered dihydropyridones 6a-d lacking ring-
strain were transformed into 1,4-tetrahydropyridones 22 by
heterogeneous catalytic hydrogenation. Furthermore, ketone
function in 22 was used for reductive amination reactions using
NaBH(OAc)3. We observed that morpholine adducts displayed a
higher degree of syn-selectivity than n-propylamine adducts
(Scheme 3). The scaffold diversity generated in branching and
folding phase is clearly depicted in terms of three-dimensional
chemical space (PMI plot; Fig. S1) and the range of molecular
properties (molecular properties plot Fig. S2) represented by the
ensuing sulfonamide compound collection. In order to make an
unbiased analysis of the novel sulfonamides formed, their
biological activity was explored in a cell painting assay (CPA).[26]
CPA is an image-based analysis that measures and quantifies a
range of morphological changes in cells induced by a compound
and condensed to generate a fingerprint for novel as well as
annotated(reference) compounds. Identification of reference
compounds with a profile similar to the desired molecules may
offer insights into the biological activity as well as modes of action
of new compounds (Fig 1a).[27] To this goal, U2OS cells were
treated with the compounds for 20 h prior to staining of cellular
organelles and cellular components, i.e., DNA, endoplasmic
reticulum, nucleoli and cytoplasmic RNA, actin, mitochondria,
Golgi and plasma membrane. Automated image analysis and
data processing results in morphological fingerprints to display
the change of 579 parameters in comparison to the DMSO-
treated cells (Fig S3). Two derivatives displayed activity in the
CPA with induction (i.e. percentage of (4a) and 35 % (5b). These
fingerprints were compared with the changed parameters
Figure 1. Influence of benzosulfonamides 4a and 5b on cell growth, mitosis and
tubulin polymerization. a) Schematic representation of morphological profiling,
e.g. the Cell painting assay;[28] b) Fingerprint comparison for 4a (10 µM) with
fenbendazole (3 µM) and tubulexin A (50 µM); c) The growth of U2OS cells was
monitored for 48 h using kinetic live-cell imaging in presence of the compounds
or DMSO and fenbendazole as controls. Data are mean values (N=6) ± SD and
are representative of three biological replicates; d) Dose-response analyses for
cell growth inhibition were carried out as described in (a). The area under the
curve was used to determine IC50 for cell growth inhibition. IC50 (4a) = 7.8 ± 1.6
µM; IC50 (5b) = 6.0 ± 0.4 µM. Data are mean values (N=3) ± SD and are
representative of two biological replicates; e) U2OS cells were treated with the
compounds for 24 h prior to staining of DNA and tubulin using DAPI (blue) and
anti-alpha-tubulin-FITC antibody (green). Scale bar: 20 µm. f) U2OS cells were
treated with the compounds for 24 h prior to staining for phospho-histone 3 as
a marker for mitotic arrest and DNA followed by automated image acquisition
and analysis to quantify the percentage of cells in metaphase (i.e., phospho-
histon 3-positive cells). Data are mean values (N = 2) ± SD and are
representative of three biological replicates; g) In vitro tubulin polymerization
assay. Tubulin polymerization was initiated in presence of GTP and was
monitored by means of turbidity measurement at 340 nm at 37 °C. Taxol and
nocodazole were used as controls for tubulin-stabilizing and- destabilizing
agents, respectively. Data are representative of three biological replicates.
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10.1002/chem.201904175
Chemistry - A European Journal
RESEARCH ARTICLE
compared to the DMSO control) of 51 % fingerprints of reference
compounds, i.e., with known biological activity, to generate target
hypotheses. Interestingly, the morphological profile of 4a
Keywords: Sulfonamides • Branching Pathway • Folding
Pathway • Cell Painting • Mitotic Inhibitors
displayed similarity to tubulin-acting agents (fenbendazole[29]
–
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74% similarity, tubulexin A[30] – 84% similarity), (Figure 1b and
Figure S4a-b), whereas the morphological profile of 5b was
similar to an inhibitor of the mitotic Polo-like kinase 1[31] (PLK1 –
56 % similarity, Figure S5 and Figure S4c).
Both, tubulin and PLK1 have essential function during mitosis.
Therefore, we monitored the growth of U2OS in presence of 4a
and 5b cells by means of real-time live-cell analysis (Figure 1a).
Both compounds reduced cell growth dose-dependently with IC50
values of 7.8 ± 1.6 µM (4a) and 6.0 ± 0.4 µM (5b) (Figure 1b and
Movies S1-S3). Inspection of cell morphology revealed the
accumulation of round cells (Figure S6) with mitotic spindles
(Figure 1e) that is indicative of mitotic arrest. Arrest in mitosis was
confirmed using phospho-histone 3 staining that revealed
increase in the fraction of mitotic cells from 5.2 ± 2.4 % (DMSO-
treated cells) to 62.5 ± 15.1 % and 19.8 ± 6.9 % in the presence
of 10 µM 4a and 5b, respectively (Figure 1f and Figure S6-7).
Tubulin polymerization is amenable to modulation by small
molecules[32] and interference with microtubule dynamics leads to
mitotic arrest. As the CPA revealed similarity of the fingerprints to
the tubulin-targeting agents fenbendazole and tubulexin A (Figure
1b), we analyzed the influence of benzosulfonamides 4a and 5b
on in vitro tubulin polymerization. Compound 4a strongly inhibited
tubulin polymerization at 20 µM, whereas compound 5b was less
potent (Figure 1g). These results confirm the CPA-generated
mode-of-action hypothesis and identified sulfonamides 4a and 5b
as novel microtubule-targeting agents. Notably, sulfonamide
class of small molecules is not typically known for anti-mitotic
activities and therefore CPA was instrumental to offer an
unexpected biological annotation to benzosulfonamides.
In conclusion, a novel scaffold diversity synthesis approach
employing a branching-folding pathway strategy is presented to
offer access to biologically relevant yet under-explored cyclic
benzosulfonamides. Different annulation reactions of common
substrates formed the core of branching pathway, and a
hydrogenolytic ring-expansion strategy was the key for folding-
route. Cell painting assay was instrumental in identifying hits from
this non-natural class of small molecules and unravelling their
unexpected anti-mitotic activity and tubulin inhibition. We believe
this approach will find further applications to reach out to novel
chemical and biological space and to help advance discovery
research.
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This research was funded in parts by the Max Planck Society and
the Innovative Medicines Initiative Joint Undertaking under the
grant agreement (Nr. 115489), resources of which are composed
of financial contribution from the European Union's Seventh
Framework Programme (FP7/2007-2013) and EFPIA companies’
in-kind contribution. Authors are grateful to Prof. H. Waldmann for
his kind support and encouragement.
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RESEARCH ARTICLE
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10.1002/chem.201904175
Chemistry - A European Journal
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This article is protected by copyright. All rights reserved.