Discovery of an indole-substituted furanone with tubulin polymerization inhibition activity

Article abstract of DOI:10.1016/j.bmcl.2021.127991

Analogs of diarylpyrrolinone lead compound 1 were prepared and tested for anti-proliferative activity in U-937 cancer cells. Alterations of 1 focused on modifying the two nitrogen atoms: a) the pyrrolinone nitrogen atom was substituted with a propyl group or replaced with an oxygen atom (furanone), and b) the substituents on the indole nitrogen were varied. These changes led to the discovery of a furanone analog 3b with sub-micromolar anti-cancer potency and tubulin polymerization inhibition activity.

Full text of DOI:10.1016/j.bmcl.2021.127991

Bioorg. Med. Chem. Lett. 41 (2021) 127991
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of an indole-substituted furanone with tubulin polymerization
inhibition activity
a
,
*
b
a
b
Patricia Mowery , Madison M. Filkorn , Brianna Hurysz , Deborah O. Kwansare ,
b
b
a
b
Megan M. Lafferty , Marissa A. McFadden , Namita D. Neerukonda , Roslyn R. Patel ,
a
b
b
b
Kelsey Pierce , Kaitlynn A. Sockett , Nathanyal J. Truax , Nathan R. Webster ,
b,*
Erin T. Pelkey
a
Department of Biology, Hobart and William Smith Colleges, Geneva, NY 14456, USA
Department of Chemistry, Hobart and William Smith Colleges, Geneva, NY 14456, USA
b
A R T I C L E I N F O
A B S T R A C T
Keywords:
Anticancer
Tubulin
Analogs of diarylpyrrolinone lead compound 1 were prepared and tested for anti-proliferative activity in U-937
cancer cells. Alterations of 1 focused on modifying the two nitrogen atoms: a) the pyrrolinone nitrogen atom was
substituted with a propyl group or replaced with an oxygen atom (furanone), and b) the substituents on the
indole nitrogen were varied. These changes led to the discovery of a furanone analog 3b with sub-micromolar
anti-cancer potency and tubulin polymerization inhibition activity.
Furanone
Indole
Introduction
including those that are substituted with indole rings, we began
exploring the synthesis of indole-substituted furanones followed by their
Furanones (also known as butenolides) are oxygen heterocycles that
are found in a wide range of biologically active natural products and
synthetic analogs (Fig. 1).1–3 The demonstrated biological activity of
biological activity. In our previous report,43 we found that pyrrolinone 1
containing a dimethoxyphenyl group and an N-methylindolyl group had
modest antiproliferative activity towards macrophage-like U-937
4
–9
10
44
furanone natural products include anticancer,
anti-HIV,
antifungal,19,20 antitus-
In the search for β-secretase
anti-
cells. In this report, we set out to study the effect that modifying both
1
1–15
16
17,18
microbial,
analgesic, antidiabetic,
nitrogen atoms had on the anti-proliferative activity (Fig. 2). First, we
examined substitution of the nitrogen atom of the pyrrolinone ring with
an alkyl group (propyl) giving N-propylpyrrolinone analogs 2, followed
by replacement of the nitrogen atom with an oxygen atom giving fur-
anone analogs 3. Second, we examined the effect of substitution of the
sive, antimalarial,22 and antifouling.
23–25
2
1
inhibitors (potential leads in the treatment of neurodegenerative dis-
eases such as Alzheimer’s), ianthellidone G was isolated from a south
Australian marine sponge.26 While the latter appears to be a very rare
example of a natural product with a 3,4-diarylfuranone structure, syn-
thetic 3,4-diarylfuranones have received significant attention after the
discovery of the anti-inflammatory agent rofecoxib, a selective inhibitor
indole nitrogen atom (R = Me vs. R = CO Et vs. R = H). Our results are
2
presented herein.
We commenced our synthetic work by preparing N-propyltetramic
2
7
45
of cyclooxygenase-II (COX-II). In addition to selective COX-II inhib-
acids 5 using our previously reported methodology (Scheme 1). Amide
2
8–30
itors,
anticancer,
new 3,4-diarylfuranone analogs of have been investigated as
coupling of indole-3-acetic acid with ethyl N-propylglycinate mediated
by DCC gave amidoesters 4. Treatment of 4 with potassium tert-butoxide
gave the corresponding tetramic acids via a Dieckmann cyclization.
Interestingly, these two steps proceeded smoothly in the case of 5c,
despite the lack of protection of the indole nitrogen. Following the work
of Sarpong and co-workers,46 selective protection of the indole nitrogen
leading to tetramic acid 5b was accomplished by treatment with
ethoxycarbonylimidazole and DBU. All three tetramic acids were
3
1–34
35
36
antifungal,
7–39
In addition furanone analogs of the antitumor agent com-
antidiabetic,
and novel imaging
3
agents.
bretastatin A4 were found to have high cytotoxic activity in three
different human cancer cell lines.40 More recently, an indolyl-
substituted furanone analog of combretastatin A4 demonstrated
4
1
modest anticancer and antibacterial activity.
Given our interest in the study of vicinal diaryl heterocycles,42
*
Corresponding authors.
E-mail addresses: mowery@hws.edu (P. Mowery), pelkey@hws.edu (E.T. Pelkey).
https://doi.org/10.1016/j.bmcl.2021.127991
Received 28 October 2020; Received in revised form 16 March 2021; Accepted 18 March 2021
Available online 26 March 2021
0
960-894X/© 2021 Elsevier Ltd. All rights reserved.

P. Mowery et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127991
esterification-Dieckmann cyclization reported by Le Gall and co-workers
Scheme 2).4
9,50
Treatment of methyl indole-3-acetates 7 with ethyl
(
glycolate and potassium tert-butoxide gave the corresponding 3-(indol-
-yl)tetronic acids 8. Interestingly, this same strategy failed when
3
attempted with the corresponding indole-substituted tetramic acids 5.
Protection of the indole nitrogen leading to 8b was accomplished by
treatment of 7c with ethoxycarbonylimidazole and DBU. Treatment of 8
with triflic anhydride gave the corresponding triflates 9. Suzuki-
Miyaura cross-coupling of the latter with 3,4-dimethoxyphenylboronic
acid was accomplished using our standard conditions which provided
3 4 2 3
furanone analogs 3a-3c: Pd(PPh ) and aqueous Na CO . Furanone 3c
was also obtained by deprotection of 3b by hydrolysis with lithium
hydroxide.
To test for biological activity, we assayed the analogs for cytotoxicity
on U-937 cells using an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl
tetrazolium bromide] assay.51 Of the six analogs tested, furanone analog
3
b was found to have a nanomolar IC50, making it a promising candidate
for further study. In comparison to our previous lead compound, 1, the
furanone and ethoxycarbonyl addition in 3b may allow for greater
hydrogen bonding with its target. It is also possible that the ethox-
ycarbonyl functionality could serve to enhance the bioavailability of 3b.
In order to determine the intracellular target of our compounds,
findings from similar published compounds were examined. Structurally
Fig. 1. Biologically active 3,4-diarylfuranones.
comparable small molecules were found to bind VEGF-R2/3 (vascular
endothelial growth factor receptor 2 and 3).5
2,53
VEGF receptors
contribute in varying levels to angiogenesis, vascular permeability, and
lymphangiogenesis.54 In addition, our compounds mimic aspects of
naturally occurring staurosporine, which is often studied for its binding
to PKC (protein kinase C).55 PKC is involved in intracellular signal
transduction pathways that regulate cellular responses such as migra-
tion, proliferation, or changes in gene expression, and it plays a pivotal
role in numerous diseases.56 Docking studies with similar com-
pounds5
3,57
suggest that the 3-pyrrolin-2-one nitrogen and furanone in
our compounds could make hydrogen bonds in the deepest part of the
PKC and VEGF-R2 binding pockets. Therefore, we tested a subset of our
analogs (1, 2a, and 3a) against five PKC isozymes and the three VEGF
receptors (Supporting Table S1). Of note, compound 3b had yet to be
synthesized when the binding assay was performed. As the company
performing the assay only offered a modified version of the assay when
3b was available, 3b was not tested since the results would not have
been comparable across compounds. The assay results with 1, 2a, and 3a
revealed little binding with the tested proteins. Compound 1 was the
Fig. 2. Proposed structural modifications of lead compound
1 for anti-
proliferative studies. IC50 = concentration at which 50% of the cells are alive.
converted into the corresponding triflates 6 under the usual protocol
with triflic anhydride. These materials proved to be relatively unstable
to purification and thus were used directly in the subsequent cross-
coupling reactions. Following our previously published methodol-
most potent analog with only 47% and 50% effectiveness against PKC-
ε
4
7
ogy, Suzuki cross-coupling of 6 with 3,4-dimethoxyphenylboronic
acid leading to target analogs 2 was accomplished using standard con-
and VEGF-R3, respectively. Since the cell line used in the cytotoxicity
5
8
studies, U-937, are known to express VEGF-R3 and high amounts of
5
9
ditions: Pd(PPh
3
)
4
and aqueous Na
2
CO
3
. Pyrrolinone 2c was also ob-
PKC-
ε
,
the weak binding results suggest that our compounds inhibit
4
8
tained by deprotection of 2b by hydrolysis with lithium hydroxide.
cell growth by targeting other cellular components.
The synthesis of the furanone analogs 3 was more straight-forward
than expected. Tetronic acids 8 were prepared using the one pot trans-
All compounds in Fig. 3 were next tested by the National Cancer
6
0
Institute (NCI) against their sixty cell line panel (NCI-60 assay). Two
Scheme 1. Synthesis of N-propylpyrrolinone analogs 2.
2

P. Mowery et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127991
Scheme 2. Synthesis of furanone analogs 3.
Fig. 3. Cytotoxicity results of pyrrolinones 2 and furanones 3 on U-937 cells.
compounds, 3a and 3b, were potent on a diverse array of cell lines and
therefore met the criteria for additional five-concentration screening.
Consistent with our findings, against the majority of cell lines tested,
compounds 3a induced growth inhibition at a low micromolar range
while 3b inhibited at nanomolar concentrations (Supporting Table S2).
Consequently, when the NCI-60 profiles of 3a and 3b were analyzed
(
Supporting Tables S3-4), they had strong, but not identical correlation
with each other suggesting that the methyl and ethoxycarbonyl at the
indole nitrogen plays a role in their biological function. The correlations
also showed that 3a and 3b matched to six and nine known tubulin
inhibitors, respectively. Tubulin is involved in microtubule function
6
1
(
cell shape, mitosis, migration, movement of organelles) and therefore
6
2
altering its function can lead to cell death.
Since 3b had the most potent NCI-60 profile, it was tested for how it
impacted tubulin polymerization. The results were compared to poly-
merization rates of untreated tubulin, which slowly polymerizes over an
hour, and two current chemotherapy drugs: paclitaxel which stabilizes
6
3
tubulin and therefore induces fast polymerization and vinblastine
which is a polymerization inhibitor.64 Tubulin incubated with 3b
showed a response consistent with tubulin destabilization (Fig. 4).
Therefore, our findings that 3b interferes with tubulin assembly and
causes cell death is consistent with studies that tubulin destabilization
compounds are known to induce apoptosis.6
Fig. 4. Tubulin polymerization. Tubulin was incubated with 10
blue diamonds), no compound (red triangle), 10
M vinblastine (yellow ×
marks), or 10 M compound 3b (green circles). Representative graph of two
independent experiments.
μ
M paclitaxel
(
μ
μ
5,66
6
9
and maytansine binds at a site on the β-subunit. Concerning the
There are multiple well-studied polymerization destabilization
binding locations of tubulin inhibitors with similar NCI-60 profiles to
7
0
binding sites on tubulin. Vinca alkaloids bind between two
α/β-tubulin
3
b, oxibendazole (NSC 758459) binds to the colchicine binding site,
heterodimers,67 colchicine interacts within the heterodimer interface,
68
plinabulin (NSC 797934) has been reported to interact with the
3

P. Mowery et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127991
colchicine site71 or within the β-tubulin subunit, and nocodazole (NSC
59882) binds a unique, non-colchicine site within the β-tubulin subunit
with no
subunit contact.72 Identifying the tubulin binding site of 3b is
72
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Declaration of Competing Interest
2
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The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
27 Th ´e rien M, Gauthier JY, Leblanc Y, et al. Synthesis of rofecoxib, (MK 0966, Vioxx®
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Acknowledgments
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Financial support of this research from the NSF (RUI: 1362813),
Hobart and William Smith Colleges, Drs. Carey and Cohen, Dr. Ed
Franks, Patchett Family, Romana Lashewycz-Rubycz Endowed Fund,
and Ed Tapper is gratefully acknowledged.
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Appendix A. Supplementary data
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Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127991.
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