Bioorganic & Medicinal Chemistry Letters 29 (2019) 1779–1784

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Bioorganic & Medicinal Chemistry Letters

journal homepage: www.elsevier.com/locate/bmcl

Design and synthesis of functionalized coumarins as potential anti-austerity T

agents that eliminates cancer cells' tolerance to nutrition starvation
Suresh Awalea, , Takahiro Okadab, Dya Fita Dibwea, Takahiro Maruyamab, Satoyuki Takaharac,
⁎

Takuya Okadac, Satoshi Endod, Naoki Toyookab,c,

⁎

a
Division of Natural Drug Discovery, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
b
Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
c
Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
d
Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan

ARTICLE INFO ABSTRACT

Keywords: Human pancreatic tumor cells have inherent ability to tolerate nutrition starvation which enables them to
Pancreatic cancer survive in the hypovascular tumor microenvironment. Discovery of agents that selectively inhibit the cancer
PANC-1 cells’ tolerance to nutrition starvation leading to cancer cell death is a new anti-austerity approach in anti-cancer
Antiausterity agent drug discovery. A series of coumarins derivatives were synthesized and evaluated for their anti-austerity activity
Preferential cytotoxicity
against PANC-1 human pancreatic cancer cell line. The compound 7-Hydroxy-2-oxo-2H-chromene-3-carboxylic
Coumarin
acid (3-phenylpropyl)amide (2c) showed highly potent selective cytotoxicity against PANC-1 cells under nu-
Drug discovery
trient-deprived conditions, with a PC50 value of 0.44 μM, without exhibiting toxicity in normal, nutrient-rich
medium. Compound 2c caused dramatic alterations in PANC-1 cell morphology, leading to cell death. The
compound 2c was found to inhibit PANC-1 cell migration and colony formation in a concentration-dependent
manner. The compound 2c is a lead structure for the anti-austerity drug development against pancreatic cancer.

Pancreatic cancer is the fatal malignancy having the lowest 5-year blood vessels are heterogeneous and cause gradient niches of nutrient
survival rate of less than 5%.1,2 It is the 3rd and 5th leading cause of death deficiency within the tumor microenvironment.8 In particular, pan-
due to cancer in Japan among women and men.3 The prognosis of this creatic tumors are hypovascular in nature9 that cannot fulfil the high
disease is extremely poor, and the patients are usually diagnosed at the nutrient demand of aggressively proliferating cells causing nutrient
advanced stage in the majority of cases.1,2 In the year 2017, an estimated starvation within the tumor microenvironment. Tumor cells under
34,000 people died due to pancreatic cancer in Japan.3 The incidence rate such microenvironment switch the energy metabolism and acquire
is dramatically increasing throughout the world.3–5 However, the five-year tolerance to nutrient starvation to survive.10 The previous study has
survival rate for this deadly malignancy remains the same since the past shown that, when normal healthy cells are starved of essential nu-
five decades, mainly because it shows resistance to conventional che- trients, the cells die within 24 h. Contrary to this, human pancreatic
motherapeutic drugs such as paclitaxel, doxorubicin, and cisplatin.1,2 tumor cells survive for the prolonged period of over 72 h even in the
Gemcitabine and 5FU based regimens are mostly used chemotherapeutic complete absence of glucose, amino acids, and serum under the phy-
agents for pancreatic cancer for the palliative purpose.2 Recently, FOLFI- siological condition of electrolytes only.10 Therefore, human pan-
RINOX (a combination of folinic acid, 5FU, irinotecan, and oxaliplatin) has creatic cancer cells have a remarkable tolerance to nutrition starva-
demonstrated a slightly improved survival rate when compared to gem- tion, and countering this resistance to nutrition starvation is a novel
citabine alone, for locally advanced pancreatic cancer.2 However, FOLFI- approach in anticancer drug discovery referred to as ‘anti-austerity
RINOX regime was found to be very toxic and showed more severe side strategy’.11 Based on this strategy, we carried out the screening of
effects than the standard therapy, and is not suitable for all patients.6 medicinal plants from diverse origins, which has provided several
Therefore, alternative treatment with improved efficacy with lower side promising candidates. One of the most successful antiausterity agent
effects and toxicity is extremely desired. discovered in this field is an arctigenin, which has completed early
Tumor growth is in general facilitated by angiogenesis to supply Phase II human clinical trial against advanced pancreatic cancer pa-
enough nutrients to the proliferating cells.7 However, newly formed tients in the National Cancer Center Hospital East (Kashiwa,

⁎
Corresponding authors.
E-mail addresses: suresh@inm.u-toyama.ac.jp (S. Awale), toyooka@eng.u-toyama.ac.jp (N. Toyooka).

https://doi.org/10.1016/j.bmcl.2019.05.010
Received 16 March 2019; Received in revised form 30 April 2019; Accepted 7 May 2019
Available online 08 May 2019
0960-894X/ © 2019 Elsevier Ltd. All rights reserved.
S. Awale, et al. Bioorganic & Medicinal Chemistry Letters 29 (2019) 1779–1784

Scheme 1. Reagents and conditions: (a) Meldrum’s acid, H2O, reflux; (b) Method A: amine, EDC, NEt3, HOAt or HOBt, DMF, 80 °C for 2a–b and 2d; Method B: amine,
EDC, N-Me-morpholine, HOBt, THF, r.t. for 2c.

Scheme 2. Reagents and conditions: (a) Meldrum’s acid, H2O, reflux; (b) phenylpropylamine, EDC, N-Me-morpholine, HOBt, THF, r.t.

Japan).11,12 It showed a significant survival benefit among cancer inhibit the proliferation and metastasis of lung cancer cells. These
patients with no toxic effects.12 compounds were also found to inhibit the expression of Aldo-Keto Re-
A number of antiausterity agents from the medicinal plants of di- ductase 1B10 (AKR1B10),21 that are known to be overexpressed in
verse origins were identified.13–17 Angelmarin, a first coumarin-based several cancers including pancreatic cancer.22 Therefore, we speculated
potent antiausterity agent was isolated from Angelica pubescens in that inhibitors of Aldo-Keto Reductase 1B10 might have antiausterity
2006.15 A number or hydroxycoumarins from Kayea assamica,16 and activity. To test this hypothesis, a series of simplified HMCB analogues
geranylated coumarins from the rhizomes of Radix Notopterygii,17 were were synthesized and evaluated for their preferential cytotoxic activity
found to be active against PANC-1 human pancreatic cancer cells. All against PANC-1 human pancreatic cancer cell line by employing the
these discoveries have inspired synthetic efforts in this field.18,19 The antiausterity strategy. In this strategy, compounds are tested against
total synthesis of angelmarin was achieved by several groups, followed human pancreatic cancer cell line in nutrient-deprived and the nutrient-
by the structure-activity relationship study of its analogs.18 Some cou- rich conditions.11,13 Compounds showing preferential cytotoxicity in
marin derivatives with alkyl and prenyl groups with varied lengths in nutrient-deprived condition are classified as antiausterity agents, and
the coumarin nucleus and their antiausterity activity have been eval- their activity is represented by a PC50 value, which is the concentration
uated, and the potency of some synthetic coumarins was comparable to at which 50% of cancer cells were killed preferentially in nutrient-de-
those of the natural products.20 Most recently, a series of synthetic prived medium (NDM) without apparent toxicity in the normal nu-
coumarins, 7-hydroxy-2-(4-methoxyphenylimino)-2H-chromene-3-car- trient-rich medium (DMEM). In order to discover coumarin-based po-
boxylic acid benzylamide (HMCB), and its analogues were found to tent antiausterity agents, a series of coumarins with varied amide and

Scheme 3. Reagents and conditions: (a) Meldrum’s acid, H2O, reflux; (b) amine, EDC, N-Me-morpholine, HOBt, THF, r.t.

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PANC-1 Table 2
In vitro evaluation coumarin derivatives 5a–d, 2c.
125
NDM Compounds R1 PC50, μM
100 DMEM
Cell survival [%]

5a H > 100
5b 5-OH > 100
75 5c 6-OH > 100
5d 8-OH 3.28
50 PC50 2c 7-OH 0.44
= 0.44 µM
25
0
-1 0 1 2 3 Table 3
Log concentration [µM] In vitro evaluation coumarin derivatives 5e–j, 2c.
Compounds R2 PC50, μM
Fig. 1. The preferential cytotoxic activity of 2c against the PANC-1 human
pancreatic cancer cell line in nutrient-deprived medium (NDM) and Dulbecco’s 5e 2-Cl-Phenyl 12.6
modified Eagle’s medium (DMEM). 5f 3-Cl-Phenyl 3.92
5g 4-Cl-Phenyl 0.51
5h 2,3-diCl-Phenyl 7.48
5i 2,4-diCl-Phenyl 3.45
Table 1
5j c-Hex 2.19
In vitro evaluation of 7-hydroxycoumarins 2a–d. 2c Phenyl 0.44
Compounds PC50, μM

2a > 100
2b > 100
2c 0.44
2d 4.7
substituent 3a–3d were converted to the corresponding coumarins
4a–4d under the same reaction condition for 1. Condensation of 4a–4d
with phenylpropylamine with EDC and HOBt provided the deoxy-, 5-,
6-, and 8-hydroxy derivatives 5a–d having the three-linker carbon
chain (Scheme 2).
hydroxyl substituents were synthesized following the procedures men- Comparison of the preferential cytotoxic activity of 5a–d and 2c
tioned in the Schemes 1–3, and their preferential cytotoxic activity revealed the dramatic influence of the hydroxyl group position in the
were evaluated against PANC-1 human pancreatic cancer cell lines by coumarin ring. Coumarins without hydroxyl or those with 5-OH or 6-
employing an antiausterity strategy. OH were virtually inactive. Contrary to that, the activity was found to
In this study, three different approaches were carried out to study be highly potent in the compounds bearing 7-OH or, 8-OH substituents.
the structure and the activity. These include variation of the linker Their activity order follows 2c > 5d ≫ 5a, 5b, 5c (Table 2).
carbon chain of the amide moiety, variation of the phenolic hydroxyl Finally, the question on the influence of substituents in the side-
group in the coumarin ring, and the modification of phenyl group chain phenyl amide group was investigated. A series of substituted N-
substituent with chlorophenyl or cyclohexane groups. propylphenyl derivatives 5e–i and cyclohexyl derivative 5j were syn-
First, to explore the importance of linker carbon chain length on the thesized as shown in Scheme 3. Condensation of carboxylic acid 1 with
amide moiety, 7-hydroxycoumarins 2a–d were synthesized by con- substituted phenylpropylamines or cyclohexylpropylamine under the
densation of known carboxylic acid 123 with appropriate amines same reaction conditions for 5a–5b gave rise to the corresponding
(Scheme 1). Commercially available dihydroxybenzyldehyde was used amides 5e–5j.
as the starting material, was subjected to condensation reaction with All the synthesized 5e–j was evaluated for their preferential cyto-
Meldrum’s acid under reflux condition in water to obtain carboxylic toxicity and compared with the activity of 2c (Table 3). Interestingly,
acid 1. It was then converted to a series of 7-hydroxycoumarins 2a–d by the influence of introducing chloro-substituent within phenyl ring was
the condensation reaction with appropriate amines by using EDC and minimum when compared to carbon linker and a hydroxyl group in
HOBt or HOAt. coumarin ring. Within monochloro substituent derivatives, the order of
All these four 7-hydroxycoumarins derivatives (2a–d) were tested activity is 5g > 5f > 5e, suggesting there is the only slight influence
for their preferential cytotoxicity against PANC-1 human pancreatic of chloro group. The activity of 4-chlorophenyl substituted 5g is
cancer cell line. The influence of linker carbon on the activity was found equivalent to those without any substituents (2c). The activity of 5h
to be dramatic, the phenylamine bearing three or four carbons were and 5i having 2,3-dichloro and 2,4-dichloro substituents were also
found to be highly active, while those bearing one or two linker carbons found to be weak compared to those without (2c > 5i > 5 h). Simi-
were inactive (2c > 2d ≫ 2a, 2b). The N-propylphenyl derivative 2c larly, when a cyclohexyl group replaces the phenyl group, the activity
was found to be the most potent compound with a PC50 value of was found to be weaker (2c > 5j). All these evidences suggested that
0.44 μM (Fig. 1), followed by N-butylphenyl derivative 2d with the 7-Hydroxy-2-oxo-2H-chromene-3-carboxylic acid (3-phenylpropyl)
PC50 value of 4.7 μM (Table 1). amide (2c) is an ideal candidate among synthesized series displaying
As the 7-hydroxycoumarins derivative with three linker carbon the most potent preferential cytotoxicity. Therefore, further investiga-
chain in the phenylamide was found to be the most active, we then tion of the biological actions of 2c was carried out.
assessed the effect of the hydroxy group on the coumarin ring. For this First, the effect of compound 2c on the cell morphology of PANC-1
purpose, the 2-hydroxybenzaldehydes with or without hydroxyl group cells under nutrient-deprived conditions was investigated using the

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Fig. 2. Morphology of the PANC-1 cells in the untreated cells (control, A) and those induced by 2c (treated, B) in nutrient-deprived medium (NDM).

100% even in the complete nutrition starvation with intact cell mor-
Control 12.5 µM 25 µM 50 µM phology and emitted bright green fluorescence (Fig. 2A) in AO-EB
staining. PANC-1 cells when treated with 2c (1.25 μM), led complete
A) alteration of morphology showing rounded cells and emitting red
fluorescence due to EB (Fig. 2B). Therefore, 2c induce PANC-1 cell
death results in membrane blebs followed by the rupture of the cell
membrane, and leakage of cellular contents into the culture media.
* During cancer invasion and metastasis, the invading cancer cells
B) 100 adapt to foreign tissue microenvironments and form small colonies of
cancer cells (micrometastases), which then grow into large tumors. This
phenomenon is termed as ‘colonization’.24 Most of the pancreatic tumor
Colony area (%)

75
patients quickly develop liver metastases soon after the time of diag-
nosis.25 The effect of 2c was investigated for its effect against PANC-1
50 cell colony formation in Nutrient rich media. PANC-1 cells were ex-
posed to 2c at the concentration of 12.5, 25, and 50 μM in the nutrient-
rich DMEM media. After the exposure for 24 h, the medium was re-
25
placed by fresh DMEM and incubated for 10 d to allow colony forma-
tion of 2c showed concentration-dependent inhibition of colony for-
0 mation (Fig. 3). The average colony area was found to be inhibited by
Control 12.5 µM 25 µM 50 µM
8%, 11% and, 19% respectively when compared with the total colony
Fig. 3. Effect of by 2c on colony formation by PANC-1 cells. (A) PANC-1 cell area occupied by the control well (88%) in the wells treated with of
colonies treated with different concentrations of compound 2c. (B) Graph 12.5, 25, and 50 μM. The inhibition effect was significant at the con-
showing mean values of the area occupied by PANC-1 cell colonies (three re- centration of 50 μM.
plications), *p < 0.05 when compared with the untreated control group. In order to understand the effect of 2c against PANC-1 cells in a real-
time, a time-lapse live imaging experiment was performed. PANC-1
cells were treated with 5 μM of compound 2c in NDM and incubated in
a stage-top incubator. The images were captured every 10 min on an
ethidium bromide (EB) – acridine orange (AO) double-staining fluor- EVOS digital cell imaging system for 24 h. Treatment of PANC-1 cells
escence assay. PANC-1 cells treated with 2c (1.25 μM) in NDM for 24 h, with 2c inhibited the cell mobility within 4 h and induced shrinkage of
together with the untreated control, and then stained with the EB/AO PANC-1 cells after 7 h, leading to cell death after 13 h, finally causing
reagent. AO is a cell-membrane permeable dye, while EB is only complete cell death within 20 h (Fig. 4, Movie 1). PANC-1 cells cultured
permeable through the membrane of dead or dying cells. The live cells under the same conditions in NDM, yet without compound 4 (control),
emit bright-green fluorescence due to AO. In the dead cells, on the other survived until the end of the experiment (24 h). Thus, this study further
hand, the red fluorescence due to EB predominates. These difference in demonstrated the live evidence of the anticancer therapeutic potential
emitting fluorescence color suggest live/dead cells in the culture as well of the 2c.
as its morphology. The PANC-1 cells in the control group survived

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Fig. 4. Captures of the live imaging of the effect of 2c (5 μM) on PANC-1 cells at different intervals of time (hour: minute).

Appendix A. Supplementary data

Supplementary data (experimental procedures, analytical data and

NMR spectral data of the synthesized compounds) to this article can be
found online at https://doi.org/10.1016/j.bmcl.2019.05.010.

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