Investigation on the Anticancer Activity of Symmetric and Unsymmetric Cyclic Sulfamides

Article abstract of DOI:10.1021/acsmedchemlett.0c00460

The sulfamide functional group has been extensively employed in organic synthesis to discover probes and drugs in various applications such as cancer, human immunodeficiency virus (HIV), virus, and diabetes. Herein, we describe the synthesis of 7-membered

Full text of DOI:10.1021/acsmedchemlett.0c00460

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Letter
Investigation on the Anticancer Activity of Symmetric and
Unsymmetric Cyclic Sulfamides
Jaden Jungho Jun, Divya Duscharla, Ramesh Ummanni, Paul R. Hanson,* and Sanjay V. Malhotra*,#
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ABSTRACT: The sulfamide functional group has been extensively
employed in organic synthesis to discover probes and drugs in
various applications such as cancer, human immunodeficiency virus
(HIV), virus, and diabetes. Herein, we describe the synthesis of 7-
membered symmetric and unsymmetric sulfamide compounds and
their biological evaluation through the National Cancer Institute
(NCI) panel of 60 human tumor cell lines (NCI-60) and the
mechanism of action study. The results of a study from the NCI-60
cell line exhibited that many synthesized cyclic sulfamide
compounds inhibited breast cancer (MDA-MB-468). The mecha-
nism of action study of a representative compound 18 showed the
inhibition of proliferation and apoptosis in A549 lung cancer cells.
KEYWORDS: Anticancer activity, Cyclic sulfamide, NCI-60 cell line, A549 lung cancer
he sulfamide is a broadly accepted functional moiety in
Tmedicinal chemistry for the design and identification of
various biologically active compounds. Sulfamide-based
inhibitors have been designed for various enzymes such as
carbonic anhydrides (CAs),1−6 protease,7−10 γ-secretase,10
serine-protease,11 thrombin,12 metalloproteinase carboxypepti-
dase A (CPA),13 matrix metalloproteinase (MMP),13−15
steroid sulfatase (STS),16,17 protein tyrosine phosphatase
inhibitors,17,18 etc. Also, there has been a report on the
anticancer activity of sulfonamide-based compounds.19 In
many cases, a free or substituted sulfamide moiety contributes
to binding to the active site of a protein showing better affinity
and exhibiting higher aqueous solubility and bioavailability.
For example, cyclic sulfamide inhibitors interact with the
catalytic aspartic acid residue of HIV protease.7,8,19,20 Cyclic
sulfamides have been applied in medicinal chemistry to identify
several valuable compounds as shown in Figure 1. Prominently,
cyclic sulfamides have been used as a structural template
applicable for the inhibitor development such as HIV,
metalloprotease, serine proteases, and γ-secretase. Compound
I was discovered by Merck as a γ-secretase targeting therapy in
Alzheimer’s disease (AD) in 2005.21 The series of this cyclic
sulfamide was one of the structural substitute analogues to the
acyclic sulfonamide derivatives which were reported in the
same year.22 Next, compound II, an orally bioavailable Factor
Xa (FXa) inhibitor, was developed by the Yamanouchi
Pharmaceutical Co. Ltd. (currently known as Astellas Pharma
Inc.).23,24 FXa, a serine protease, is involved in blood clotting
by cleaving prothrombin into active thrombin. Novel 5-
membered cyclosulfamide compound III as a Norwalk virus
inhibitor was developed via structure−activity relationship
(SAR) studies.25 N-Cyclopropyl sulfamide compound IV
having a fused 6-membered ring system is another example
of γ-secretase inhibitors studied by Merck for the treatment of
AD.26 The Korea Institute of Science and Technology (KIST)
has developed carbapenem compounds V containing a pendant
cyclic sulfamide, which was found to display potent
antibacterial activity.27
As discussed above, sulfamides have been shown to provide
biological activities against different enzymes and have been
developed for various diseases including cancer. However,
cyclic sulfamides have not been actively investigated in cancer
drug development. With this need, we set our objective in this
study to explore the anticancer activity of seven-membered
sulfamide compounds. Due to the intrinsic properties of this
highly polarized moiety when attached to an organic scaffold, it
is an attractive consideration to incorporate the sulfamide
moiety for inducing desired physiochemical properties such as
enhanced water solubility, better bioavailability, etc., to the
druglike compounds. Encouraged by the possibilities offered
by this moiety, we synthesized a set of new seven-member
cyclic sulfamide compounds and investigated their potential as
Received: August 20, 2020
Accepted: January 8, 2021
Published: January 15, 2021
https://dx.doi.org/10.1021/acsmedchemlett.0c00460
© 2021 American Chemical Society
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Figure 1. Representative examples of biologically active cyclic sulfamides.
Scheme 1. Synthesis of Cyclic Sulfamide Compounds
a
b
c
d
e
SO2Cl2, Et3N, CH2Cl2. Benzyl bromide (BnBr) or benzyl chloride (BnCl), K2CO3, CH3CN. PMBCl, K2CO3, CH3CN. LiAlH4, THF. Swern
f
g
h
i
oxidation or Dess−Martin periodinane. Ph3P+CH3Br−, n-BuLi, THF. Grubbs Cat-II, benzene. OsO4, NMO, H2O/acetone. m-CPBA, CH2Cl2.
j
VCl3(THF)3, CH2Cl2, Zn; PMBCl = p-methoxybenzyl chloride, THF = tetrahydrofuran, m-CPBA = m-chloroperoxybenzoic acid, DIAD =
diisopropyl azodicarboxylate, TFA = trifluoroacetic acid, NMO = N-methylmorpholine.
anticancer agents. The structural modifications were based on
the assumption that the variation of physicochemical proper-
ties and thereby different biological activity could be achieved
with a change in substituents. Herein we are describing the
results of our detailed studies.
We have devoted our efforts to the development of synthetic
methods for the sulfur-containing small molecule compounds
in various ways.28−30 The synthesis of amino ester-derived C2-
symmetric and unsymmetric sulfamides and further synthesis
are described in Scheme 1. Amino esters are useful chiral
auxiliary groups that are employed in medicinal chemistry
synthesis and have been utilized in a wide range of areas such
as peptide synthesis, asymmetric synthesis, and medicinal
chemistry. The construction of chiral carbons in different
positions of cyclic sulfamide was effectively possible by the
employment of amino ester. Condensation of a slight excess of
amino ester HCl salt with SO2Cl2 in CH2Cl2 at 0 °C provided
sulfamides 3 and 4 in high yield. For the monobenzylation, 1
equiv of benzyl chloride was consumed to afford 7 which was
used for next benzylation with p-methoxybenzyl chloride to
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Scheme 2. Synthesis of C2-Symmetric Cyclic Sulfamide 34
a
b
c
d
Methyl (S)-2-hydroxy-4-methylpentanoate, PPh3, DIAD, THF. BnCl or BnBr, K2CO3, CH3CN. TFA, CH2Cl2. BnCl or BnBr, K2CO3,
e
f
g
h
CH3CN. LiAlH4, THF. Oxalyl chloride, DMSO, Et3N, CH2Cl2,-78 °C. Ph3P+CH3Br−, n-BuLi, THF. Grubbs Catalyst-II, benzene, reflux.
furnish unsymmetric sulfamide 8. Benzylation using benzyl
bromide (BnBr) or benzyl chloride (BnCl) and reduction by
the addition of lithium aluminum hydride (LAH) carefully into
a reaction mixture at 0 °C were the straightforward method to
generate primary alcohol intermediates 9−11. When Dess−
Martin periodinane or Swern oxidation reagent is added into
analogues 9−11, two hydroxyl groups were transformed to the
aldehydes to give intermediates 12−14. Under the Wittig
reaction condition,31,32 the reaction of 5−7 using n-butyl
lithium and Ph3P+CH3Br− afforded analogues 18−20,
respectively. For the construction of seven-membered ring
18−20 from dienes 15−17, we explored ring closing
metathesis (RCM) utilizing Grubbs catalyst II (3−6 mol %)
in heating benzene. The highlight of our synthetic approach
represent the innovative way to construct cyclic sulfamide
compounds.
Next, we performed dihydroxylation and epoxidation from
18 and 19 which gave dihydroxyl compound 21 and 22 and
epoxy sulfamide 23 and 24. Reaction of the aldehyde 12
employing Pinacol coupling with a vanadium(II) reagent,
[V2Cl3(THF)6]192[Zn2Cl6],33 produced a single diastereomer
25. The nuclear Overhauser effect (NOE) study allowed us to
determine the stereochemistry of each chiral center around a
seven-membered ring as shown in Scheme 1.
Synthesis of seven-membered cyclic sulfamide compound 34
was conducted from the reaction of chlorosulfonyl isocyanate
(CSI), L-valine methyl ester, and t-butanol to generate Boc-
group protected sulfamide intermediate 26 in good yields.
Sulfamide 27 was then successfully obtained by the reaction of
methyl (S)-2-hydroxy-4-methylpentanoate and sulfamide 26
under the Mitsunobu reaction condition.34,35 The Mitsunobu
reaction is a well-known method to invert the configuration of
alcohols. Benzylation on the sulfamide nitrogen gave sulfamide
28 in 77% yield, followed by the deprotection of the Boc group
using TFA at room temperature to furnish intermediate 29 in
high yield. It was washed with saturated aqueous NaHCO3
solution to remove TFA salt and further benzylation
constructed meso sulfamide 30. Two methyl ester groups
were transformed into primary hydroxyl groups by the LAH
reduction to furnish compound 31. This diol compound was
converted to the unstable dialdehyde compound 32 through
the Swern oxidation at low temperature (−78 °C). Wittig
reaction of 32 generated terminal olefin compound 33 which
was converted to cyclized meso sulfamide 34 by RCM using the
second-generation Grubbs catalyst in refluxing benzene (see
Scheme 2). Other compounds shown in this paper were
synthesized as in the cited methods in the Supporting
Information. Compounds 18−46 including the Cancer
Chemotherapy National Service Center (NSC) numbers are
illustrated in Table 1.
The standard cell culture protocol of the National Cancer
Institute panel of 60 human tumor cell lines (NCI-60) and for
drug sensitivity analysis in these cell lines has been described
previously in the hereby cited literature.36−38 All cultured cells
were incubated in a humidified incubator with 5% CO2 in the
air at 37 °C. To confirm the absence of contamination, the cell
lines were tested for Mycoplasma periodically. The NCI-60
cancer cell lines were maintained in RPMI 1640 medium with
5% fetal bovine serum (FBS) and 2 mM L-glutamine (Lonza,
Walkersville, MD). Cells were distributed into 96-well
microtiter plates at a proper density and maintained for 1
day with no drug. Some of the plates were then administered
to decide the cell density at time zero. Concisely, the panel is
systematized into nine subpanels on behalf of diverse
histologies: leukemia, melanoma, and cancers of lung, colon,
kidney, ovary, breast, prostate, and central nervous system. All
test compounds prepared in DMSO were added to cultivated
cells at five concentrations with 10-fold dilutions, the highest
being 10−4 M and the others being 10−5, 10−6, 10−7, and 10−8
M. Control cells were treated with DMSO alone and incubated
under standard culture conditions for 48 h. The percentage
growth inhibition was determined relative to cells without drug
treatment and the time zero control. After the termination of
the assay by addition of cold trichloroacetic acid, and the cells
were fixed and stained with the treatment of sulforhodamine B.
The bound stain is solubilized, and the absorbance detection of
samples can be read in an automated microplate reader. 50%
growth inhibition (GI50, cytostatic parameter) is the
concentration for 50% max inhibition of cell proliferation,
and it was calculated from time zero, control growth, and the
five-concentration level absorbance. Inhibitory concentrations
(LC50, cytotoxic parameter) are the concentration of drug or
chemical that kills 50% of cells with a one-time exposure and
represent the average of two independent experiments. Cell
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Table 1. Compounds Submitted to the NCI-60 Cell Lines
lines with a horizontal bar pointing to the left have a Gl50 that
is greater than the mean and are more resistant than the mean,
whereas cell lines with a horizontal bar pointing to the right
have a Gl50 that is less than the mean and are more sensitive.
The in vitro NCI-60 cell screening is a two-stage process
started with the evaluation of the submitted compound at a
single high dose (one-dose screen, 10−5 μM) in the full cell
panel. Compounds showing compelling growth inhibition in
the one-dose screen are evaluated for five-dose screening (five
concentration levels). Only the compounds exhibiting more
than 60% of growth inhibition in at least 8 tumor cell lines
were selected for further testing, and the others were assumed
inactive. All 22 compounds were initially evaluated at a single
dose of 10 μM. Only the compounds exhibiting more than
60% of growth inhibition in at least 8 tumor cell lines were
selected for further testing, and the others were assumed
Table 2. Cytostatic (GI50 and TGI) and Cytotoxic (LC50)
Parameters of Active Compounds
compounds
18 (NSC
764190)
21 (NSC
751486)
23 (NSC
751478)
25 (NSC
764189)
log GI50
log TGI
log LC50
median
delta
range
median
delta
range
median
delta
−4.94
1.63
2.57
−4.00
0.22
0.22
−5.49
0.58
0.85
−5.10
0.22
0.62
−5.31
1.25
1.44
−5.12
0.00
0.00
−5.30
0.00
0.00
−5.30
0.00
0.00
−4.00
0.00
−4.80
0.18
−5.12
0.00
−5.30
0.00
range
0.00
0.28
0.00
0.00
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Figure 2. (A) A549 cells were treated with compound 18 (same as LSC-JHJ-III-128-13) at μM or DMSO. On exposure of A549 cells to 18, the
change in morphology of cells was observed. (B) The A549 cell was treated with compound 18 at 10 μM or DMSO. On exposure of A549 cells to
compound, 50% growth inhibition is observed after 36 h.
Subsequently, the antiproliferative activity of the most active
four compounds was determined at different concentrations of
10-fold scale such as 100, 10, 1.0, 0.1, and 0.01 μM. The mean
GI50 and LC50 values against a 60 cell line panel are
summarized in Table S1 (please refer to the Supporting
Information).
These compounds showed varied patterns against all cell
lines. Compounds 25 showed nearly the same value for GI50,
total growth inhibition (TGI), and LC50 suggesting potential
toxicity and, therefore, should not be considered for further
investigation. Compounds 21 and 23 showed a small
differential range between cytostatic markers (GI50, TGI)
and the cytotoxicity marker (LC50) suggesting a narrow
therapeutic index. However, compound 18 displayed a very
interesting selective cytotoxicity pattern against several cell
lines. It was particularly potent at a nanomolar concentration
against RPMI-8226 (leukemia), HCT-116 (colon cancer), SF-
295 (CNS cancer), OVCAR-4 (ovarian cancer), PC-3
(prostate cancer), and MDA-MB-468 (breast cancer) cancer
cell lines. Also, comparing the cytostatic data (GI50, TGI) and
cytotoxic data (LC50), it is evident that compound 18 showed
a remarkable difference between cytostatic indicators (GI50,
TGI) and the cytotoxic indicator (LC50) suggesting a broad
therapeutic index. In an earlier study,19 sulfonamide had shown
the antiproliferative properties against A549 nonsmall cell lung
Figure 3. Effect of compound 18 on the anchorage-independent
cancer (NSCLS) cells in vitro. Therefore, to understand the
mode of action, we further investigated the mechanism using
A549. The five-dose graph and dose−response curves of 18 for
the individual disease wise subpanel of NCI-60 cells are
presented in Figure S1 (please refer to the Supporting
Information).
The log GI50, TGI (cytostatic parameter), and LC50
(cytotoxic parameter) for the active compounds 18, 21, 23
and 25 against the 60 cell lines are summarized in Table 2,
growth of A549 cells. In clonogenic assays, cells were allowed to grow
in soft agar containing 18 (0−50 μM) for 9 days to form colonies. (A)
Images of the colony-forming assay and (B) number of colonies
stained with crystal violet.
inactive. All 22 compounds were initially evaluated at a single-
dose screening. Four of our compounds showed significant
antiproliferative activity at 10 μM. The results of the single-
dose screen are given in the Supporting Information.
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Figure 4. Effect of compound 18 (NSC 764190) on migration of the A549 cell. The representative images of the in vitro scratch assay are shown
here. After creating scratches of A549 cell monolayers, cells growing in media containing the test compound (0−50 μM) or DMSO vehicle were
analyzed with a phase-contrast microscope, and images are presented. Compound 18 inhibited migration of A549 cells.
Figure 5. Senescence induced by compound 18 was quantified using SA-β-gal-staining. SA-β-gal positive cells are indicated with the arrow mark.
The number of SA-β-gal positive cells increased with increasing concentration of compound indicating that compound 18 induces senescence of
A549 cells.
along with the log median values (median value of multiple
experiments), log delta values (the maximum sensitivity over
the mean), and the log range values (the maximum difference
between the least sensitive and the most sensitive cell
lines).39,40 These parameters offer important information
about potency and selectivity of anticancer agents. Large
values of the delta and range imply high selectivity for some
histological cancers over others.41
Inhibitory effects of 18 on the proliferation of A549 lung
epithelial cancer cells were evaluated by treating the overnight
grown cells with test compound (1 μM). As shown in Figure
2A, upon treatment with test compound, A549 cells lost
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morphology and appeared as dead cells with no further
proliferation. In a time-dependent experiment with A549 cells,
50% growth inhibition was observed with 18 after 36 h (Figure
2B).
Characterization data for the synthesized compounds,
copies of their NMR spectra, and biochemical assays
protocol (PDF)
As we observed the antiproliferative activity of 18 against
A549 cells and the effect of compound 18 on anchorage-
independent growth A549 cells, a soft agar-based colony-
forming assay was performed. The colonies stained in soft agar
plates have clearly confirmed that the compound 18 inhibits
the formation of colonies by cancer cells. In these assays, a
dose-dependent inhibition on clonogenic growth by A549 cells
by 18 indicates the efficacy of 18 toward inhibition of A549
cell growth (Figure 3A,B).
Toward identifying NCEs with novel anticancer potential,
understanding their effects on migration properties of cancer
cells is also important. In vitro scratch or wound healing assays
are the suitable assay to evaluate the effect of test compounds
on cell migration for epithelial or mesenchymal cells. As shown
in Figure 4, the results confirm that compound 18
(NSC764190) inhibited migration of cells by 50% approx-
imately even at the lowest tested concentration whereas, in
DMSO plates, cells showed migration the same as the control
untreated assays (Figure 4, upper left panel).
As we observed the effect of 18 on proliferation and
migration of A549 cells, we next determined whether 18
induces apoptosis and/or inhibits cell proliferation. Hence, we
determined cell death and cell cycle progression using flow
cytometry. After postexposure of A549 cells to 18 for 48 h,
propidium iodide (PI) was applied to measure cell cycle
progression and cell death.
The flow cytometer results showed an increase in SubG1
population, indicating that compound 18 is inducing cell death
(Figure 5).
AUTHOR INFORMATION
■
Corresponding Authors
Paul R. Hanson − Department of Chemistry, University of
Kansas, Lawrence, Kansas 66045-7582, United States;
orcid.org/0000-0001-5356-0069; Phone: 785-864-3277;
Email: phanson@ku.edu
Sanjay V. Malhotra − Department of Cell, Development and
Cancer Biology and Center for Experimental Therapeutics,
Knight Cancer Institute, Oregon Health & Science University,
Portland, Oregon 97201, United States; orcid.org/0000-
0003-4056-5033; Email: malhotsa@ohsu.edu
Authors
Jaden Jungho Jun − Department of Pharmaceutical Sciences
and Computational Chemical Genomics Screening Center,
National Institutes of Health (NIH) National Center of
Excellence for Computational Drug Abuse Research, Drug
Discovery Institute, School of Pharmacy, University of
Pittsburgh, Pittsburgh, Pennsylvania 15261, United States;
Department of Chemistry, University of Kansas, Lawrence,
Kansas 66045-7582, United States; orcid.org/0000-
0002-8585-7809
Divya Duscharla − Department of Applied Biology, CSIR-
Indian Institute of Chemical Technology, Hyderabad
500007, India
Ramesh Ummanni − Department of Applied Biology, CSIR-
Indian Institute of Chemical Technology, Hyderabad
500007, India; orcid.org/0000-0003-1123-282X
Complete contact information is available at:
To gain additional insight into the mechanisms by which 18
treatment induces cell death and inhibits proliferation, we have
investigated caspase activation and senescence in A549 cells
treated with the compound. A significant increase in the
caspase activity could not be observed in compound treated
cells compared to the control (data not shown). Therefore, we
assessed the endogenous level of β-galactosidase as an
indicator for senescence in A549 cells upon treatment with
18. Interestingly, we could observe more cells with an
increased level of SA-β-gal in cells upon treatment with the
compound, and the number of cells positive for SA-β-gal also
increased with increasing concentration. These results support
the hypothesis that the exposure of cells to compound 18 leads
to the induction of cellular senescence in A549 cells for cell
cycle arrest.
In conclusion, a set of seven-member cyclic sulfamide has
been synthesized and tested for potential anticancer activity
against nine different cancer panels. Generally, compounds
showed selectively sensitivity against a host of cell lines. Almost
every compound is strongly inhibited on breast cancer (MDA-
MB-468). A mechanism study with a representative compound
18 (NSC764190) using A549 (nonsmall cell lung cancer) cells
suggests inhibition caused by apoptosis.
https://pubs.acs.org/10.1021/acsmedchemlett.0c00460
Author Contributions
#S.V.M. is the lead author.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This investigation was generously supported by partial funds
provided by the Petroleum Research Fund (PRF-AC,
administered by the ACS), the National Institutes of Health
(National Institute of General Medical Sciences RO1-
GM58103), and a minority supplement (RO1-GM58103-S1,
MdSJ). The authors thank Justin Douglas and Sarah
Neuenswander in the University of Kansas Nuclear Magnetic
Resonance (NMR) Laboratory and Dr. Todd Williams for
high-resolution mass spectrometry (HRMS) analysis. Support
for the NMR instrumentation was provided by NIH shared
instrumentation grants P20 GM103418, S10RR024664, and
S10 OD016360 and National Science Foundation (NSF)
academic research infrastructure grants 9512331, 9977422, and
0320648. We also acknowledge the IICT communication
number IICT/Pubs./2020/370.
ASSOCIATED CONTENT
■
REFERENCES
■
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The Supporting Information is available free of charge at
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