Synthesis and anticancer activity of benzoselenophene and heteroaromatic derivatives of 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI)

Article abstract of DOI:10.1039/c6ob02729f

The current study reports the synthesis of different derivatives of benzoselenophene analogs as well as a diverse series of compounds (14a-p, 15 and 16) from 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI) and benzoselenophene or heteroaromatic acids. The overall yield of scaffold 12 was improved by an one-pot reaction, which helps in large-scale synthesis of CBI, a duocarmycin alkylation subunit analog. The series of compounds were evaluated for their cytotoxicity against SK-OV3 ovarian cancer cell lines, which revealed that benzoselenophene can enhance or maintain the anticancer activity of the duocarmycin analog upon replacing the indole moiety. CBI-benzoselenophenes with N-amido substituents at the C-5 position, 14g, 14f and 16 (IC₅₀ = 0.5, 1.2 and 1.6 nM, respectively), were found to be more potent than the CBI-TMI and other benzoselenophene analogs. The CBI-benzoselenophene analogs, 14f and 14g (containing N-acetamido and N-butyramido substituents, respectively), were found to be 8 and 120 times more potent than the corresponding indole analogs of CBI, 14q and 14r, respectively.

Full text of DOI:10.1039/c6ob02729f

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Synthesis and anticancer activity of benzoselenophene
and heteroaromatic derivatives of 1,2,9,9a-
Cite this: DOI: 10.1039/c6ob02729f
tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI)†
Amol B. Mhetre,a Hangeun Lee,a Heekyoung Yang,b Kyoungmin Lee,b
Do-Hyun Namb and Dongyeol Lim*a
The current study reports the synthesis of different derivatives of benzoselenophene analogs as well as a
diverse series of compounds (14a–p, 15 and 16) from 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-
one (CBI) and benzoselenophene or heteroaromatic acids. The overall yield of scaffold 12 was improved
by an one-pot reaction, which helps in large-scale synthesis of CBI, a duocarmycin alkylation subunit
analog. The series of compounds were evaluated for their cytotoxicity against SK-OV3 ovarian cancer cell
lines, which revealed that benzoselenophene can enhance or maintain the anticancer activity of the duo-
carmycin analog upon replacing the indole moiety. CBI-benzoselenophenes with N-amido substituents
at the C-5 position, 14g, 14f and 16 (IC50 = 0.5, 1.2 and 1.6 nM, respectively), were found to be more
potent than the CBI-TMI and other benzoselenophene analogs. The CBI-benzoselenophene analogs, 14f
and 14g (containing N-acetamido and N-butyramido substituents, respectively), were found to be 8 and
120 times more potent than the corresponding indole analogs of CBI, 14q and 14r, respectively.
Received 14th December 2016,
Accepted 4th January 2017
DOI: 10.1039/c6ob02729f
www.rsc.org/obc
CC-1065, duocarmycin SA and yatakemycin are cyclopropyl-
pyrrolo[e]indolone (CPI) containing alkaloids belonging to a
Introduction
class of naturally occurring antitumor agents (Fig. 1).7–11
Initial studies have explained the highly potent antitumor
activity of these natural products by their characteristic duplex
DNA alkylation and DNA binding affinity.12,13 For example,
CC-1065 binds to double stranded B-DNA within the minor
groove with a sequence preference for 5′-d(A/GNTTA)-3′ and
5′-d(AAAAA)-3′ and alkylates the N3 position of 3′-adenine with
the CPI segment.14–16 In CC-1065, duocarmycin SA and duo-
Despite substantial work being done towards the development
of efficient anticancer therapies, cancers are still delineated as
a major cause of death, accounting for approximately 13% of
all deaths worldwide.1 While some cancer types can be treated
effectively, most clinically approved drugs show
a poor
response owing to their high toxicity and lack of selectivity.
Antibody–drug conjugates (ADCs) have been attracting growing
interest in current cancer therapy due to their potential tar-
geted delivery of cytotoxic drugs, and less toxicity toward
normal cells.2 Around 50 distinct ADCs are currently in clinical
trials among that 35 ADCs are investigated for solid tumors.3
In recent years, duocarmycin analogs are used as potent pay-
loads in the development of ADCs with the main aim of
improving the therapeutic index by their effective mechanism
of action.4–6 The potency of the conjugated cytotoxic agent
should be sufficiently high so that it can kill tumor cells at the
amounts delivered by antibody retention in the tumor. Thus
the selection of a potent candidate for ADCs has become
crucial in current preclinical and clinical research.
aDepartment of Chemistry, Sejong University, Seoul 143-747, Republic of Korea.
E-mail: dylim@sejong.ac.kr
bDepartment of Neurosurgery, Samsung Medical Center, Sungkyunkwan University
School of Medicine, Seoul, Republic of Korea
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c6ob02729f
Fig. 1 Natural products (DNA alkylating agents).
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carmycin A (Fig. 1), the substituted indole is a common struc-
Taking these facts into consideration and our expectation
tural unit on the right hand side of the DNA alkylating unit, to achieve improved anticancer activity, the indole moiety of
which plays a crucial role in enhancing binding affinity and the duocarmycin subunit was replaced with the benzoseleno-
selectivity.13,17,18 Benzoselenophene is expected to have a phene analog (Fig. 2). 1,2,9,9a tetrahydrocyclopropa[c]benzo[e]
similar or an even better effect than the indole in enhancing indol-4-one (CBI)26–28 was selected as the DNA alkylating
anticancer activity of duocarmycin and CC-1065 analogs due to agent, which is one of the most extensively studied alkylation
the biological significance of the selenium element19 and its subunits of duocarmycin. It has the advantage of being easily
structural features. The larger size of the selenium atom synthesized, more stable, and highly cytotoxic than CPI.29 This
changes the bond length and bond angle with the adjacent study describes the syntheses and anticancer activities of sub-
carbon and ultimately affects the structural unit, which makes stituted benzoselenophenes and different heteroaromatic
it different from indole. Selenophene-containing compounds derivatives of CBI. The results from the structure–activity
have diverse biological effects20 including antioxidant,21 anti- relationship (SAR) study of the highly potent anticancer agents
nociceptive,22 and anti-inflammatory properties23 as well as are also provided.
being efficacious maturation-inducing agents.24 They also
exhibit potent in vitro and in vivo antitumor activities which
involve DNA damage and nuclear protein kinase activation.25
It would be interesting to study the effect of introduction of
Results and discussion
selenophene compounds into the duocarmycin family.
Chemistry
The SAR study of duocarmycin analogs revealed that substi-
tution at the C-5 position of the DNA binding unit is crucial
for inducing cytotoxicity against cancer cell lines,30,31 so we
mostly focused on the synthesis of C-5 substituted benzosele-
nophene analogs. According to this, first we synthesized
various selenophene fused aromatic compounds by two
methods (Scheme 1). In the first method, the aryl selenide was
the intermediate formed from 2-chloro-5-nitro-benzaldehyde
and diethyl 2,2′-diselanediyldiacetate using dithiothreitol
(DTT) and 8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the redu-
cing agent and base, respectively. The resulting intermediate
undergoes cyclization under heating conditions to afford the
desired 5-nitro benzoselenophene ester 1a. For the synthesis
Fig. 2 Structural comparison between seco-CBI-TMI and seco-CBI-
benzoselenophene.
Scheme 1 Synthesis of selenophene carboxylic acids.
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of electron-rich benzoselenophene analogs, the aryl methyl
selenides32,33 were first treated with ethyl bromoacetate and
then cyclized with the base to obtain the desired products
1b–e. The heteroaryl-fused selenophenes, 1f–h, were also
prepared by a similar procedure to that described for 1b–e.
The esters, 1a–h, were then hydrolyzed to prepare the corres-
ponding carboxylic acids 2a–h (Scheme 1).
Scheme 4 One-pot reaction of scaffold 12.
To prepare more benzoselenophene analogs, the nitro
group of 1a was modified to produce diverse amide and urea
analogs. First, palladium-catalyzed nitro reduction of 1a was
performed to obtain the amine 3. Then the product 3 was con-
verted into different amide and urea esters, which hydrolyzed
to provide their corresponding acids (4–9) with excellent
overall yields (Scheme 2). Demethylation of 5-methoxy benzo-
selenophene ester 1b was performed by using BCl3 and tetra
(n-butyl)ammonium iodide, and then alkylation of the pheno-
lic (OH) intermediate was carried out with 2-chloro-N,N-di-
methylethanamine under the basic conditions to obtain the
N,N-dimethylethoxy derivative of the benzoselenophene ester,
which was hydrolyzed to obtain benzoselenophene carboxylic
acid 10 (Scheme 3).
tions as described previously.35 To avoid separate purification
after each step, we performed a one-pot synthesis of com-
pound 12 from 11 with iodination, alkylation and cyclization
reactions, which provided the desired product in 76% yield
(Scheme 4). Then the desired CBI compound 13 was syn-
thesized from 12 as reported previously.35 Finally, a potent
library of analogs, 14a–r, were synthesized by Boc deprotection
of 13 with 4 N HCl/ethyl acetate, followed by coupling with
different carboxylic acids using 1-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide (EDCI) (Scheme 5). The spiro-
cyclized derivatives of 14d and 14g were also prepared by treat-
ment with a solution of 15% aq. NaHCO3 in DMF (1 : 1) at 0 to
20 °C for 3 h which resulted in 15 and 16, respectively
(Scheme 6).
In order to synthesize CBI, first we synthesized scaffold 11
from benzaldehyde by a previously reported procedure,34 and
then synthesized scaffold 12 from 11 with three different reac-
Biological activity
A diverse series of compounds (14a–r, 15 and 16) along with
CBI-TMI36,37 were assayed for cytotoxic potential against the
human ovarian cancer cell line (SK-OV-3). The cells growing on
McCoy’s 5A Medium, which contained 10% fetal bovine serum
(FBS) and 1% P/S, were treated with different concentrations of
14a–r, 15 and 16 as well as CBI-TMI, which is one of the most
potent analogs of the class of duocarmycin compounds.31
The IC50 values in nM for the screened compounds against
the SK-OV-3 cell line are shown in Table 1. The CBI-benzo-
selenophene analog with 5,6-dimethoxy substituents i.e. com-
pound 14d (IC50 = 7.4 nM) was found only 3 times less potent
than CBI-TMI (IC50 = 2.5 nM). The analog 14e with a longer,
flexible N,N′-dimethylethoxy substituent was equipotent
(IC50 = 7.4 nM) to the 5,6-dimethoxy substituted analog 14d.
The amide analogs 14f and 14g (containing N-acetamido and
N-butyramido substituents, respectively) exhibit higher anti-
cancer activities (IC50 = 1.6 and 0.5 nM respectively) than
CBI-TMI (IC50
=
2.5 nM) and the analogs 14d–e.
Comparatively, the indole analogs of N-acetamido and
N-butyramido substituents 14q–r (IC50 = 11.9 and 58 nM,
respectively) were found much less active than CBI-TMI. This
trend is clearly different from that of the same compounds
which are found equally potent against L1210 leukemia cell
lines.31 For the comparison of benzoselenophene and indole
with the same substituents, the benzoselenophene analogs 14f
and 14g were found 8 and 120 times more potent than the
corresponding indole analogs 14q and 14r, respectively.
Scheme 2 Synthesis of amide and urea analogs.
This increased potency may be due to the hydrophobicity of
benzoselenophene and attractive van der Waals interactions
imposed by the increased curvature of benzoselenophene.
Compound 14h with an N-hexanamide substituent was less
Scheme 3 Synthesis of N,N-dimethylaminoethoxy benzoselenophene
acid.
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Scheme 5 Syntheses of CBI analogs of substituted benzoselenophenes, indole and heteroaromatic compounds (14a–r).
locate more inside of the DNA minor groove than the corres-
ponding indole analog. N-Substituted urea analogs 14j–k
(IC50 = 8.2 and 7.5 nM, respectively) were less active than
amide substituted analogs 14f–h, but equipotent to dimethoxy
substituted analogs 14d. There were no significant differences
in biological activity after spirocyclization of seco-CBI analogs,
for example, compound 14g compared to 16 (IC50 = 0.5 versus
1.2 nM) and 14d compared to 15 (IC50 = 7.4 versus 4.0 nM).
In the CBI-heteroaromatic analogs, compound 14l with the
selenofused-pyridine moiety was found to be least cytotoxic
among all the other compounds examined (IC50 = 110 nM).
Compound 14p with the pyrrolo-thiophene moiety was 3.5-
and 2-fold more potent than the selenofused-thiophene analog
14m and the thieno-thiophene analog 14n, respectively. After
the biological study we selected N-amido benzoselenophene
derivatives of duocarmycin as starting payloads in our current
ADC study.
Scheme 6 Spirocyclization of 14d and 14g.
Table 1 IC50 (nM) of screened compounds against the SK-OV3 cell line
IC50(nM)
SK-OV-3
IC50(nM)
SK-OV-3
Compound
Compound
CBI-TMI
14a
14b
14c
14d
14e
14f
14g
14h
14i
2.5
NDa
ND
ND
7.4
7.4
1.6
0.5
4.3
49
14k
14l
14m
14n
14o
14p
14q
14r
15
7.5
110
6.8
3.4
ND
1.8
11.9
58
Conclusions
4.0
1.2
—
16
In summary, we synthesized various benzoselenophene esters,
N-substituted amido and urea derivatives from the nitro benzo-
selenophene ester. We also improved the overall yield of
scaffold 12 from 11 by an one-pot reaction.
14j
8.2
—
a 23% inhibition at 10 nM.
In addition, we synthesized a diverse series of CBI-benzo-
active (IC50 = 4.3 nM) than 14f–g, but had comparable potency selenophene, heteroaromatic and indole analogs (14a–r).
over the series of compounds tested. We also observed that the Moreover, the in vitro cytotoxicity study and SAR showed that
analog of branched and longer substituents at the amide posi- the benzoselenophene compounds 14f and 14g were more
tion, 14i, exhibits less cytotoxicity (IC50 = 49 nM). This fact potent than CBI-TMI, as well superior to the rest of the syn-
implies that the C-5 substituent of benzoselenophene can thesized benzoselenophene series of compounds. In compari-
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son with indole analogs with the acetamido and butyramido (60F-254) with UV light and visualized with ninhydrin,
substituents, 14q and 14r, the activities of benzoselenophene p-anisaldehyde, phosphomolybdic acid or KMnO4 solution
analogs 14f and 14g are 8 and 120 times more potent, respect- stains. Column chromatography was performed with silica gel
ively. Overall, these results show that the benzoselenophene (100–200 mesh) with the indicated solvent system.
derivative can play an important role as a DNA binding unit
Synthetic procedure for amide and urea derivatives of
benzoselenophene
and can enhance or maintain the cytotoxicity of the duocarmy-
cin analog after replacing the indole moiety. Notably N-amido
substituents at the C-5 position are crucial for their improved
Ethyl 5-aminobenzo[b]selenophene-2-carboxylate (3). To a
anticancer activity, and such candidates can be used to solution of ethyl 5-nitrobenzo (b) selenophene-2-carboxylate
develop effective therapeutics for advanced chemotherapy.
1a 38 (1.3 g, 4.36 mmol) in dry ethyl acetate, was added 10%
Pd/C under a N2 atmosphere. The reaction mixture was stirred
under a H2 atmosphere for 8 h. On completion of the reaction,
the mixture was filtered through a Celite pad followed by
washing with ethyl acetate (3 × 20 mL). The filtrate was concen-
trated under reduced pressure to provide a crude residue,
Experimental section
General experimental
All reagents were obtained from commercial suppliers and which was purified by silica column chromatography using
used without further purification, unless specified. The start- ethyl acetate/hexane (1 : 3) as an eluent to obtain the desired
ing carboxylic acids of the analogs 14m and 14p, i.e. thieno pure benzoselenophene amine intermediate 3 (1.11 g, 95%).
[3,2-b]thiophene-2-carboxylic acid and 4H-thieno[3,2-b]pyrrole- 1H NMR (500.1 MHz, CDCl3) δ 8.12 (s, 1H), 7.64 (d, J = 8.6 Hz,
5-carboxylic acid, respectively, were purchased from Aldrich. 1H), 7.17 (d, J = 2.2 Hz, 1H), 6.82 (dd, J = 8.5, 2.2 Hz, 1H), 4.37
Dry DMF and ethyl acetate were purchased from Sigma Aldrich (q, J = 7.1 Hz, 2H), 3.72 (brs, NH, 2H), 1.40 (t, J = 7.2 Hz, 3H);
(>99.9%). Tetrahydrofuran (THF) and dichloromethane 13C NMR (125.7 MHz, CDCl3) δ 163.0, 143.4, 141.2, 135.7,
(CH2Cl2) were distilled over sodium and benzophenone. 132.8, 132.3, 125.1, 116.3, 110.7, 60.5, 13.3; HRMS (ESI); m/z
A saturated solution of HCl in ethyl acetate was prepared by calcd for C11H11NO2Se [M]+: 269.0017, found 270.0017
purging pure HCl gas (99.99%, manufactured by RIGAS, [M + H]+.
Korea) in dry ethyl acetate at 0 to −5 °C for 1 h and stored in a
5-Acetamidobenzo[b]selenophene-2-carboxylic acid (4).
deep freezer. H and 13C NMR spectra were collected at reson- Compound 3 (0.691 g, 2.58 mmol) was dissolved in 10 mL dry
ance frequencies of 500.1 and 125.7 MHz, respectively. The CH2Cl2 and then pyridine (0.62 mL, 7.74 mmol) was added.
solvents used for NMR were DMSO-d6, acetone-d6, CDCl3 and The reaction mixture was stirred for 15 min at room tempera-
MeOH-d4 as indicated. The chemical shifts for 1H NMR are ture, after that acetic anhydride (0.37 mL, 3.87 mmol) was
reported in ppm from tetramethylsilane (0 ppm) or referenced added slowly under a N2 atmosphere. The reaction mixture
to the solvent (DMSO-d6 2.50; acetone-d6 2.05; MeOH-d4 3.31 was stirred continuously at room temperature until complete
and CDCl3 7.26 ppm) on the δ scale. Chemical shifts (δ) for conversion was observed by TLC. The reaction mixture was
13C NMR spectra are referenced to the signals for residual diluted with water and extracted with CH2Cl2 (3 × 10 mL). The
deuterated solvents (DMSO-d6 39.5; acetone-d6 29.84, 206.26; combined organic layer was washed with brine and dried over
MeOH-d4 49.00 and CDCl3 77.16 ppm) Multiplicities Mg2SO4, filtered and concentrated under vacuum. The crude
1
are reported by the following abbreviations:
s (singlet), product was purified by silica column chromatography, and
d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet ethyl acetate/hexane (1 : 1) was used as an eluent to afford the
of doublet), brs (broad singlet), J (coupling constants in hertz). desired ethyl 5-acetamidobenzo[b]selenophene-2-carboxylate
Analytical reverse-phase high performance liquid chromato- as a pale yellow solid (0.765 g, 96%). 1H NMR (500.1 MHz,
graphy (RP-HPLC) was carried out using a C18 (4.6 × 150 mm) CDCl3) δ 8.18–8.17 (m, 2H), 7.77 (d, J = 8.7 Hz, 1H), 7.69 (brs,
reverse-phase column at a flow rate of 1 mL min−1 with UV 1H, NH), 7.40 (dd, J = 8.7, 1.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H),
detection at 214 and 254 nm. Linear gradients of CH3CN/H2O 2.20 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H); 13C NMR (125.7 MHz,
solvents, each containing 0.1% TFA were used as follows: con- CDCl3) δ 168.5, 163.9, 141.9, 139.4, 137.9, 135.6, 134.2, 126.2,
dition A (10 to 80% CH3CN gradient over 20 min), condition B 120.0, 118.2, 61.8, 24.7, 14.4; HRMS (ESI); m/z calcd for
(30 to 100% CH3CN gradient over 20 min). For preparative C13H13NO3Se [M]+: 311.0061, found 312.0114 [M + H]+. The
HPLC, a C18 column (5 μM, 10 × 150 mm) was employed at a obtained ethyl 5-butyramidobenzo[b]selenophene-2-carboxy-
flow rate of 4 mL min−1 using the gradient condition B. High late (0.765 g, 2.47 mmol) was dissolved in 10 mL MeOH and
resolution mass spectra (HRMS) were recorded using two then 10 mL of aqueous 3 N NaOH solution was added. The
different instruments: (i) fast atom bombardment ionization mixture was stirred at room temperature for 24 h. After com-
using
a double-focusing magnetic sector mass analyzer plete hydrolysis, the reaction mixture was concentrated under
(ii) electrospray ionization using an ion trap analyzer (for all reduced pressure to afford a crude residue which was acidified
other compounds). Only the strongest and/or structurally with 2 N HCl solution. The required product was extracted
important absorptions of IR spectra were reported in wave- with CH2Cl2 (3 × 15 mL). The combined organic layer was con-
numbers (cm−1). All reactions were monitored by thin-layer centrated to obtain a crude product which was purified by
chromatography (TLC) performed on glass packed silica gel plates silica column chromatography by using ethyl acetate/hexane
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(1 : 1) as an eluent to provide the desired product 4 as a yellow synthesis of 4, and the desired product 6 was obtained as a
solid (0.63 g, 92%). 1H NMR (500.1 MHz, DMSO-d6) δ 10.06 brown solid (232 mg, 95%). 1H NMR (500.1 MHz, MeOH-d4)
(s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.66 δ 8.17 (s, 1H), 8.05 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.46 (dd, J =
(s, 1H), 7.39 (dd, J = 2.1, 8.6 Hz, 1H), 2.05 (s, 3H); 13C NMR 8.6, 1.5 Hz, 1H), 2.39 (t, J = 7.4 Hz, 2H), 1.72 (t, J = 7.1 Hz, 2H),
(125.7 MHz, DMSO-d6) δ 168.5, 166.8, 151.8, 142.9, 136.6, 1.40–1.38 (m, 4H), 0.94 (t, J = 6.6 Hz, 3H); 13C NMR
136.5, 127.9, 125.9, 117.8, 116.1, 24.1; LCMS (ESI); m/z calcd (125.7 MHz, DMSO-d6) δ 171.3, 167.6, 150.3, 142.7, 136.5 (2C),
for C11H9NO3Se [M]+: 282.97, found 284.1 [M + H]+.
128.6, 125.9, 117.9, 116.1, 36.3, 30.9, 24.8, 21.9, 13.9; LCMS
5-Butyramidobenzo[b]selenophene-2-carboxylic acid (5). The (ESI); m/z calcd for C15H17NO3Se [M]+: 339.04, found 340.0
intermediate amide ester was synthesized by a similar method [M + H]+.
used for the synthesis of an amide intermediate of compound
5-(3-Butyl-ureido)-benzo[b]selenophene-2-carboxylic acid (7).
4 from starting amine 3, i.e. compound 3 (200 mg, 0.75 mmol) The compound 3 (50 mg, 0.19 mmol) was partially dissolved
was treated with butyric anhydride (0.182 mL, 1.13 mmol) and in anhydrous CH2Cl2 (10 mL) under a nitrogen atmosphere,
pyridine (0.18 mL, 2.25 mmol) in CH2Cl2. The crude product and then reaction vessel was submerged in an ice bath. A solu-
was purified via silica column chromatography with ethyl tion of butyl isocyanate (56 mg, 0.57 mmol) in anhydrous
acetate/hexane (1 : 1) as an eluent to provide the desired ethyl CH2Cl2 (60 mL) was slowly added to the cooled reaction vessel
5-butyramidobenzo[b]selenophene-2-carboxylate as a brown over a course of 20 min stirring. Once the addition completed,
1
solid (227 mg, 90%). H NMR (500.1 MHz, CDCl3) δ 8.40 (brs, the ice bath was removed, and then reaction continued with
1H, NH), 8.15 (s, 1H), 8.04 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.40 stirring at room temperature for 12 h until disappearance of
(d, J = 8.4 Hz, 1H), 4.34 (q, J = 6.7 Hz, 2H), 2.34 (t, J = 7.1 Hz, starting compound observed on TLC. The reaction mixture was
2H), 1.73 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H), 0.95 (t, J = concentrated under vacuum to obtain a yellow solid product
7.2 Hz, 3H); 13C NMR (125.7 MHz, CDCl3) δ 170.4, 162.1, which was washed with ether/pentane (1 : 4) solution, and the
139.8, 137.4, 135.6, 134.0, 132.3, 124.1, 118.7, 116.7, 59.9, 37.6, solid product was filtered and dried under vacuum to provide
17.3, 12.5, 11.9 LCMS (ESI); m/z calcd for C15H17NO3Se [M]+: the pure desired 5-(3-butyl-ureido)-benzo[b]selenophene-2-car-
339.04, found 340.0 [M + H]+. The obtained ester, ethyl 5-butyr- boxylic acid ethyl ester as a brown solid (55 mg, 81%). IR (KBr
amidobenzo[b]selenophene-2-carboxylate (166 mg, 0.49 mmol) cm−1) 3316, 3079, 2969, 2960, 2932, 2859, 1716, 1626, 1573,
was hydrolyzed by a similar method used for the synthesis of 1555, 1446, 1295, 1240, 1162, 1024, 1002, 908, 827, 748;
compound 4, and the desired acid (5) was obtained as a pale 1H NMR (500.1 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.28 (s, 1H),
yellow solid (150 mg, 99%). 1H NMR (500.1 MHz, MeOH-d4) 8.11 (d, J = 1.8 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.44 (dd, J =
δ 8.25 (s, 1H), 8.17 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.8, 2.1 Hz, 1H), 6.19 (t, J = 5.4 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H),
8.6 Hz, 1H), 2.38 (t, J = 7.1 Hz, 2H), 1.74 (q, J = 7.2 Hz, 2H), 3.10 (q, J = 6.7 Hz, 2H), 1.43 (m, 2H), 1.35–1.31 (m, 5H), 0.90
1.01 (t, J = 7.1 Hz, 3H); 13C NMR (125.7 MHz, MeOH-d4) (t, J = 7.3 Hz, 3H); 13C NMR (125.7 MHz, DMSO-d6) δ 163.2,
δ 174.7, 167.7, 143.4, 140.9, 140.4, 137.6, 134.9, 127.2, 121.2, 155.2, 141.4, 138.5, 136.1, 135.2, 134.4, 126.1, 119.1, 115.3,
119.1, 39.9, 20.4, 14.1; LCMS (ESI); m/z calcd for C13H13NO3Se 61.3, 38.7, 31.8, 19.4, 14.1, 13.6; HRMS Calcd for
[M]+: 311.01, found 312.0 [M + H]+.
(C16H20N2O3Se) 369.0717 [M + H]+, found 369.0716. The result-
5-Hexanamidobenzo[b]selenophene-2-carboxylic acid (6). ing 5-(3-butyl-ureido)-benzo[b]selenophene-2-carboxylic acid
Compound 3 (300 mg, 1.12 mmol) was dissolved in 10 mL pyr- ethyl ester (55 mg, 0.15 mmol) was dissolved in THF–MeOH–
idine, and then hexanoic acid (0.42 mL, 3.36 mmol) and DCC H2O (4 : 1 : 1, 1.5 mL) and then treated with LiOH (19 mg,
(346 mg, 1.68 mmol) were added under a N2 atmosphere. The 0.45 mmol). The suspension was stirred at 23 °C for 18 h and
reaction mixture was stirred at room temperature for 4 h until quenched with 6 mL H2O. The solution was acidified with
complete conversion was observed by TLC. The reaction 10 mL of 10% aqueous HCl solution and then the precipitate
mixture was quenched with 10 mL water and then extracted was extracted in CH2Cl2 (2 × 10 mL), washed with brine, dried
with CH2Cl2 (3 × 10 mL). The organic layer was washed with over Mg2SO4 and filtered. The filtrate was evaporated under
brine, dried over Mg2SO4, filtered and concentrated under reduced pressure to afford a crude product which was purified
vacuum. The crude product was purified by column chromato- by silica column chromatography with 5% MeOH in CH2Cl2 as
graphy using ethyl acetate/hexane (1 : 1) as an eluent to provide an eluent to provide a faint yellow solid product 7 (49 mg,
desired ethyl 5-hexanamidobenzo[b]selenophene-2-carboxylate 97%). IR (KBr cm−1) 3217, 2960, 2931, 2861, 2561, 1674, 1626,
(264 mg, 65%). 1H NMR (500.1 MHz, CDCl3) δ 8.18 (s, 1H), 1577, 1560, 1452, 1296, 1224, 1160, 1055, 882, 749, 666;
8.12 (s, 1H), 7.95 (brs, 1H, NH), 7.72 (d, J = 8.6 Hz, 1H), 7.41 1H NMR (500.1 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.21 (s, 1H),
(d, J = 8.3 Hz, 1H), 4.36 (q, J = 6.9 Hz, 2H), 2.36 (t, J = 7.4 Hz, 8.11 (s, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H),
2H), 1.72 (s, 2H), 1.40–1.32 (m, 7H), 0.87 (s, 3H); 13C NMR 6.18 (brs, 1H), 3.08 (m, 2H), 1.41–1.28 (m, 4H), 0.89 (t, J =
(125.7 MHz, CDCl3) δ 172.1, 163.9, 141.7, 139.2, 137.6, 135.8, 7.2 Hz, 3H); 13C NMR (125.7 MHz, DMSO-d6) δ 164.7, 155.3,
134.14, 126.0, 120.3, 118.3, 61.7, 37.7, 31.5, 25.4, 22.5, 14.3, 141.8, 138.4, 138.2, 135.3, 133.9, 126.1, 118.9, 115.3, 38.6, 31.9,
13.9; LCMS (ESI); m/z calcd for C17H21NO3Se [M]+: 367.07, 19.5, 13.6; HRMS Calcd for (C14H16N2O3Se) 341.0404 [M + H]+,
observed 368.1 [M + H]+. The obtained ethyl 5-pentanamido- found 341.0406.
benzo[b]selenophene-2-carboxylate (264 mg, 0.72 mmol) was
5-[3-(4-Fluoro-phenyl)-ureido]-benzo[b]selenophene-2-
hydrolyzed by the above mentioned same procedure for the carboxylic acid (8). The intermediate 5-[3-(4-fluoro-phenyl)-
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ureido]-benzo[b]selenophene-2-carboxylic acid ethyl ester was
The ethyl 5-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-
synthesized by using compound 3 (100 mg, 0.37 mmol) and 6-((tert-butoxycarbonyl)amino)hexanamido)benzo[b]-seleno-
1-fluoro-4-isocyanato-benzene (152 mg, 1.11 mmol). The reac- phene-2-carboxylate (586 mg, 0.82 mmol) was dissolved in dry
tion method was similar to that described for the synthesis of CH2Cl2 and 20% TFA in CH2Cl2 was added to the reaction
the intermediate ester of compound 7 from the corresponding solution at 0 °C and the mixture was stirred for 2 h. The reac-
amine 3. The crude product was washed with ether/pentane tion mixture was concentrated and dissolved in 50 mL of di-
(1 : 4) solution to obtain a brown solid (145 mg, 96%). IR (KBr ethylamine–CH2Cl2 (1 : 1) solution with stirring for 2 h. After
cm−1) 2970, 2327, 2141, 1704, 1655, 1510, 1418, 1365, 1280, this the solvent was evaporated to obtain a crude residue. The
1
1217, 953, 897, 831, 736, 731; H NMR (500.1 MHz, DMSO-d6) crude residue was dissolved in 10 mL of pyridine and acetic
δ 8.99 (s, 1H), 8.91 (s, 1H), 8.32 (s, 1H), 8.19 (d, J = 1.3 Hz, 1H), anhydride (0.23 mL, 2.46 mmol) and stirred continuously at
7.99 (d, J = 8.7 Hz, 1H), 7.53–7.48 (m, 3H), 7.11 (t, J = 8.8 Hz, room temperature for 3 h. The reaction mixture was concen-
2H), 4.33 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR trated and dissolved in MeOH–H2O (9 : 1), and then NaOH
(125.7 MHz, DMSO-d6) δ 163.2, 158.3, 156.4, 152.8, 141.5, (163 mg, 4.07 mmol) was added. The mixture was stirred at
137.7, 136.5, 136.2, 136.1, 134.4, 126.3, 120.0, 119.6, 116.2, room temperature for 24 h. The reaction solution was acidified
115.3, 115.1, 61.4, 14.2; HRMS Calcd for (C18H15FN2O3Se) with 20% HCl solution and concentrated by using a lyophili-
407.0310 [M + H]+, found 407.0312. Then, the obtained inter- zer. The crude product was purified by silica column chromato-
mediate (145 mg, 0.36 mmol) was hydrolyzed by a similar graphy by using MeOH–CH2Cl2 (1 : 4) as an eluent to afford
procedure used for the synthesis of compound 7. Compound 8 the desired product 9 (20 mg, 5%). 1H NMR (500.1 MHz,
was obtained as an off-white solid after purification by silica MeOH-d4) δ 8.07 (s, 1H), 7.92 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H),
column chromatography using 5% MeOH in CH2Cl2 as an 7.40 (d, J = 9.0 Hz, 1H), 4.42 (dd, J = 5.5, 2.5 Hz, 1H), 3.13 (t, J =
eluent (105 mg, 78%). IR (KBr cm−1) 3365, 3089, 2584, 1657, 7.0 Hz, 2H), 1.99 (s, 3H), 1.86 (s, 3H), 1.75–1.68 (m, 1H),
1611, 1504, 1313, 1200, 1157, 1047, 901, 876, 830, 706; 1.54–1.38 (m, 5H); 13C NMR (125.7 MHz, MeOH-d4) δ 171.8,
1H NMR (500.1 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.73 (s, 1H), 171.6, 171.2, 169.8, 142.5, 138.7, 135.0, 129.5, 129.3, 125.3,
8.26 (s, 1H), 8.17 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.49–7.45 (m, 118.6, 117.3, 53.9, 38.5, 31.3, 28.4, 22.6, 20.9, 20.8 LCMS (ESI);
3H), 7.12 (t, J = 8.7 Hz, 2H); 13C NMR (125.7 MHz, DMSO-d6) m/z calcd for C19H23N3O5Se [M]+: 453.08; found 454.1 [M + H]+.
δ 164.7, 158.3, 156.4, 152.7, 141.8, 138.5, 137.4, 136.3, 136.0,
133.9, 126.4, 120.0, 119.3, 116.1, 115.3, 115.2; HRMS Calcd for phene-2-carboxylic acid (10). To a solution of 5-methoxy benzo-
(C16H11FN2O3Se) 378.9997 [M + H]+, found 378.9996.
selenophene derivative (770 mg, 2.72 mmol) in 10 mL
Synthesis of 5-(2-(dimethylamino)ethoxy)benzo[b]seleno-
5-(2,6-Diacetamidohexanamido)benzo[b]selenophene-2- anhydrous CH2Cl2, tetra n-butylammonium iodide (2.51 g,
carboxylic acid (9). The mixture of Fmoc-Lys(Boc)-OH (436 mg, 6.80 mmol) was added under a N2 atmosphere at −78 °C. After
0.93 mmol) and compound 3 (300 mg, 1.12 mmol) was
2 min stirring, 6.8 mL of BCl3 (1M CH2Cl2 solution,
dissolved in MeOH (18 mL) and water (2 mL) and the solution 6.80 mmol) was slowly added, and then the reaction mixture
was stirred for 15 min. After that 4-(4,6-dimethoxy-1,3,5- was stirred for 2 h at 0 °C. The reaction mixture was quenched
triazin-2-yl)-4-methyl morpholinium chloride (DMT-MM) with 20 mL ice water and extracted with CH2Cl2 (3 × 200 mL).
(386 mg, 1.39 mmol) was added slowly to the reaction mixture The combined organic layer was washed with brine, dried over
and stirred continuously for 8 h. The reaction mixture was Mg2SO4, filtered and concentrated under vacuum to obtain a
diluted with 25 mL water and then the reaction product crude phenolic product. The crude product was dissolved in
was extracted with CH2Cl2 (3 × 20 mL). The combined organic 50 mL acetone. 2-Chloro-N,N-dimethylethanamine hydro-
layer was washed with brine and dried over Mg2SO4, filtered chloride (1.17 g, 8.16 mmol) and potassium carbonate (1.88 g,
and concentrated under reduced pressure to obtain
a
13.6 mmol) were added to this solution with stirring at 65 °C
crude residue. The crude residue was purified by silica column for 7 h. The reaction mixture was extracted with 200 mL of
chromatography with ethyl acetate/hexane (1 : 1) to afford CH2Cl2 and then concentrated under reduced pressure to
the desired ethyl 5-(2-((((9H-fluoren-9-yl)methoxy)carbonyl) afford a crude residue which was purified by silica gel column
amino)-6-((tert-butoxycarbonyl)amino)hexanamido)benzo[b] chromatography with ethyl acetate/hexane (1 : 1) as an eluent
selenophene-2-carboxylate as a brown solid (586 mg, 88%). to provide the intermediate, ethyl 5-(2-(dimethylamino)ethoxy)
1H NMR (500.1 MHz, CDCl3) δ 8.70 (s, 1H), 8.19 (s, 1H), 8.15 benzo[b]selenophene-2-carboxylate (397 mg, 43%). 1H NMR
(s, 1H), 7.74–7.72 (m, 3H), 7.57–7.54 (m, 2H), 7.41–7.35 (m, (500.1 MHz, CDCl3) δ 8.20 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.34
3H), 7.27 (s, 2H), 5.73 (s, 1H), 4.68 (s, 1H), 4.42–4.36 (m, 4H), (d, J = 2.3 Hz, 1H), 7.07 (dd, J = 8.8, 2.4 Hz, 1H), 4.37 (q, J =
4.21–4.18 (m, 1H), 3.85–3.83 (m, 1H), 3.73–3.71 (m, 2H), 7.2 Hz, 2H), 4.11 (t, J = 5.7 Hz, 2H), 2.76 (t, J = 5.7 Hz, 2H), 2.35
3.17–310 (m, 2H), 1.55–1.39 (m, 14H); 13C NMR (125.7 MHz, (s, 6H), 1.39 (t, J = 7.2 Hz, 3H); 13C NMR (125.7 MHz, CDCl3)
MeOH-d4) δ 171.5, 169.6, 163.0, 155.7, 142.8, 140.8 (2C), δ 164.0, 157.3, 142.2, 137.5, 136.0, 134.1, 126.5, 117.8, 110.2,
140.5 (2C), 138.6, 136.9, 134.6, 133.3, 126.9 (2C), 126.2 (2C), 66.4, 61.6, 58.3, 45.9 (2C), 14.3.
125.1 (2C), 124.1, 119.2, 119.1 (2C), 117.3, 79.5, 66.4,
The
ethyl
5-(2-(dimethylamino)ethoxy)benzo[b]seleno-
65.8, 60.8, 53.7, 46.3, 43.2, 28.1, 27.6 (3C), 21.4, 13.5 LCMS phene-2-carboxylate (160 mg), (0.47 mmol) was hydrolyzed by
(ESI); m/z calcd for C37H41N3O7Se [M]+: 719.21, found 720.1 a similar procedure used for the synthesis of compound 4. The
[M + H]+.
desired product was obtained as a brown solid (136 mg, 93%).
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1H NMR (500.1 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.80 (d, J = solid, 68%; IR (KBr cm−1) 3328, 2942, 1621, 1593, 1514, 1470,
8.8 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.14 (dd, J = 8.7, 1.8 Hz, 1380, 1335, 1225, 1133, 1085, 963, 867, 770, 715; 1H NMR
1H), 4.43 (t, J = 4.2 Hz, 2H), 3.50 (t, J = 4.3 Hz, 2H), 2.82 (500.1 MHz, acetone-d6) δ 9.50 (s, 1H), 8.26–8.24 (m, 2H), 7.90
(s, 6H); 13C NMR (125.7 MHz, DMSO-d6) δ 165.0, 155.9, 142.4, (brs, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.55
140.7, 135.7, 133.1, 127.2, 117.1, 110.9, 62.9, 55.2, 42.9 (2C); (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.40 (t, J = 7.7 Hz,
LCMS (ESI); m/z calcd for C13H15NO3Se [M]+: 313.02, found 1H), 7.00 (d, J = 7.9 Hz, 1H), 4.78 (t, J = 10.0 Hz, 1H), 4.65 (d,
314.0 [M + H]+.
J = 10.9 Hz, 1H), 4.23 (t, J = 8.1 Hz, 1H), 4.05–4.03 (m, 4H),
General procedures for the synthesis of CBI derivatives 3.85–3.81 (m, 1H); 13C NMR (125.7 MHz, DMSO-d6) δ 162.0,
(14a–r). To compound 13 (50 mg, 0.15 mmol) in a round 155.6, 154.2, 143.2, 141.8, 130.3, 130.0, 129.8 (2C), 127.4,
bottomed flask was added 4 mL saturated solution of HCl in 127.0, 123.3, 123.1, 122.9, 122.3, 119.8, 115.4, 106.6, 100.1,
ethyl acetate at −78 °C, then the reaction mixture was stirred at 55.9, 55.5, 47.5, 41.0; HRMS Calcd for (C23H18ClNO3Se)
the same temperature for 30 min and then at room tempera- 472.0219 [M + H]+, found 472.0217.
ture for 1 h. After salt formation was observed by TLC, ethyl
(S)-(1-(Chloromethyl)-5-hydroxy-1H-benzo[e]indol-3(2H)-yl)
acetate was evaporated under nitrogen flow and then comple- (5,6-dimethoxybenzo[b]selenophen-2-yl)methanone (14d),
1
tely dried under high vacuum for 1 h. The resulting residue yellow solid, 49%; H NMR (500.1 MHz, acetone-d6) δ 9.27 (s,
was dissolved in anhydrous DMF (0.5 mL) and added to the 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.87 (d,
reaction mixture of acid (1.1 eq.) and EDCI (86 mg, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.56–7.52 (m, 2H), 7.41–7.38 (m,
0.45 mmol) in anhydrous DMF at 0 °C after 45 min stirring. 1H), 4.78 (t, J = 10.7 Hz, 1H), 4.68 (dd, J = 10.8, 2.0 Hz, 1H),
The reaction mixture was stirred at 0 °C to room temperature 4.25–4.21 (m, 1H), 4.05 (dd, J = 11.2, 3.2 Hz, 1H), 3.93 (s, 3H),
for 8 h. After completion of the reaction, the reaction mixture 3.89 (s, 3H), 3.81 (dd, J = 11.2, 8.7 Hz, 1H); 13C NMR
was diluted with water and extracted with ethyl acetate (125.7 MHz, DMSO-d6) δ 160.6, 160.5, 152.5, 147.9, 146.6,
(3 × 15 mL). The combined organic layer was washed with 140.4, 139.3, 133.5, 133.3, 128.5, 128.2, 125.6, 121.5, 121.1,
brine, dried over Mg2SO4, filtered and concentrated under 120.6, 113.5, 107.1, 105.9, 98.6, 54.1, 53.9, 53.8, 45.8, 39.5;
vacuum to provide a crude product which was purified by HRMS Calcd for (C24H20ClNO4Se) 502.0324 [M + H]+, found
column chromatography to provide the desired product.
Spectral characteristics of 14a–p. (S)-(1-Chloromethyl-5-
502.0322.
(S)-(1-(Chloromethyl)-5-hydroxy-1H-benzo[e]indol-3(2H)-yl)
hydroxy-1,2-dihydro-benzo[e]indol-3-yl)-(5-methoxy-benzo[b] (5-(2-(dimethylamino)ethoxy)benzo[b]selenophen-2-yl)metha-
selenophen-2-yl)-methanone (14a), yellow solid, 62%; IR none (14e), yellow solid, 52%; IR (KBr cm−1) 3050, 2910, 1630,
(KBr cm−1) 3292, 2340, 1623, 1593, 1398, 1332, 1225, 1152, 1550, 1430, 1380, 1360, 1210, 1080, 821, 680; 1H NMR
1
1136, 1058, 890, 861, 806, 756; H NMR (500.1 MHz, acetone- (500.1 MHz, acetone-d6) δ 9.42 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H),
d6) δ 9.40 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.21 (s, 1H), 7.97 8.19 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H),
(d, J = 8.8 Hz, 1H), 7.90 (brs, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.56 7.64 (d, J = 2.4 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.40 (t, J =
(d, J = 2.6 Hz, 2H), 7.41 (t, J = 7.7 Hz, 1H), 7.08 (dd, J = 8.8, 8.0 Hz, 1H), 7.17 (dd, J = 8.8, 3.0 Hz, 1H), 4.76 (t, J = 9.9 Hz,
2.5 Hz, 1H), 4.78 (t, J = 10.1 Hz, 1H), 4.65 (d, J = 10.8 Hz, 1H), 1H), 4.65 (dd, J = 10.9, 1.8 Hz, 1H), 4.58 (t, J = 5.0 Hz, 2H),
4.23 (t, J = 8.4 Hz, 1H), 4.03–4.02 (m, 1H), 3.88 (s, 3H), 3.83 4.25–4.21 (m, 1H), 4.04 (dd, J = 11.2, 3.1 Hz, 1H), 3.83 (dd, J =
(dd, J = 11.0, 8.6 Hz, 1H); 13C NMR (125.7 MHz, DMSO-d6) 11.1, 8.6 Hz, 1H), 3.69 (t, J = 5.0 Hz, 2H), 3.03 (s, 6H); 13C NMR
δ 162.2, 157.6, 154.1, 144.1, 142.9, 141.8, 133.4, 129.8, 127.3, (125.7 MHz, MeOH-d4) δ 165.0, 157.6, 155.9, 144.2, 142.6,
126.5, 123.2, 123.1, 122.8, 122.6, 122.3, 116.3, 115.4, 109.5, 136.9, 131.5, 131.2, 128.7, 127.6, 124.7, 124.6, 124.5, 123.8,
100.1, 55.5, 55.3, 47.5, 41.0; HRMS Calcd for (C23H18ClNO3Se) 123.5, 123.3, 117.8, 111.6, 101.2, 63.4, 57.7, 57.4, 47.5, 43.9
472.0219 [M + H]+, found 472.0220.
(2C), 43.3; HRMS Calcd for (C26H25ClN2O3Se) 527.0641 [M]+,
(S)-(1-Chloromethyl-5-hydroxy-1,2-dihydro-benzo[e]indol-3- found 527.0639.
yl)-(6-methoxy-benzo[b]selenophen-2-yl)-methanone (14b),
(S)-N-(2-(1-(Chloromethyl)-5-hydroxy-2,3-dihydro-1H-benzo
yellow solid, 58%; IR (KBr cm−1) 3304, 2938, 1626, 1592, 1516, [e]indole-3-carbonyl)benzo[b]selenophen-5-yl)acetamide (14f),
1390, 1341, 1230, 1153, 1047, 875, 860, 806, 753; 1H NMR yellow solid, 60%; IR (KBr cm−1) 3454, 3129, 2957, 2931, 2831,
(500.1 MHz, acetone-d6) δ 9.49 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 1648, 1621, 1589, 1519, 1465, 1391, 1334, 1224, 1157, 1025,
8.21 (s, 1H), 7.91 (d, J = 5.8 Hz, 1H), 7.88 (d, J = 4.7 Hz, 1H), 905, 857, 818, 717, 695; 1H NMR (500.1 MHz, acetone-d6)
7.86 (s, 1H), 7.67 (s, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.39 (t, J = δ 9.31 (s, 1H), 9.28 (s, 1H), 8.50 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H),
7.6 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 4.79 (t, J = 10.0 Hz, 1H), 8.22 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H),
4.67 (d, J = 10.8 Hz, 1H), 4.23 (t, J = 8.4 Hz, 1H), 4.05–4.03 (m, 7.57–7.52 (m, 2H), 7.40 (t, J = 8.0 Hz, 1H), 4.81 (t, J = 10.5 Hz,
1H), 3.91 (s, 3H), 3.84–3.80 (m, 1H); 13C NMR (125.7 MHz, 1H), 4.68 (d, J = 10.8 Hz, 1H), 4.24 (t, J = 8.0 Hz, 1H), 4.05 (dd,
DMSO-d6) δ 162.0, 158.4, 154.1, 143.7, 141.9, 140.2, 135.7, J = 11.2, 3.2 Hz, 1H), 3.84 (dd, J = 10.2, 8.5 Hz, 1H), 2.12 (s,
129.8 (2C), 128.0, 127.2, 123.1 (2C), 122.7, 122.2, 115.2, 3H); 13C NMR (125.7 MHz, acetone-d6) δ 169.0, 163.4, 155.1,
114.7, 108.6, 100.1, 55.5, 54.7, 47.4, 41.0; HRMS Calcd for 145.3, 143.6, 143.2, 138.3, 137.4, 131.3, 130.8, 128.3, 126.5,
(C23H18ClNO3Se) 472.0219 [M + H]+, found 472.0220.
124.3, 124.2, 123.6 (2C), 119.9, 117.8, 117.0, 101.5, 56.7, 47.6,
(S)-(1-(Chloromethyl)-5-hydroxy-1H-benzo[e]indol-3(2H)-yl)- 43.0, 24.3; HRMS Calcd for (C24H19ClN2O3Se) 499.0328
(7-methoxybenzo[b]selenophen-2-yl)methanone (14c), yellow [M + H]+, found 499.0326.
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(S)-N-[2-(1-Chloromethyl-5-hydroxy-1,2-dihydro-benzo[e]
1H), 7.41–7.39 (m, 2H), 5.83 (s, 1H), 4.76 (t, J = 9.3 Hz, 1H),
indole-3-carbonyl)-benzo[b]selenophen-5-yl]butyramide (14g), 4.64 (d, J = 10.8 Hz, 1H), 4.20 (m, 1H), 4.03 (d, J = 10.7 Hz, 1H),
yellow solid, 71%; IR (KBr cm−1) 3283, 2927, 2859, 1737, 1659, 3.82 (t, J = 9.7 Hz, 1H), 3.23 (m, 2H), 1.50 (m, 2H), 1.37 (m,
1606, 1579, 1519, 1448, 1390, 1362, 1333, 1226, 1135, 1078, 2H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (125.7 MHz, DMSO-d6)
1
856, 738, 690; H NMR (500.1 MHz, acetone-d6) δ 9.38 (s, 1H), δ 162.2, 155.3, 154.1, 143.4, 142.4, 141.8, 138.4, 133.7, 130.1,
9.30 (s, 1H), 8.54 (s, 1H), 8.26–8.24 (m, 2H), 7.98 (d, J = 8.6 Hz, 129.8, 127.3, 125.6, 123.2, 123.1, 122.8, 122.2, 118.2, 115.3,
1H), 7.90 (brs, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.57–7.53 (m, 2H), 115.1, 100.1, 55.5, 47.5, 40.9, 38.6, 31.8, 19.4, 13.6; HRMS
7.40 (t, J = 7.8 Hz, 1H), 4.82 (t, J = 9.6 Hz, 1H), 4.68 (d, J = 11.1 Calcd for (C27H26ClN3O3Se) 556.0906 [M
Hz, 1H), 4.24 (m, 1H), 4.05 (d, J = 10.9 Hz, 1H), 3.84 (t, J = 10.5 556.0905.
+
H]+, found
Hz, 1H), 2.37 (t, J = 7.3 Hz, 2H), 1.72 (q, J = 7.4 Hz, 2H), 0.97 (t,
(S)-1-(2-(1-(Chloromethyl)-5-hydroxy-2,3-dihydro-1H-benzo
J = 7.3 Hz, 3H); 13C NMR (125.7 MHz, acetone-d6) δ 172.0, [e]indole-3-carbonyl)benzo[b]selenophen-5-yl)-3-(4-fluorophenyl)
163.4, 155.1, 145.2, 143.6, 143.1, 138.2, 137.3, 131.2, 130.8, urea (14k), pale yellow solid, 51%; IR (KBr cm−1) 3285, 3068,
128.3, 126.4, 124.2 (2C), 123.6, 123.5, 119.9, 117.9, 116.9, 2970, 1663, 1606, 1577, 1521, 1500, 1387, 1205, 1153, 1077,
101.5, 56.6, 47.6, 42.9, 39.6, 19.6, 14.0; HRMS Calcd for 831, 807, 760, 705, 668; 1H NMR (500.1 MHz, acetone-d6)
(C26H23ClN2O3Se) 527.0641 [M + H]+, found 527.0639.
δ 9.20 (s, 1H), 8.30 (s, 1H), 8.22 (s, 2H), 8.12 (d, J = 8.4 Hz, 1H),
(S)-N-(2-(1-(Chloromethyl)-5-hydroxy-2,3-dihydro-1H-benzo 8.09 (s, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.77–7.75 (m, 2H),
[e]indole-3-carbonyl)benzo[b]selenophen-5-yl)heaxanamide 7.47–7.41(m, 3H), 7.35 (dd, J = 8.7, 2.0 Hz, 1H), 7.28 (t, J =
(14h), yellow solid, 64%; IR (KBr cm−1) 3282, 2952, 2928, 2859, 7.6 Hz, 1H), 6.93 (t, J = 8.8 Hz, 2H), 4.68 (t, J = 9.9 Hz, 1H), 4.55
1737, 1660, 1606, 1578, 1519, 1448, 1380, 1218, 1153, 1045, (d, J = 10.6 Hz, 1H), 4.11 (t, J = 9.2 Hz, 1H), 3.92 (dd, J = 11.2,
1
878, 758, 712, 668; H NMR (500.1 MHz, DMSO-d6) δ 10.40 (s, 3.2 Hz, 1H), 3.71 (dd, J = 11.1, 8.5 Hz, 1H); 13C NMR
1H), 9.99 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 8.12 (d, J = 8.4 Hz, (125.7 MHz, DMSO-d6) δ 162.2, 158.3, 156.4, 154.2, 152.8,
1H), 8.00 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.82 (brs, 143.8, 142.5, 141.9, 137.5, 136.1, 134.7, 130.1, 129.9, 127.3,
1H), 7.52 (t, J = 7.7 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.37 (t, J = 125.9, 123.3, 123.2, 122.8, 122.3, 120.0, 119.9, 118.7, 115.9,
7.8 Hz, 1H), 4.76 (t, J = 10.1 Hz, 1H), 4.45 (d, J = 10.1 Hz, 1H), 115.3, 115.2, 100.2, 55.6, 47.5, 41.0; HRMS Calcd for
4.20 (m, 1H), 4.00 (dd, J = 11.1, 2.9 Hz, 1H), 3.89 (dd, J = 11.1, (C29H21ClFN3O3Se) 594.0499 [M + H]+, found 594.0501.
7.3 Hz, 1H), 2.34 (t, J = 7.4 Hz, 2H), 1.63 (t, J = 7.2 Hz, 2H),
(S)-(1-(Chloromethyl)-5-hydroxy-1H-benzo[e]indol-3(2H)-yl)
1.33–1.31 (m, 4H), 0.89 (t, J = 6.7 Hz, 3H); 13C NMR (selenopheno[2,3-b]pyridin-2-yl)methanone (14l), pale yellow
(125.7 MHz, acetone-d6) δ 172.2, 163.4, 155.1, 145.2, 143.6, solid, 80%; IR (KBr cm−1) 3102, 2975, 2942, 1693, 1634, 1521,
143.1, 138.3, 137.3, 131.3, 130.6, 128.3, 126.5, 124.3, 124.2, 1459, 1400, 1273, 1145, 878, 829, 763, 658; 1H NMR
123.6, 123.5, 119.9, 117.9, 117.0, 101.5, 56.7, 47.6, 43.0, 37.8, (500.1 MHz, acetone-d6) δ 9.36 (s, 1H), 8.62 (s, 1H), 8.35 (d, J =
32.2, 26.0, 23.1, 14.4; HRMS Calcd for (C28H27ClN2O3Se) 7.9 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 7.89 (d, J =
555.0954 [M + H]+, found 555.0952.
8.3 Hz, 2H), 7.57–7.54 (m, 1H), 7.50 (dd, J = 7.9, 4.6 Hz, 1H),
N,N′-(6-((2-((S)-1-(Chloromethyl)-5-hydroxy-2,3-dihydro-1H- 7.41 (t, J = 7.9 Hz, 1H), 4.78 (m, 1H), 4.66 (d, J = 10.7 Hz, 1H),
benzo[e]indole-3-carbonyl)benzo[b]selenophen-5-yl)amino)- 4.23 (m, 1H), 4.05 (d, J = 11.5 Hz, 1H), 3.87–3.77 (m, 1H); 13C
6-oxohexane-1,5-diyl)diacetamide (14i), yellow solid, 45%; NMR (125.7 MHz, CDCl3 + MeOH-d4) δ 165.4, 163.1, 155.0,
IR (KBr cm−1) 3258, 2937, 2864, 1736, 1690, 1616, 1579, 1500, 148.0, 143.2, 141.0, 136.2, 134.7, 130.0, 127.8, 127.3, 124.0,
1448, 1385, 1234, 1131, 878, 808, 760, 710, 668; 1H NMR 123.9, 123.4, 122.2, 120.6, 116.1, 100.0, 56.2, 46.0, 42.7; HRMS
(500.1 MHz, MeOH-d4) δ 8.31 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), Calcd for (C21H15ClN2O2Se) 443.0066 [M + H]+, found 443.0063.
8.01 (s, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.73–7.71 (m, 2H),
(S)-(1-(Chloromethyl)-5-hydroxy-1H-benzo[e]indol-3(2H)-yl)
7.51–7.47 (m, 2H), 7.36 (t, J = 7.8 Hz, 1H), 4.57 (d, J = 10.4 Hz, (thieno[3,2-b]thiophen-2-yl)methanone (14m), pale yellow
1H), 4.47–4.43 (m, 1H), 4.10–4.06 (m, 1H), 3.94 (dd, J = 11.3, solid, 54%; IR (KBr cm−1) 3079, 2971, 2881, 1708, 1667, 1629,
2.8 Hz, 1H), 3.60 (t, J = 9.4 Hz, 1H), 3.16 (t, J = 7.2 Hz, 3H), 2.02 1588, 1369, 1205, 1184, 1146, 1024, 824, 711, 682; 1H NMR
(s, 3H), 1.91–1.80 (m, 4H), 1.79–1.72 (m, 1H), 1.55 (t, J = (500.1 MHz, CDCl3) δ 8.39 (brs, 1H), 8.31 (d, J = 8.4 Hz, 1H),
7.1 Hz, 2H), 1.47–1.41 (m, 2H); 13C NMR (125.7 MHz, MeOH- 8.17 (s, 1H), 7.94 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.61 (d, J =
d4) δ 173.5, 173.3, 173.0, 165.0, 155.9, 143.6, 142.6, 139.3, 5.3 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.36
137.3, 131.6, 131.4, 130.8, 128.6, 126.8, 124.7, 124.6, 124.5, (d, J = 5.3 Hz, 1H), 4.73 (d, J = 10.7 Hz, 1H), 4.67–4.63 (m, 1H),
123.6, 121.2, 119.4, 117.7, 101.2, 57.4, 55.6, 47.5, 43.2, 40.2, 4.09–4.05 (m, 1H), 3.95 (dd, J = 11.4, 2.9 Hz, 1H), 3.47 (t, J =
32.9, 30.1, 24.3, 22.5, 22.4; HRMS Calcd for (C32H33ClN4O5Se) 10.9 Hz, 1H); 13C NMR (125.7 MHz, DMSO-d6) δ 160.7, 154.1,
669.1383 [M + H]+, found 669.1382.
142.0, 141.7, 140.8, 138.8, 132.2, 129.8, 127.3, 123.3, 123.2,
(S)-1-Butyl-3-(2-(1-(chloromethyl)-5-hydroxy-2,3-dihydro-1H- 123.1, 122.8, 122.2, 120.2, 115.2, 100.2, 55.4, 47.5, 41.1; HRMS
benzo[e]indole-3-carbonyl)benzo[b]selenophen-5-yl)urea (14j), Calcd for (C20H14ClNO2S2) 400.0233 [M + H]+, found 400.0232.
pale yellow solid; 58% IR (KBr cm−1) 3285, 2952, 2927, 2859,
(S)-(1-(Chloromethyl)-5-hydroxy-1H-benzo[e]indol-3(2H)-yl)
1704, 1669, 1652, 1606, 1578, 1516, 1448, 1390, 1369, 1226, (selenopheno[3,2-b]thiophen-5-yl)methanone (14n), pale
1
1153, 1104, 878, 856, 838, 759, 712, 669; H NMR (500.1 MHz, yellow solid, 72%; IR (KBr cm−1) 3075, 2971, 2881, 1657, 1629,
acetone-d6) δ 9.32 (s, 1H), 8.30 (s, 1H), 8.25 (d, J = 8.3 Hz, 1H), 1588, 1369, 1220, 1184, 1082, 1024, 825, 710, 681, 658; 1H
8.14 (s, 1H), 8.02 (s, 1H), 7.89–7.85 (m, 3H), 7.54 (t, J = 7.1 Hz, NMR (500.1 MHz, MeOH-d4) δ 8.24 (s, 1H), 8.20 (d, J = 8.1 Hz,
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1H), 7.78 (d, J = 7.7 Hz, 1H), 7.71 (brs, 2H), 7.52 (t, J = 7.1 Hz, Development Institute (KHIDI), and funded by the Ministry of
1H), 7.46 (brs, 1H), 7.37 (t, J = 7.1 Hz, 1H), 4.71–4.69 (m, 1H), Health & Welfare, Republic of Korea (HI14C3418). HRMS (ESI)
4.61 (d, J = 10.9 Hz, 1H), 4.14 (m, 1H), 3.98 (d, J = 11.4 Hz, 1H), and LCMS data were obtained using the facilities of the Korea
3.68 (t, J = 10.1 Hz, 1H); 13C NMR (125.7 MHz, DMSO-d6) Basic Science Institute.
δ 161.7, 154.1, 145.6, 142.0, 141.7, 140.2, 131.1, 129.8, 127.2,
125.4, 123.6, 123.1 (2C), 122.7, 122.2, 115.1, 100.2, 55.4, 47.5,
41.1; HRMS Calcd for (C20H14ClNO2SSe) 447.9677 [M + H]+,
found 447.9674.
Notes and references
(S)-(1-(Chloromethyl)-5-hydroxy-1H-benzo[e]indol-3(2H)-yl)
(selenopheno[3,2-b]furan-5-yl)methanone (14o), yellow solid,
54%; IR (KBr cm−1) 3075, 2971, 2881, 1667, 1629, 1588, 1571,
1471, 1369, 1200, 1194, 1146, 1024, 824, 710, 681, 658;
1H NMR (500.1 MHz, acetone-d6) δ 9.27 (s, 1H), 8.25 (d, J = 8.4
Hz, 1H), 8.19 (s, 1H), 7.95 (s, 1H), 7.89–7.87 (m, 2H), 7.56–7.53
(m, 1H), 7.42–7.40 (m, 1H), 7.06 (d, J = 1.8 Hz, 1H), 4.84 (dd,
J = 10.6, 9.1 Hz, 1H), 4.69 (dd, J = 10.7, 2.1 Hz, 1H), 4.27 (m,
1H), 4.06 (dd, J = 11.2, 3.2 Hz, 1H), 3.84 (dd, J = 11.2, 8.4 Hz,
1H); 13C NMR (125.7 MHz, DMSO-d6) δ 161.8, 157.3, 154.1,
148.3, 143.8, 142.1, 129.8, 127.3, 126.5, 123.2, 123.1, 122.8,
122.2, 116.8, 115.1, 110.0, 100.2, 55.3, 47.6, 41.1; HRMS Calcd
for (C20H14ClNO3Se) 431.9906 [M + H]+, found 431.9904.
(S)-(1-(Chloromethyl)-5-hydroxy-1H-benzo[e]indol-3(2H)-yl)
(4H-thieno[3,2-b]pyrrol-5-yl)methanone (14p), yellow solid,
70%; IR (KBr cm−1) 3269, 3028, 2942, 2428, 1720, 1651, 1568,
1498, 1456, 1405, 1319, 1247, 1063, 992, 812, 750, 680; 1H
NMR (500.1 MHz, acetone-d6) δ 10.52 (s, 1H), 9.17 (s, 1H), 8.22
(d, J = 8.5 Hz, 1H), 8.04 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.66 (s,
1H), 7.51 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 6.89 (s,
1H), 6.60 (s, 1H), 4.72 (t, J = 10.3 Hz, 1H), 4.66 (d, J = 10.5 Hz,
1H), 4.24 (m, 1H), 4.05 (dd, J = 10.9, 2.6 Hz, 1H), 3.77 (t, J =
10.5 Hz, 1H); 13C NMR (125.7 MHz, DMSO-d6) δ 159.1, 154.1,
142.6, 141.0, 130.0, 129.9, 128.6, 127.2, 123.5, 123.1, 122.9,
122.6, 122.0, 114.6, 111.9, 105.3, 100.4, 54.9, 47.6, 41.2; HRMS
Calcd for (C20H15ClN2O2S) 382.0543 [M]+, found 382.0541.
Spectral characterization of compounds (14s–t) is described
in ref. 31.
1 World Health Organization, mediacentre, http://www.who.
int/mediacentre/factsheets/fs297/en/, (accessed July 2016).
2 A. Mullard, Nat. Rev. Drug Discovery, 2013, 12, 329–332.
3 N. Diamantis and U. Banerji, Br. J. Cancer, 2016, 114, 362–
367.
4 R. Y. Zhao, H. K. Erickson, B. A. Leece, E. E. Reid,
V. S. Goldmacher, J. M. Lambert and R. V. J. Chari, J. Med.
Chem., 2012, 55, 766–782.
5 R. V. J. Chari, K. A. Jackel, L. A. Bourret, S. M. Derr,
B. M. Tadayoni, K. M. Mattocks, S. A. Shah, C. Liu,
W. A. Blättler and V. S. Goldmacher, Cancer Res., 1995, 55,
4079–4084.
6 S. C. Jeffrey, M. Y. Torgov, J. B. Andreyka, L. Boddington,
C. G. Cerveny, W. A. Denny, K. A. Gordon, D. Gustin,
J. Haugen, T. Kline, M. T. Nguyen and P. D. Senter, J. Med.
Chem., 2005, 48, 1344–1358.
7 D. H. Swenson, L. H. Li, L. H. Hurley, J. S. Rokem,
G. L. Petzold, B. D. Dayton, T. L. Wallace, A. H. Lin and
W. C. Krueger, Cancer Res., 1982, 42, 2821–2828.
8 M. Ichimura, T. Ogawa, K. Takahashi, E. Kobayashi,
I. Kawamoto, T. Yasuzawa, I. Takahashi and H. Nakano,
J. Antibiot., 1990, 43, 1037–1038.
9 Y. Igarashi, K. Futamata, T. Fujita, A. Sekine, H. Senda,
H. Naoki and T. Furumai, J. Antibiot., 2003, 56, 107–
113.
10 K. S. MacMillan, T. Nguyen, I. Hwang and D. L. Boger,
J. Am. Chem. Soc., 2009, 131, 1187–1194.
11 D. L. Boger, C. W. Boyce, R. M. Garbaccio and
J. A. Goldberg, Chem. Rev., 1997, 97, 787–828.
12 K. S. MacMillan and D. L. Boger, J. Med. Chem., 2009, 52,
5771–5780.
Cell growth inhibition assay
SK-OV-3 cells floated on McCoy’s 5A Medium, into which 10%
FBS and 1% P/S were added and inoculated into a 96-well plate
at a concentration of 3 × 104/100 µL per well, and cultured at
37 °C for 4 h, and then treated with100 µL of each compound,
so that a final concentration of 10 nM was attained. The cells
were cultured at 37 °C for 72 h. As a control, the cells were
treated with DMSO as a solvent of the compounds to attain a
final concentration of 0.1%. Each well was treated with 10 µL
of a WST-1 assay reagent and cultured at 37 °C for 2 h. Then,
the absorbance was measured with an automatic microplate
reader at 450 nm. A cell growth inhibition level was calculated
by {(A450control − A450compound)/A450control} × 100.
13 D. L. Boger and D. S. Johnson, Proc. Natl. Acad. Sci. U. S. A.,
1995, 92, 3642–3649.
14 V. L. Reynolds, I. J. Molineux, D. J. Kaplan, D. H. Swenson
and L. H. Hurley, Biochemistry, 1985, 24, 6228–6237.
15 C. S. Lee, D. Sun, R. Kizu and L. H. Hurley, Chem. Res.
Toxicol., 1991, 4, 203–213.
16 L. H. Hurley, D. R. Needham-VanDevanter and C. S. Lee,
Proc. Natl. Acad. Sci. U. S. A., 1987, 84, 6412–6416.
17 N. Amishiro, A. Okamoto, C. Murakata, T. Tamaoki,
M. Okabe and H. Saito, J. Med. Chem., 1999, 42, 2946–
2960.
18 D. L. Boger, J. Zhou and H. Cai, Bioorg. Med. Chem., 1996,
4, 859–867.
19 H. Zeng and G. F. Combs Jr., J. Nutr. Biochem., 2008, 19,
1–7.
Acknowledgements
This research was supported by a grant of the Korea Health 20 R. F. Schumacher, A. R. Rosario, A. C. G. Souza,
Technology R&D Project through the Korea Health Industry
P. H. Menezes and G. Zeni, Org. Lett., 2010, 12, 1952–1955.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2017

View Article Online
Organic & Biomolecular Chemistry
Paper
21 R. F. Schumacher, A. R. Rosario, A. C. G. Souza, C. I. Acker, 29 D. Boger, US pat, 20050026987, 2005.
C. W. Nogueria and G. Zeni, Bioorg. Med. Chem., 2011, 19, 30 Y. Wang, H. Yuan, W. Ye, S. C. Wright, H. Wang and
1418–1425. J. W. Larrick, J. Med. Chem., 2000, 43, 1541–1549.
22 E. A. Wilhelm, C. R. Jesse, C. F. Bortolatto, C. W. Nogueria 31 J. P. Parrish, D. B. Kastrinsky, F. Stauffer, M. P. Hedrick,
and L. Savegonago, Pharmacol., Biochem. Behav., 2009, 93,
419–425.
I. Hwang and D. L. Boger, Bioorg. Med. Chem., 2003, 11,
3815–3838.
23 S. H. Abdel-Hafez, Eur. J. Med. Chem., 2008, 43, 1971–1977.
24 L. Cappellaci, P. Franchetti, G. A. Sheikh, H. N. Jayram,
32 K. B. Sharpless and R. F. Lauer, J. Am. Chem. Soc., 1973, 95,
2697–2699.
V. V. Gurudutt, T. Sint, G. Perra, S. Poma, P. L. Colla and 33 R. Dubey, H. Lee, D.-H. Nam and D. Lim, Tetrahedron Lett.,
M. Grifantini, Nucleosides Nucleotides, 1997, 16, 1045–1048. 2011, 52, 6839–6842.
25 S. H. Juang, C. C. Lung, P. C. Hsu, K. S. Hsu, Y. C. Li, 34 D. L. Boger, J. A. McKie, H. Cai, B. Cacciari and
P. C. Hong, H. S. Shiah, C. C. Kuo, C. W. Huang, P. G. Baraldi, J. Org. Chem., 1996, 61, 1710–1729.
Y. C. Wang, L. Huang, T. S. Chen, S. F. Chen, K. C. Fu, 35 J. P. Lajiness and D. L. Boger, J. Org. Chem., 2011, 76, 583–
C. L. Hsu, M. J. Lin, C. J. Chang, C. L. Ashendel, 587.
T. C. Chan, K. M. Chou and J. Y. Chang, Mol. Cancer Ther., 36 A. Sato, L. McNulty, K. Cox, S. Kim, A. Scott, K. Daniell,
2007, 6, 193–202.
26 D. L. Boger, T. Ishizaki, P. A. Kitos and O. Suntornwat,
J. Org. Chem., 1990, 55, 5823–5832.
K. Summerville, C. Price, S. Hudson, K. Kiakos,
J. A. Hartley, T. Asao and M. Lee, J. Med. Chem., 2005, 48,
3903–3918.
27 D. L. Boger, W. Yun, N. Han and D. S. Johnson, Bioorg. 37 D. L. Boger and W. Yun, J. Am. Chem. Soc., 1994, 116, 7996–
Med. Chem., 1995, 3, 611–621. 8006.
28 D. L. Boger, W. Yun and N. Han, Bioorg. Med. Chem., 1995, 38 D. Lim, D. H. Nam, R. Dubey and H. Lee, US pat,
3, 1429–1453.
20140213790, 2014.
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