Leucettamine B analogs and their carborane derivative as potential anti-cancer agents: Design, synthesis, and biological evaluation

Article abstract of DOI:10.1016/j.bioorg.2020.103729

Leucettamine B is a natural product found in marine sponge Leucetta microraphis. Several of analogs of its family, such as aplysinopsine and clathridine, are medicinally active molecules which have applications in many pharmaceuticals and healthcare products; however, thus far, leucettamine B has not been studied. In this report, we describe the synthesis of a new class of analogs of leucettamine B obtained by Knoevenagel condensation using a microwave reactor. The 25 newly synthesized compounds were tested against MDA-MB-468, SW480, and Mahlavu cell lines for anticancer activity. Among them, the carborane-based compound (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)-3-(1-closo-carboranyl)-2-thioxo -thiazolidin-4-one (49) and (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)-3-(2-(pyrrolidin-1-yl)ethyl)-2-thioxothiazolidin-4-one (31) derivatives were found to have the most potential for use against tumor cells. The carborane derivative 49 had the lowest IC₅₀ value against the SW480 cell line (4.7 μM) and the Mahlavu (6.6 μM) cell line. Furthermore, compound 31 also had a low IC₅₀ value against SW480 (7.5 μM). Our research shows that leucettamine B analogs might have potential for use in cancer chemotherapy.

Full text of DOI:10.1016/j.bioorg.2020.103729

Journal Pre-proofs
Leucettamine B Analogs and their Carborane Derivative as Potential Anti-
Cancer Agents: Design, Synthesis, and Biological Evaluation
Ming-Hua Hsu, Cheng-Ying Hsieh, Mohit Kapoor, Jui-Hsun Chang, Hsueh-
Liang Chu, Tsai-Mu Cheng, Kai-Cheng Hsu, Tony Eight Lin, Fu-Yuan Tsai,
Jia-Cherng Horng
PII:
S0045-2068(19)32165-0
DOI:
https://doi.org/10.1016/j.bioorg.2020.103729
YBIOO 103729
Reference:
To appear in:
Bioorganic Chemistry
Received Date:
Revised Date:
Accepted Date:
18 December 2019
4 March 2020
5 March 2020
Please cite this article as: M-H. Hsu, C-Y. Hsieh, M. Kapoor, J-H. Chang, H-L. Chu, T-M. Cheng, K-C. Hsu, T.
Eight Lin, F-Y. Tsai, J-C. Horng, Leucettamine B Analogs and their Carborane Derivative as Potential Anti-
Cancer Agents: Design, Synthesis, and Biological Evaluation, Bioorganic Chemistry (2020), doi: https://doi.org/
1
0.1016/j.bioorg.2020.103729
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Full-Length Article
Leucettamine B Analogs and their Carborane Derivative as Potential Anti-Cancer
Agents: Design, Synthesis, and Biological Evaluation
a
b
c
a
d
Ming-Hua Hsu *, Cheng-Ying Hsieh , Mohit Kapoor , Jui-Hsun Chang , Hsueh-Liang Chu , Tsai-Mu
e
f
f
g
b
Cheng , Kai-Cheng Hsu , Tony Eight Lin , Fu-Yuan Tsai , Jia-Cherng Horng
aDepartment of Chemistry, National Changhua University of Education, Changhua 50007, Taiwan
bDepartment of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
cChitkara University Institute of Engineering and Technology, Chitkara University, Punjab 140 401,
India
dGraduate Institute of Translational Medicine, College of Medicine and Technology, Taipei Medical
University, Taipei 11031, Taiwan
eInstitute for Translational Medicine, College of Medical Science and Technology, Taipei Medical
University, Taipei 11031, Taiwan
fGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology,
Taipei Medical University, Taipei 11031, Taiwan
gCenter for General Education, Chang Gung University, Taoyuan 33302, Taiwan
_
*
_________
Corresponding author. Tel: +886 4 723 2105#3511 fax: +886 4 7211190
E-mail addresses: minghuahsu@cc.ncue.edu.tw
1

Abstract
Leucettamine B is a natural product found in marine sponge Leucetta microraphis. Several of
analogs of its family, such as aplysinopsine and clathridine, are medicinally active molecules which have
applications in many pharmaceuticals and healthcare products; however, thus far, leucettamine B has not
been studied. In this report, we describe the synthesis of a new class of analogs of leucettamine B obtained
by Knoevenagel condensation using a microwave reactor. The 25 newly synthesized compounds were
tested against MDA-MB-468, SW480, and Mahlavu cell lines for anticancer activity. Among them, the
carborane-based compound (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)-3-(1-closo-carboranyl)-2-thioxo
-thiazolidin-4-one (49) and (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)-3-(2-(pyrrolidin-1-yl)ethyl)-2-
thioxothiazolidin-4-one (31) derivatives were found to have the most potential for use against tumor
cells. The carborane derivative 49 had the lowest IC value against the SW480 cell line (4.7 μM) and
5
0
the Mahlavu (6.6 μM) cell line. Furthermore, compound 31 also had a low IC value against SW480
5
0
(7.5 μM). Our research shows that leucettamine B analogs might have potential for use in cancer
chemotherapy.
_________________________
Keywords:
Leucettamine B
Barbituric acid
Thiazolidinone
Carborane
2

1
. Introduction
Despite of novel medicines and vaccines development, Cancer remains a major cause of death in both
developed and developing countries [1]. In 2012, the number of cancer related cases and deaths reached
4.1 million with 8.2 million cancer-related deaths worldwide. In Southeast Asia alone, hundreds of
1
thousands of people were affected by different kinds of life-threatening cancers like breast cancer, gastric
cancer, colorectal carcinoma, and hepatocellular carcinoma (HCC) [2, 3]. The pathogenesis of cancers is
the result of an accumulation of genetic changes in healthy cells that turns them into tumor cells [4, 5].
This results in the complexities at the cellular and genetic level, which makes cancer treatment or therapy
challenging. Conventionally chemotherapy, radiotherapy, and surgical treatment are the primary
strategies for cancer patients. But people with solid and late stage cancers usually suffer from tumor
metastasis and various genetic or epigenetic alterations because of poor prognosis and limited treatment
efficiency [5, 6]. Therefore, developing effective pharmacological agents to improve early and late stage
cancer therapy are necessary.
O
O
O
N Me
O
N
O
O
O
N Me
Me
N Me
HN
N
N
N
HN
1
Me
Aplysinopsine
N
NH
NH2
3 Leucettamine B
O
2 Clathridine
Fig. 1: Biologically active heterocyclic molecules containing aminoimidazole ring
The naturally occurring heterocycles have had significant impact in the field of medicinal chemistry
and particularly in cancer treatment. Heterocyclic derivatives containing an amino group such as
aplysinopsine (1), clathridine (2), etc., are one of the most researched family of complexes for anticancer
[7], anti-inflammation [8] and Alzheimer’s disease/Down syndrome [9, 10]. Leucettamine B (3), which
is isolated from Leucetta microraphis and consists of a five-membered aminoimidazole ring and
piperonal moiety, is also a member of this family. As leucettamine B has not been explored in the field
of anti-cancer drugs, in this study, we investigated the biological activity of leucettamine B and its
derivatives on various cell lines.
3

Five and six-membered heterocycles and their derivatives such as barbiturates (4, Fig. 2), and
pyrimidines, are the critical moiety in various pharmaceuticals and naturally occurring complex
molecules. These scaffolds have been investigated for their various biological activities such as
anticonvulsant [11], anti-inflammation [12], and anticancer [13-16] and many more [17]. Singh et al.,
[18] synthesized a series of indole and barbituric acid hybrids (5, Fig. 2) that exhibited antitumor
1
8
activities. And Zanda et al., [19] demonstrated an isotope F labeled barbiturates (6, Fig. 2) that could
be PET tracer for the diagnosis of Alzheimer’s disease. Gilmer [20] presented a barbiturate homodimer
(7, Fig. 2) capable of being a potential matrix metalloproteinase inhibitor (MMP inhibitor). Furthermore,
our unpublished results showed that (E)-5-(3-phenylallylidene)pyrimidine-2,4,6(1H,3H,5H)-trione,
possessed inhibition activity toward HCC cell lines, HepG2, and Hep3B.
Fig. 2: Medicinally important barbiturates and their derivatives
In addition to the molecules mentioned above, several other heterocyclic moieties have played
pivotal roles in drug development from many decades, such as thiazolidinone [21-30], thioxothiazolidin-
4
-one [31-35], and hydantoin [36-39]. Among them, thiazolidin-2,4-dione (TZD) scaffold is widely
applied in many drugs. Ciglitazone (8, Fig. 3) was synthesized in the 1980s as the first anti-hyperglycemic
drug in the TZD class [40]. After that, englitazone and rosiglitazone were also developed based on the
previous studies (9, Fig. 3).
4

O
O
Et
NH
Me
NH
S
S
O
N
O
O
O
Me
8
9
Ciglitazone
Rosiglitazone
O
Me
O
Me
S
S
O
O
N N
N N
R
O
R
N
NH
N
S
S
HN
O
1
0
11
O
R = H, Cl, Br, NO , NHSO CH , OCH
3
2
2
3
Fig. 3: Five membered heterocyclic derivatives in pharmaceuticals
Fletcher [27] focused on the library of thiazolidine-2,4-dione analogs, comparing different poly-
substituted phenyl rings with the N-carboxylated side chain. It appeared that the hydrophobic substituent
would increase the biological activity against Mcl-1 or Bcl-xL. Abdellatif [28] synthesized a series of
thiazolidine derivatives containing a pyrazole core, which showed remarkable anti-diabetic and anti-
inflammation activity. According to their result, the spacers affect the binding ability of the molecule
with the receptor (10－11, Fig. 3).
Recently, boron-containing scaffolds have gained much attention due to their wide-ranging
application in small molecule drugs [41-45]. One of the most common entities among the most
investigated boron complexes are carboranes. Over the last two decades, several researchers have
invested their efforts in these boron–carbon–hydrogen clusters, as they provide high boron content and a
site for the functionalization with other medicinally active moiety functional groups [46]. Interesting and
unique properties of these clusters make the carboranes a perfect fit for several medicinal applications.
For example: (i) carboranes are inorganic in nature and hence provide high stability to the drug molecule
intracellularly; (ii) they are hydrophobic in nature due to the presence of a low polar B-H bond and hence
5

they facilitate the transportation of drug molecules across cell membranes, and (iii) they are easy to
functionalize and derivatize to the drug like molecule for better structure-activity relationship.
Lee et al. choose the nicotinamide phosphoribosyltransferase (Nampt) as the target to study the
carborane-based inhibitors [47]. Nampt was an enzyme that essential in metabolism and cell survival,
and FK866 was the first high potential small-molecule inhibitor of it. They replaced the
benzoylpiperidine part of FK866 with carborane isomers and similarly sized groups (Fig. 4). The
synthesized compounds were measured for their half-maximal inhibitory concentrations (IC ) to A549,
5
0
DLD-1, and T-47D cell lines. Their results revealed that the biological activity of carborane derivatives
(D－F, Fig. 4) was 10 times than FK866 and 100 times than the adamantine derivative (C, Fig. 4). The
Fig. 4: carborane-based inhibitors of nicotinamide phosphoribosyltransferase
ethyl (A, Fig. 4) and benzyl (B, Fig. 4) derivatives did not show significant activity. In a further
experiment, to confirm that carborane derivatives were mainly directed to Nampt inhibition. Its
enzymatic product NMN was used to perform cell rescue assays against the A549. With the increasing
of NMN, the cell viability of A549 was raised. It proved the carborane units could interact with the
enzyme through hydrophobic interactions that stronger than FK866. Hey-Hawkins [48] revised the
structure of Rev-5901 (12) inhibitor of lipoxygenases (LO), by replacing one of the phenyl rings of Rev-
5
901 by meta-carborane. Their results showed that carborane-based prodrug and Rev-5901 have similar
IC values. Additionally, derivatives of Rev-5901 are more selective against melanoma and colon cancer
5
0
cell lines (13－14, Fig. 4).
6

N
X
N
X
N
O
OH
OH
OH
4
4
1
2 Rev-5901
= C
13
14
O
=
BH
Fig. 4: Rev-5901 and its carborane derivatives
In light of the above evidence, we became interested in investigating the biological activity of
leucettamine B derivatives functionalized with various heterocycles and carborane. Herein, we describe
the direct conjugation of various heterocyclic molecules and carborane with piperonal and its derivatives.
A total of 25 different leucettamine B analogs were synthesized and treated against the human cancer
cell lines, SW480, MDA-MB-468, MDA-MB-231, and Mahlavu.
2
2
. Results and discussion
.1. Chemistry
O
O
O
O
N Me
O
O
N
NH
X
NH2
Leucettamine B
3
15
Y
X = N or S; Y = O or S
Proposed Design
O
O
O
O
O
N
n
N
S
n
N
n
N
O
N
Y
Y
1
6
17
N
=
N
N
N
N
O
Fig. 5: Synthetic Layout for development of leucettamine B analogs
The synthetic strategies adopted to obtain the target compounds are depicted in Figure 5. The
7

proposed synthetic route started with the condensation of piperonal and various barbituric acids or five-
membered heterocyclics under microwave conditions. Alkyl chains carrying heterocyclic moieties have
been used for the derivatization of ring nitrogen. Previously we showed that the side chain containing the
N-heterocyclic moiety can help the molecules to gain better access to the target active site due to their
flexible nature [49]. To establish the structure activity relationship, we derivatized the second nitrogen
atom with alkyl chain to yield N,N-dialkylated products. Afterward, the piperonal derivatives were
alkylated with an alkyl chain having terminal alkyne, which underwent a reaction with decaborane(14).
The reaction optimization of barbiturate-conjugated derivatives (20–22) using Knoevenagel
condensation was started by heating the appropriate substrates overnight in an oil bath. The desired
product was obtained at low yields, which were somewhat improved by using Chen et al. conditions [50].
In the presence of ionic liquid, the yield was increased, and the reaction time was reduced to 30 min. The
use of ionic liquid was not possible, however, as it is expensive and requires intense efforts if it is recycled
every time. Delgado et al., used an infrared lamp to irradiate the reaction for 45 min and yield was
improved from 43% to 82% [51]. We obtained the desired conjugates in good yields by using microwaves
and ethanol as the solvent. The piperonal and barbituric acid derivatives were heated at 120°C for 30 min
in ethanol under microwave conditions. After the mixture cooled down, it was filtered and washed with
water to get the products 20–22 (Scheme 1) with a yield range from 89% to 96%.
Scheme 1: Microwave assisted Knoevenagel condensation of piperonal and heterocyclic
derivatives
8

After obtaining the optimized conditions in hand, we tried to replace the barbituric acid with five-
membered heterocyclic moieties in condensation with piperonal. But to our surprise, the yields were
very low. After several attempts of optimization, glacial acetic acid was found to be suitable as the
solvent [52-55]. The derivatives 24–27 were obtained in good to high yields (90-94%) under
microwave-assisted reaction at 140 °C for 30 min (Scheme 1).
To establish the structure-activity relationship and gain better insight into the biological activity of
the lead molecule, we then alkylated the nitrogen using alkyl chains having piperidine, pyrrolidine, and
morpholine as terminal groups. The reaction was carried out in dimethylformamide at 80 °C with
potassium carbonate as base (Scheme 2, top) to afford N-alkylated products 30–37 in good yields. For
the synthesis of 38–45, we treated excess of alkyl chlorides with the substrate to make sure the
transformation led to dialkylated species (Scheme 2, bottom).
Scheme 2: Mono-and di-alkylation of conjugated heterocycles
9

To explore the anti-cancer activity of carborane conjugated heterocyclic derivatives, decaborane(14)
was selected as the commercially available starting material, a precursor of carborane. The structure of
decaborane(14) is very similar to carborane but it has two fewer carbons. Upon reaction with alkyne,
decaborane(14) forms an o-carborane structure [56-59]. Our synthetic strategy is based upon the work
published by Valliant et al [60]. Acetonitrile was used as a ligand for decaborane(14) to form complex
under reflux temperature. The residue obtained during the reaction course was filtered and dried under
reduced pressure to get the (CH CN) B H as a white solid. No further purification was required for
3
2
10 12
the acetonitrile-decaborane complex. Compound 47 was obtained through N-alkylation of 24 with
propargyl bromide (46) and potassium carbonate in acetone. The coupling reaction of 47 and
(
CH CN) B H (48) was carried out in toluene in the presence of catalytic silver nitrate. The reagents
3 2 10 12
were sealed in an autoclave and heated overnight (Scheme 3). Upon completion, it was purified by
column chromatography to give a chartreuse powder in moderate yield (51%). However, it took a long
reaction time and required the expensive silver catalyst. Later, I choose another method from Prof.
Nakamura’s report.[61]. The N,N-dimethylaniline (DMA) was used instead of the silver catalyst, and the
heating method changed to microwave. The reaction completed within 30 min, got 84% yield of 49 after
column chromatography. The molecule structure of carborane derivative was confirmed by single X-ray
1
11
diffraction analysis (Fig. 6). Additionally, the structure was confirmed by H-NMR and B-NMR.
Scheme 3: Synthesis of carborane derivative using decaborane(14) as starting material
1
0

Fig. 6: Molecule structure of compound 49
2
.2. Biological evaluation
All of the new compounds were screened against MDA-MB-468, SW480, and Mahlavu cell lines at
concentrations of 100 μM and 10 μM. Compounds having five-membered heterocyclic rings 24 －27
were found to be more potent than barbituric acid derivatives 20 －22 against MDA-MB-468 cell line
(Fig. 6). Among the five-membered ring heterocyclic derivatives 24－27, N-alkylated derivatives were
proved to be more biologically active as compare to their unsubstituted counter-parts. This could be due
to the presence of a hydrophobic moiety at the terminal position of the alkyl chain, which makes access
to the targeting site much easier.
1
1
50
00
5
0
0
NC 20 21 22 24 25 26 27 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 47 49
-
50
MDA-MB-468 (100 μM)
1
1

1
1
20
00
8
6
4
2
0
0
0
0
0
NC 20 21 22 24 25 26 27 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 47 49
MDA-MB-468 (10 μM)
Fig. 6: Biological evaluation of conjugates against MDA-MB-468 cancer cell lines. NC stands for
the control group under the same conditions but without any compound.
In the case of carborane derivative, the cell viability decreased drastically making them the most
potent derivative of all. This surge in the biological activity might be due to the hydrophobic nature of
carborane. In the case of SW480 cell line (Fig. 7), similar trends were obtained to MDA-MB-468 using
1
00 μM concentration. N-Alkylated derivatives were shown to have a much better activity profile as
compared to pristine molecules. The N-Alkyl chain with a terminal piperidine moiety proved to be a
better anti-cancer candidate than the pyrrolidine or morpholine groups. When the concentration was
changed from 100 μM to 10 μM, piperonal conjugated with thioxothiazolidin-4-one (31, 33, 35, 37)
showed a somewhat better anti-cancer activity profile than thiazolidinone (30, 32, 34, 36).
1
1
20
00
8
6
4
2
0
0
0
0
0
NC 20 21 22 24 25 26 27 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 47 49
SW480 (100 μM)
1
2

2
1
1
00
50
00
5
0
0
NC 20 21 22 24 25 26 27 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 47 49
SW480 (10 μM)
Fig. 7: Biological evaluation of conjugates against SW480 cancer cell lines. NC stands for the
control group under the same conditions but without any compound.
In hydantoin 38, 40, 42, 44 and thiohydantoin 39, 41, 43, 45 derivatives, 39 and 41 were found to be
much more potent anti-cancer agents than 38, 40, 42, 44 at 100 μM but no significant difference was
observed between them in 10 μM. Thioxothiazolidin-4-one derivatives 31, 33, 35, 37 were found to be
much more potent than thiazolidinone 30, 32, 34, 36.
Carborane derivative 49 was found to be the most potent lead molecule in both cell lines. The
hydrophobic properties of carborane derivative 49 prevents its degradation in an aqueous environment
and hence increase its lifetime intracellularly. In the case of the Mahlavu cell line (Fig. 8), similar trends
were observed for all the families of molecules with carborane derivative 49 as the most potent molecule.
1
1
20
00
8
6
4
2
0
0
0
0
0
NC 20 21 22 24 25 26 27 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 47 49
Mahlavu (100 μM)
1
3

1
1
20
00
8
6
4
2
0
0
0
0
0
NC 20 21 22 24 25 26 27 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 47 49
Mahlavu (10 μM)
Fig. 8: Biological evaluation of conjugates against Mahlavu cancer cell lines. NC stands for the
control group under the same conditions but without any compound.
The above studies revealed that dialkylated molecules have a better anti-cancer profile as compared to
mono-alkylated scaffolds. The thio group in heterocyclic molecules was found to be significant for their
anti-cancer activity.
The most potent derivatives 49 and 31 were subjected to two more cancer cell lines at different
concentrations. We selected ten different concentrations, 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625,
0
.78125 and 0 μM as our screening conditions. The results are shown in Fig. 9. As can be seen, 49 has
the highest activity in the SW480 cell line followed by the Mahlavu, A549, MDA-MB-468, and MDA-
MB-231 lines. Among the five cancer cell lines, 31 also has the best activity on the SW480 cell line, but
did not show as potent activity as 49 in the remaining cell lines. Their IC values were calculated and
5
0
are summarized in Table 1. Our research shows that 49 and 31 have potential for use against various
tumor cells.
To explore the structures relative to the mechanism of the inhibitors in this study, we predict
potential targets by using the Similarity Ensemble Approach server[62]. This approach quarried a ligand
and compared it to chemically similar ligands to estimate possible protein target prediction. While
compound 49 showed potency in A549 and SW480 cell lines, no protein targets were predicted. It might
be due to its unique carborane moiety. In contrast, compound 31 was predicted to target various
1
4

mammalian proteins that were related to cancer, the results were shown in Supporting Information, Table
S1. Several predicted protein targets have been implicated in colorectal cancer, such as CLK3[63],
CLK1[64], IKKB[65], and GSK3A[66], to name a few (Table S1). Besides, Table 1 shown that
compound 31 was most active in the colorectal cell line SW480. Together, this suggests that compound
3
1 may function as an inhibitor for pathways related to colorectal cancer. It was worth noting that
DYRK2 also had a high Max Tc value of 0.47. As we knew, leucettamine B has the potential inhibition
of CLKs and DYRKs. It also could be considered that these kinases played a significant part in the anti-
cancer field.
Fig. 9: Biological activity profile of compound 49 and 31 against cancer cell lines
Table. 1 IC values (in μM) of conjugates 31 and 49 against various cell lines
5
0
A549
SW480
7.5 ± 2.69
4.7 ± 0.82
MDA-MB-468
119.3 ± 10.90
17.3 ± 1.32
MDA-MB-231
53.1 ± 6.55
Mahlavu
86.4 ± 13.08
6.6 ± 0.64
3
4
1
9
48 ± 2.36
10.8 ± 0.85
25.6 ± 2.48
3
. Conclusions
We synthesized 25 new compounds as the analogs of leucettamine B. The newly conjugated
compounds 24 －27 were obtained through Knoevenagel condensation under microwave conditions in
1
5

good to high yields in a short period of time. The N-alkylation successfully took place under mild
conditions to obtain mono- and di-alkylated compounds in high yields. Furthermore, the carborane
derived conjugate 49 was successfully produced using a silver nitrate mediated coupling reaction. The
MTT assay shows that the activities of the conjugated system of five-membered heterocyclics are much
better than barbituric acids. In the case of the five-membered ring conjugated heterocyclics series,
thioxothiazolidin-4-one derivatives were found to be much more potent than thiazolidinone. Similarly,
thiohydantoin is more toxic towards cancer cells as compared to hydantoin. This may be because the
sulfur double bond has a larger space than the oxygen double bond. It makes a compound with the sulfur
double bond able to prolong its residence time. The terminal side chain with piperidine and pyrrolidine
have more suppressive ability than morpholine. Among the 25 compounds, 49 and 31 are the most potent
against tumor cells. Compound 49 has the lowest IC value in the SW480 (4.7 μM) and Mahlavu (6.6
5
0
μM) cell lines. Compound 31 also has a low IC value in SW480 (7.5μM). Our research indicates that
5
0
the N-alkylated analogs of leucettamine B have the potential in the anticancer field and the hydrophobic
characteristic of carborane in the terminal side chain will enhance the bioactivity of these compounds.
4
4
. Experimental Section
.1. Chemistry
Commercially available reagents were used directly without any further purification. Acetone, ethyl
acetate, hexane, dichloromethane, and ether were purchased from Macron Fine Chemicals (Center Valley,
PA, U.S.A.). Dimethylformamide was purchased from Merck (Darmstadt, Germany) and dried over a
solvent purified system made by LC Technology Solutions (Salisbury, MA, U.S.A.). Piperonal,
barbituric acid, 2-thiobarbituric acid, 1,3-dimethylbarbituric acid, 2,4-thiazolidine-dione, rhodanine,
hydantoin, 2-thiohydantoin, 1-(2-chloroethyl)piperidine hydrochloride, 1-(2-chloroethyl)pyrrolidine
hydrochloride, 4-(2-chloroethyl)morpholine hydrochloride and 4-(3-chloropropyl)morpholine were
purchased from Sigma-Aldrich (St. Louis, MO, U.S.A.) or Alfa-Aesar (Ward Hill, MA, U.S.A.).
Decaborane(14) was purchased form Energy Chemical (Shanghai city, China). (CH CN) B H (48)
3
2
10 12
1
6

was synthesized according to the previous literature.[67] Analytical thin-layer chromatography (TLC)
was performed on pre-coated plates (silica gel 60 F-254), purchased from Merck. Column
chromatography was carried out by using Merck Reagents Silica Gel 60 (particle size 0.063-0.200 mm,
7
0-230 mesh ASTM). The microwave-assisted reactions were loaded in a borosilicate glass sealed-vessel
1
and performed in Monowave 300 (Anton Paar, Graz, Austria) microwave reactor. H NMR spectra were
obtained on a Bruker Avance 500 (500 MHz) or Bruker Avance 300 (300 MHz) (Bruker, Billerica, MA,
1
U.S.A.) by use of CDCl and (CD ) SO as the solvent. H NMR chemical shifts were referenced to the
3
3 2
1
3
CDCl singlet (7.24 ppm) and (CD ) SO singlet (2.50 ppm). C NMR spectra were obtained on a Bruker
3
3 2
Avance 500 (125 MHz) or Bruker Avance 300 (75 MHz), by use of CDCl and (CD ) SO as the solvent.
3
3 2
1
3
11
C NMR chemical shifts were referenced to the CDCl (77.23 ppm) and (CD ) SO (39.52 ppm). B
3
3 2
NMR spectra were obtained on a Bruker Avance 300 (96 MHz). High-resolution mass spectra were
obtained utilizing a FINNIGAN/MAT-95XL mass spectrometer (Thermo Fisher Scientific company,
Walthamcity, MA, U.S.A.).
4
.2. Standard procedures for the synthesis of conjugated derivatives from piperonal and various
barbituric acids and 5-membered heterocycles. For compounds 20–22, piperonal (1.0 g, 6.66 mmol)
and corresponding barbituric acid (13 mmol) were loaded into an autoclave, and ethanol (16 mL) was
added. After heating to 120°C for 30 min in a microwave reactor, the reaction mixture was cooled down.
The product was collected by filtration and washed with water and used for the next step without any
further purification (yield from 89% to 96%). For compounds, 24–27, Piperonal (1.0 g, 6.66 mmol), and
corresponding 5-membered heterocycles (13 mmol) were loaded into an autoclave, and acetic acid (16
mL) was added. The reaction mixture was heated to 140°C for 30 min in the presence of base piperidine
for 24, 25, 27 (0.5 ml, 5.06 mmol), β-alanine for 26 (0.276 g, 3.1 mmol). The mixture was filtrated,
washed with acetic acid, water and used for the next step without any further purification (yield from
8
7% to 94%).
.2.1. 5-(Benzo[d][1,3]dioxol-5-ylmethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (20). Yellow
4
1
solids (93% yield); M.P.: >300°C; H NMR (500 MHz, (CD ) SO): δ 6.18 (s, 2 H), 7.07 (d, J = 10 Hz, 1
3
2
1
7

1
3
H), 7.74 (t, J = 5 Hz, 1 H), 8.20 (s, 1 H), 8.25 (s, 1 H), 11.19 (s, 1 H), 11.31 (s, 1 H); C NMR (125
MHz, (CD ) SO): δ 102.3, 108.3, 112.4, 115.9, 126.7, 133.6, 147.3, 150.1, 151.8, 154.9, 162.2, 163.8.
3
2
+
HR ESI-MS found 305.0160 [M+2Na–H] (calc. for C H N O Na is 305.0145). The spectroscopic data
1
2
8
2
5
2
were found to be in accordance with the data in the literature [51].
4
.2.2 5-(Benzo[d][1,3]dioxol-5-ylmethylene)-2-thioxodihydropyrimidine-4,6(1H,5H)dione (21).
1
Orange-red solids (89% yield); M.P.: >300°C; H NMR (500 MHz, (CD ) SO): δ 6.19 (s, 2H), 7.09 (d,
3
2
1
3
J = 5 Hz, 1H), 7.79 (d, J = 10 Hz, 1H), 8.21 (s, 1H), 8.28 (s, 1H), 12.29 (s, 1H), 12.38 (s, 1H); C NMR
(
75 MHz, (CD ) SO): δ 102.6, 108.5, 112.5, 116.0, 126.9, 134.5, 147.5, 152.5, 156.0, 160.0, 162.2, 178.3.
3
2
+
HR ESI-MS found 277.0159 [M+H] (calc. for C H N O S is 277.0278). The spectroscopic data were
1
2
9
2
4
found to be in accordance with the data in the literature [50].
4
.2.3. 5-(benzo[d][1,3]dioxol-5-ylmethylene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)trione (22).
1
Orange solids (96% yield); M.P.: 206－208°C; H NMR (500 MHz, (CD ) SO): δ 3.21 (d, J = 10 Hz,
3
2
1
3
6
H), 6.18 (s, 2H), 7.08 (d, J = 5 Hz, 1H), 7.73 (d, J = 10 Hz, 1H), 8.16 (s, 1H), 8.27 (s, 1H); C NMR
(
125 MHz, (CD ) SO): δ 28.04, 28.63, 102.3, 108.2, 112.2, 115.8, 126.8, 133.4, 147.3, 151.0, 151.8,
3
2
+
1
55.7, 160.8, 162.5. HR ESI-MS found 289.0961 [M+H] (calc. for C H N O is 289.0825). The
14 13 2 5
spectroscopic data were found to be in accordance with the data in the literature [68].
4
.2.4. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)thiazolidine-2,4-dione (24). Dark yellow solids (94%
1
yield); M.P.: 261－263°C; H NMR (500 MHz, (CD ) SO): δ 6.12 (s, 2H), 7.08 (d, J = 8 Hz, 1H), 7.12 –
3
2
1
3
7
1
.15 (m, 2H), 7.71 (s, 1H), 12.52 (s, 1H); C NMR (125 MHz, (CD ) SO): δ 102.0, 109.1, 109.2, 120.9,
3 2
+
25.9, 127.2, 131.9, 149.3, 167.3, 167.8. HR ESI-MS found 328.0308 [M+DMSO+H] (calc. for
C H NO S is 328.0308). The spectroscopic data were found to be in accordance with the data in the
1
3
14
5 2
literature [69].
4
.2.5. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-2-thioxothiazolidin-4-one (25). Yellow brown
1
solids (91% yield); M.P.: 216°C (dec.); H NMR (500 MHz, (CD ) SO): δ 6.13 (s, 2H), 7.08~7.12 (m,
3
2
1
3
2
H), 7.16 (dd, J = 1.5 Hz, J = 7.5 Hz, 1H), 7.56 (s, 1H), 13.74 (br, 1H); C NMR (125 MHz, (CD ) SO):
3 2
δ 102.1, 109.3, 109.5, 122.9, 126.7, 127.2, 131.9, 148.317, 149.7, 169.4, 195.4. HR ESI-MS found
1
8

+
2
64.9444 [M] (calc. for C H NO S is 264.9867). The spectroscopic data were found to be in
11 7 3 2
accordance with the data in the literature [69].
4
.2.6. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)imidazolidine-2,4-dione (26). Almond white solids
1
(
87% yield); M.P.: 239－241°C; H NMR (500 MHz, (CD ) SO): δ 6.06 (s, 2H), 6.36 (s, 1H), 6.94 (d, J
3
2
1
3
=
10 Hz, 1H), 7.12 (d, J = 10 Hz, 1H), 7.26 (s, 1H), 10.44 (br, 1H), 11.16 (br, 1H); C NMR (125 MHz,
(
CD ) SO): δ 101.4, 108.7, 108.7, 108.8, 124.8, 126.3, 127.0, 147.5, 147.8, 155.6, 165.6. HR ESI-MS
3 2
+
found 254.0244 [M+Na] (calc. for C H N NaO is 254.0304). The spectroscopic data were found to be
1
1
7
2
4
in accordance with the data in the literature [69].
4
.2.7. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-2-thioxoimidazolidin-4-one (27). Dark olive green
1
solids (90% yield); M.P.: 236°C (dec.); H NMR (500 MHz, (CD ) SO): δ 6.09 (s, 2H), 6.43 (s, 1H),
3
2
1
3
6
.97 (d, J = 10 Hz, 1H), 7.26 (d, J = 10 Hz, 1H), 7.44 (s, 1H), 12.07 (s, 1H), 12.30 (s, 1H); C NMR
(
125 MHz, (CD ) SO): δ 101.7, 108.8, 109.3, 112.2, 126.1, 126.3, 126.5, 147.9, 148.4, 165.8, 178.7. HR
3
2
+
ESI-MS found 249.0373 [M+H] (calc. for C H N O S is 249.0334). The spectroscopic data were found
1
1
9
2
3
to be in accordance with the data in the literature [9].
.3. Standard procedures for the synthesis of piperonal-alkylheterocycle derivatives from
4
piperonal derivatives with various alkyl chlorides (30–45). Potassium carbonate (0.498 g, 3.6mmol).
was added to a solution containing a piperonal derivative (24–27, 1.3 mmol) in anhydrous
dimethylformamide (10 mL). After the reaction mixture was stirred at 35°C for 15 min, corresponding
alkyl chloride (for 30 to 37 is 1.56 mmol, 38 to 45 is 2.86 mmol) was added to the mixture. The reaction
mixture was heated to 80°C for 12 h. After the reaction was cooled down, the mixture was filtered and
diluted with water (5 mL). The solution was extracted with dichloromethane (30 mL × 3). The combined
organic layer was washed by brine and dried over MgSO . After the solvent was removed under reduced
4
pressure, the crude product was purified by column chromatography on silica gel in dichloromethane,
hexane, triethylamine (range from 1:19:0 to 1:4:0.05) to give compounds 30–45.
4
.3.1. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-3-(2-(pyrrolidin-1-yl)ethyl)thiazolidine-2,4-dione
1
(
30). Orange red solids (82% yield); M.P.: 107－109°C; H NMR (500 MHz, CDCl ): δ 1.74 (d, J = 5
3
1
9

Hz, 4H), 2.55 (s, 4H), 2.71 (t, J = 10 Hz, 2H), 3.86 (t, J = 10 Hz, 2H), 6.02 (s, 2H), 6.86 (d, J = 10 Hz,
1
3
1
5
H), 6.94 (s, 1H), 7.01 (d, J = 10 Hz, 1H), 7.75 (s, 1H); C NMR (125 MHz, CDCl ): δ 23.77, 41.10,
3
3.22, 54.36, 102.1, 109.2, 109.3, 119.5, 126.7, 127.8, 133.7, 148.7, 149.9, 166.6, 168.0. HR ESI-MS
+
found 347.1067 [M+H] (calc. for C H N O S is 347.1066).
1
7
19
2
4
4
4
.3.2. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-3-(2-(pyrrolidin-1-yl)ethyl)-2-thioxothiazolidin-
1
-one (31). Orange solids (85% yield); M.P.: 134－136°C; H NMR (500 MHz, CDCl ): δ 1.75 (s, 4H),
3
2
1
1
.59 (s, 4H), 2.76 (t, J = 5 Hz, 2H), 4.26 (t, J = 3 Hz, 2H), 6.04 (s, 2H), 6.88 (d, J = 10 Hz, 1H), 6.93 (s,
1
3
H), 7.03 (d, J = 10 Hz, 1H), 7.60 (s, 1H); C NMR (75 MHz, CDCl ): δ 23.74, 43.33, 52.34, 54.49,
3
02.2, 109.4, 109.5, 120.7, 127.6, 127.9, 133.4, 148.9, 150.2, 168.0, 193.3. HR ESI-MS found 363.0839
+
[
M+H] (calc. for C H N O S is 363.0837).
1
7
19
2
3 2
4
.3.3. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-3-(2-(piperidin-1-yl)ethyl)-thiazolidine-2,4-dione
1
1
(
32). Yellow white solids (84% yield); M.P.: 171 －173°C; H NMR (500 MHz, CDCl ): H NMR
3
(
300MHz, CDCl ): δ 1.38 (d, J = 5 Hz, 2H), 1.51 (t, J = 5 Hz, 4H), 2.42 (s, 4H), 2.54 (t, J = 5 Hz, 2H),
3
3
.84 (t, J = 5 Hz, 2H), 6.02 (s, 2H), 6.87 (d, J = 10 Hz, 1H), 6.95 (s, 1H), 7.02 (d, J = 10 Hz, 1H), 7.75
1
3
(
s, 1H); C NMR (125 MHz, CDCl ): δ 24.48, 26.19, 39.49, 54.75, 55.76, 102.1, 109.3, 109.6, 119.5,
3
+
1
26.5, 127.8, 133.6, 148.8, 149.9, 166.7, 168.0. HR ESI-MS found 361.1221 [M+H] (calc. for
C H N O S is 361.1222).
1
8
21
2
4
4
.3.4. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-3-(2-(piperidin-1-yl)ethyl)-2-thioxothiazolidin-4
1
-
one (33). Yellow solids (76% yield); M.P.: 167－169°C; H NMR (500 MHz, CDCl ): δ 1.39 (s, 2H),
3
1
.53 (t, J = 5 Hz, 4H), 2.47 (s, 4H), 2.61 (t, J = 5 Hz, 2H), 4.25 (t, J = 5 Hz, 2H), 6.04 (s, 2H), 6.89 (d, J
1
3
=
5 Hz, 1H), 6.94 (s, 1H), 7.03 (d, J = 10 Hz, 1H), 7.60 (s, 1H); C NMR (75 MHz, CDCl ): δ 24.40,
3
2
1
4
6.10, 28.80, 35.68, 41.99, 54.85, 55.00, 102.2, 109.4, 109.6, 120.8, 127.6, 127.9, 133.2, 148.9, 150.2,
+
68.0. HR ESI-MS found 377.0992 [M+H] (calc. for C H N O S is 377.0994).
1
8
21
2
3 2
.3.5. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-3-(2-morpholinoethyl)thiazolidine-2,4-dione (34).
1
Pale yellow crystals (78% yield); M.P.: 165－167°C; H NMR (500 MHz, CDCl ): δ 2.48 (s, 4 H), 2.59
3
(t, J = 5 Hz, 2H), 3.63 (s, 4H), 3.85 (t, J = 5 Hz, 2H), 6.03 (s, 2H), 6.88 (d, J = 10 Hz, 1H), 6.96 (s, 1H),
2
0

1
3
7
1
.04 (d, J = 5 Hz, 1H), 7.76 (s, 1H); C NMR (125 MHz, CDCl ): δ 38.96, 53.72, 55.49, 67.22, 102.1,
3
09.3, 109.3, 119.4, 126.8, 127.8, 133.7, 148.8, 149.9, 166.7, 168.0. HR ESI-MS found 363.1013
+
[
M+H] (calc. for C H N O S is 363.1015).
1
7
19
2
5
4
.3.6. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-3-(2-morpholinoethyl)-2-thioxothiazolidin-4-one
1
(
35). Yellow solids (79% yield); M.P.: 136－138°C; H NMR (500 MHz, CDCl ): δ 2.52 (s, 4H), 2.66
3
(t,
J = 5 Hz, 2H), 3.64 (s, 4H), 4.24 (t, J = 5 Hz, 2H), 6.04 (s, 2H), 6.89 (d, J = 10 Hz, 1H), 6.94 (s, 1H),
1
3
7
1
.04 (d, J = 10 Hz, 1H), 7.60 (s, 1H); C NMR (125 MHz, CDCl ): δ 41.68, 53.96, 54.91, 67.22, 102.3,
3
09.4, 109.6, 120.8, 127.6, 127.9, 133.3, 149.0, 150.3, 168.1, 193.4.HR ESI-MS found 379.0781 [M+H]+
(
calc. for C H N O S is 379.0786).
17 19 2 4 2
4
.3.7. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-3-(3-morpholinopropyl)thiazolidine-2,4-dione
1
(
36). White solids (75% yield); M.P.: 169－171°C; H NMR (500 MHz, CDCl ): δ 1.25 (s, 2H), 1.85 (t,
3
J = 5 Hz, 2H), 2.40 (t, J = 5 Hz, 4H), 3.65 (s, 4H), 3.84 (t, J = 5 Hz, 2H), 6.05 (s, 2H), 6.90 (d, J = 10
1
3
Hz, 1H), 6.98 (s, 1H), 7.05 (d, J = 10 Hz, 1H), 7.78 (s, 1H); C NMR (125 MHz, CDCl ): δ 24.09, 40.85,
3
5
3.83, 56.53, 67.09, 67.16, 102.1, 109.3, 119.5, 126.8, 127.7, 133.6, 148.8, 149.9, 166.8, 168.1. HR ESI-
+
MS found 377.1167 [M+H] (calc. for C H N O S is 377.1171).
1
8
21
2
5
4
.3.8.
(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-3-(3-morpholinopropyl)-2-thioxothiazolidin-4-
1
one (37). Dark orange solids (71% yield); M.P.: 151－153°C; H NMR (500 MHz, CDCl ): δ 1.89 (t, J
3
=
5 Hz, 2H), 2.37 (s, 4H), 2.42 (t, J = 5 Hz, 2H), 3.62 (s, 4H), 4.20 (t, J = 5 Hz, 2H), 6.04 (s, 2H), 6.89
1
3
(
d, J = 5 Hz, 1H), 6.93 (s, 1H), 7.03 (d, J = 10 Hz, 1H), 7.59 (s, 1H); C NMR (125 MHz, CDCl ): δ
3
2
1
4
2
3.37, 43.50, 53.88, 56.45, 67.21, 102.2, 109.4, 109.6, 121.0, 127.5, 127.9, 133.1, 149.0, 150.3, 168.3,
+
93.4. HR ESI-MS found 393.0946 [M+H] (calc. for C H N O S is 393.0943).
1
8
21
2
4 2
.3.9.
(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-1,3-bis(2-(pyrrolidin-1-yl)ethyl)imidazolidine-
1
,4-dione (38). Pale yellow solids (72% yield); M.P.: 86－88°C; H NMR (500 MHz, CDCl ): δ 1.59 (s,
3
4
H), 1.73 (s, 4H), 2.17 (t, J = 5 Hz, 2H), 2.25 (s, 4H), 2.54 (d, J = 5 Hz, 4H), 2.71 (t, J = 5 Hz, 2H), 3.72
1
3
(
q, J = 5 Hz, 4H), 5.96 (s, 2H), 6.75 (d, J = 5 Hz, 2H), 6.78 (s, 1H), 6.79 (s, 1H); C NMR (125 MHz,
2
1

CDCl ): δ 23.70, 38.37, 41.01, 52.65, 53.53, 54.17, 101.6, 108.4, 109.6, 112.4, 123.8, 127.0, 128.2, 147.8,
3
+
1
48.0, 156.3, 164.4. HR ESI-MS found 427.2341 [M+H] (calc. for C H N O is 427.2345).
2
3
31
4
4
4
.3.10. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-1,3-bis(2-(pyrrolidin-1-yl)ethyl)-2-thioxoimidaz
1
-
olidin-4-one (39). Dark orange solids (84% yield); M.P.: 70 －72°C; H NMR (500 MHz, CDCl ): δ
3
1
.73 (s, 4H), 1.79 (s, 4H), 2.55 (s, 4H), 2.62 (s, 4H), 2.68 (t, J = 5 Hz, 2H), 2.91 (t, J = 5 Hz, 2H), 3.47
(t, J = 5 Hz, 2H), 3.70 (t, J = 5 Hz, 2H), 5.97 (s, 2H), 6.78 (s, 1H), 6.80 (d, J = 10 Hz, 1H), 7.35 (d, J =
1
3
1
1
0 Hz, 1H), 8.03 (s, 1H); C NMR (125 MHz, CDCl ): δ 23.75, 30.06, 40.28, 54.24, 54.28, 54.42, 55.07,
3
01.6, 108.6, 111.0, 123.7, 128.1, 129.3, 137.3, 148.2, 149.2, 163.9, 170.0. HR ESI-MS found 443.2127
+
[
M+H] (calc. for C H N O S is 443.2117).
2
3
31
4
3
4
2
.3.11.
(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-1,3-bis(2-(piperidin-1-yl)ethyl)imidazolidine-
1
,4-dione (40). White solids (74% yield); M.P.: 117－119°C; H NMR (500 MHz, CDCl ): δ 1.28 (d, J
3
=
5 Hz, 2H), 1.35 (s, 2H), 1.37 (t, J = 5 Hz, 4H), 1.53 (t, J = 5 Hz, 4H), 1.99 (t, J = 5 Hz, 2H), 2.11 (s,
4
6
5
H), 2.43 (s, 4H), 2.57 (t, J = 5 Hz, 2H), 3.70 (q, J = 5 Hz, 4H), 5.96 (s, 2H), 6.75 (d, J = 10 Hz, 2H),
1
3
.78 (s, 1H), 6.80 (s, 1H); C NMR (125 MHz, CDCl ): δ 24.35, 24.48, 26.11, 26.28, 36.64, 39.73,
3
4.66, 55.18, 56.31, 101.6, 108.5, 109.6, 112.3, 123.8, 127.1, 128.4, 147.8, 148.0, 156.8, 164.5. HR ESI-
+
MS found 455.2664 [M+H] (calc. for C H N O is 455.2658).
2
5
35
4
4
4
.3.12. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-1,3-bis(2-(piperidin-1-yl)ethyl)-2-thioxoimidazo
1
-
lidin-4-one (41). Orange solid (81% yield); M.P.: 125－127°C; H NMR (500 MHz, CDCl ): δ 1.41 (t,
3
J = 5 Hz, 4H), 1.54 (s, 4H), 1.59 (s, 4H), 2.43 (s, 4H), 2.51 (s, 2H), 2.51 (s, 4H), 2.76 (t, J = 5 Hz, 2H),
.45 (t, J = 5 Hz, 2H), 3.68 (t, J = 5 Hz, 2H), 5.98 (s, 2H), 6.79 (d, J = 10 Hz, 1H), 6.81 (s, 1H), 7.36 (d,
3
1
3
J = 5 Hz, 1H), 8.04 (s, 1H); C NMR (125 MHz, CDCl ): δ 24.46, 26.12, 28.32, 38.72, 54.57, 54.89,
3
5
7.02, 57.97, 101.6, 108.6, 111.0, 123.6, 128.1, 129.4, 137.4, 148.2, 149.2, 164.1, 170.0. HR ESI-MS
+
found 471.2429 [M+H] (calc. for C H N O S is 471.2430).
2
5
35
4
3
4
.3.13.
(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-1,3-bis(2-morpholinoethyl)imidazolidine-2,4-
1
dione (42). Pale yellow solid (65% yield); M.P.: 131－133°C; H NMR (500 MHz, CDCl ): δ 2.02 (t, J
3
=
5 Hz, 2H), 2.20 (s, 4H), 2.49 (s, 4H), 2.59 (t, J = 5 Hz, 2H), 3.48 (s, 4H), 3.64 (t, J = 5 Hz, 4H), 3.71
2
2

1
3
(
q, J = 5 Hz, 4H), 5.96 (s, 2H), 6.75 (d, J = 10 Hz, 2H), 6.78 (s, 1H), 6.80 (s, 1H); C NMR (125 MHz,
CDCl ): δ 36.20, 39.14, 53.65, 54.83, 56.01, 67.22, 101.7, 108.5, 109.5, 112.7, 123.8, 126.8, 128.0, 147.9,
3
+
1
48.1, 156.8, 164.4. HR ESI-MS found 459.2242 [M+H] (calc. for C H N O is 459.2244).
2
3
31
4
6
4
.3.14. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-1,3-bis(2-morpholinoethyl)-2-thioxoimidazoli
1
-
din-4-one (43). Pale yellow solids (77% yield); M.P.: 134－136°C; H NMR (500 MHz, CDCl ): δ 2.48
3
(s, 4H), 2.56 (s, 4H), 2.57 (s, 2H), 2.80 (t, J = 5 Hz, 2H), 3.46 (t, J = 5 Hz, 2H), 3.66 (q, J = 5 Hz, 4H),
3
.68 (s, 2H), 3.71 (t, J = 5 Hz, 4H), 5.97 (s, 2H), 6.79 (d, J = 10 Hz, 1H), 6.83 (s, 1H), 7.29 (d, J = 10
1
3
Hz, 1H), 8.08 (d, J = 5 Hz, 1H); C NMR (125 MHz, CDCl ): δ 28.01, 38.29, 23.72, 53.83, 56.67, 57.54,
3
6
4
4
7.09, 101.6, 108.6, 110.8, 124.0, 128.3, 129.2, 137.1, 148.2, 149.4, 163.5, 170.0. HR ESI-MS found
+
75.2019 [M+H] (calc. for C H N O S is 475.2015).
2
3
31
4
5
.3.15. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-1,3-bis(3-morpholinopropyl)imidazolidine-2,4
1
-
dione (44). Pale yellow oil (62% yield); H NMR (500 MHz, CDCl ): δ 1.30 (t, J = 5 Hz, 2H), 1.80 (t,
3
J = 5 Hz, 2H), 2.02 (t, J = 5 Hz, 2H), 2.12 (s, 4 H), 2.34 (s, 4H), 2.37 (d, J = 5 Hz, 2H), 3.53 (s, 4H), 3.64
1
3
(
d, J = 5 Hz, 8H), 5.96 (s, 2H), 6.73 (d, J = 5 Hz, 2H), 6.76 (s, 1H), 6.79 (d, J = 10 Hz, 1H); C NMR
(
125 MHz, CDCl ): δ 24.19, 24.92, 37.79, 40.61, 53.67, 53.76, 56.21, 56.36, 66.93, 67.14, 101.6, 108.4,
3
+
1
09.5, 112.1, 123.6, 126.8, 128.1, 147.8, 148.0, 155.9, 164.2. HR ESI-MS found 487.2566 [M+H] (calc.
for C H N O is 487.2557).
2
5
35
4
6
4
.3.16. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-1,3-bis(3-morpholinopropyl)-2-thioxoimidazoli -
1
din-4-one (45). Brown oil (79% yield); H NMR (500 MHz, CDCl ): δ 1.78 (t, J = 5 Hz, 2H), 2.01 (t, J
3
=
5 Hz, 2H), 2.34 (t, J = 5 Hz, 2H), 2.36 (s, 4H), 2.42 (s, 4H), 2.47 (t, J = 5 Hz, 2H), 3.32 (t, J = 5 Hz,
2
1
2
1
4
H), 3.60 (t, J = 5 Hz, 2H), 3.62 (t, J = 5 Hz, 4H), 3.66 (t, J = 5 Hz, 4H), 5.96 (s, 2 H), 6.78 (d, J = 5 Hz,
1
3
H), 6.79 (s, 1H), 7.30 (d, J = 5 Hz, 1H), 8.01 (d, J = 5 Hz, 1H); C NMR (125 MHz, CDCl ): δ 25.62,
3
6.30, 28.87, 39.27, 53.73, 53.78, 56.01, 57.69, 67.05, 101.6, 108.6, 110.8, 123.8, 128.2, 129.2, 137.2,
+
48.1, 149.3, 163.5, 170.1. HR ESI-MS found 503.2321 [M+H] (calc. for C H N O S is 503.2328).
2
5
35
4
5
.3.17. Synthesis of (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-3-(prop-2-yn-1-yl)thiazolidine-2,4-
dione (47). Compound 47 was synthesized according to a previous report [54]. Sulfur yellow solids (86%
2
3

1
yield); M.P.: 167－169°C; H NMR (300 MHz, CDCl ): δ 2.28 (t, J = 2.4 Hz, 1H), 4.51 (d, J = 2.4 Hz,
3
2
7
1
H), 6.07 (s, 2H), 6.92 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 2 Hz, 1H), 7.07 (dd, J = 1.5 Hz, J = 6.9 Hz, 1H),
1
3
.86 (s, 1H); C NMR (75 MHz, CDCl ): δ 30.84, 72.37, 77.43, 102.2, 109.4, 118.6, 127.1, 127.5, 134.8,
3
+
48.8, 150.2, 165.4, 167.1. HR ESI-MS found 310.0154 [M+Na] (calc. for C H NO SNa is 310.0150).
1
4
9
4
The spectroscopic data were found to be in accordance with the data in the literature [54].
.3.18. Synthesis of (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-3-(1-carboranyl)-2-thioxothiazolidi
4
-n-4-one (49). The reaction conditions referred to Professor Nakamura’s report [61]. The substrate 47
(0.100 g, 0.35 mmol) and decaborane(14) (51 mg, 0.42 mmol) were added into chlorobenzene (3 mL) in
autoclave. DMA (67 μL, 0.53 mmol) was added to the mixture, then heated to 130°C for 30 min in a
microwave reactor. After the reaction cooled down, it was dried under vacuum. The crude oil was purified
by column chromatography (dichloromethane : hexane = 2 : 3 v/v). The product 49 was obtained as
1
chartreuse crystal (0.119 g, 84% yield); M.P.: 179－181°C; H NMR (500 MHz, CDCl ): δ 1.6 – 3.0 (m,
3
1
0H, B–H(cluster)), 3.97 (s, 1H, C–H(cluster)), 4.39 (s, 2H), 6.06 (s, 2H), 6.90 (d, J = 8 Hz, 1H), 6.95
1
3
(
d, J = 1 Hz, 1H), 7.05 (dd, J = 1 Hz, J = 8 Hz, 1H), 7.83 (s, 1H). C NMR (125 MHz, CDCl ): δ 45.37,
3
1
1
1
6
0.20, 72.23, 102.1, 109.1, 109.2, 117.0, 126.9, 127.3, 136.1, 148.7, 150.4, 165.4, 167.4. B{ H} NMR
(
160 MHz, CDCl ): δ -0.95 (s, 1B), -4.54 (s, 2B), -9.70 (s, 2B), -11.2 (s, 3B), -12.6 (s, 2B). HR ESI-MS
3
+
found 408.2043 [M+H] (calc. for C H B NO S is 408.2044).
1
4
20 10
4
4
.4. Biology
Vero, SW480, MDA-MB-468, MDA-MB-231, Mahlavu cell lines were cultured in Dulbecco's
modified Eagle medium (DMEM) with 10% (v/v) fetal bovine serum (FBS) (Gibco, Carlsbad, CA,
U.S.A.). A549 cell line was cultured in Roswell Park Memorial Institute (RPMI) 1640 with 10% (v/v)
FBS. The cell viability assays were evaluated by the resazurin dye reduction assay. Briefly, cells (1 ×
1
04 cells/well) were seeded in 96-well plates (Falcon, Becton Dickinson, NJ, U.S.A.) with culture
medium for 16 h and then washed twice with phosphate-buffered saline solution (PBS). One hundred
microliters starvation medium (0.1 % FBS containing DMEM/RPMI medium) was added into each well
and incubated for 24 h. Afterward, those cells in 96-well plates were treated with chemical compounds
2
4

containing starvation medium (compounds concentrations at 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625,
.78125 and 0 μM) and incubated for 48 h. Resazurin (final concentration 0.02 mg/mL) was added to
0
each well of the 96-well plates and incubated for 4 h. The value of absorbance at 570 nm and 600 nm
were detected by a plate reader. The IC were calculated using nonlinear regression and the formula was
5
0
as y = Bottom + (Top-Bottom) / (1+(IC /X)^ HillSlope).
5
0
Acknowledgments
We thank National Changhua University of Education, National Tsing Hua University, and Ministry
of Science and Technology of the Republic of China for financial support. Authors thank to Ms. Miranda
Jane Loney (ABRC, Academia Sinica, Taiwan) for her attentive editing of this manuscript. This work
was supported by the Ministry of Science and Technology (MOST 106-2113-M-018-008)(MOST 107-
2
113-M-018-008)(MOST 108-2113-M-018-009).
Conflict of interest
The authors have declared no conflict of interest.
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