Novel selenium-containing acenaphtho[1,2-b]pyrrole derivatives: Synthesis and bioactivity

Article abstract of DOI:10.1080/10426507.2015.1072187

Seven novel selenium-containing acenaphtho[1,2-b]pyrrole derivatives were designed and synthesized and their cytotoxic effects were evaluated by the MTT tetrazolium dye assay. Two compounds presented good anticancer activities.

Full text of DOI:10.1080/10426507.2015.1072187

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Novel selenium-containing acenaphtho[1,2-
b]pyrrole derivatives: Synthesis and bioactivity
Jisong Wang, Fuli Yang, Liang Zheng, Gang Ren, Jiude Qi, Zhijun Wang & Liwei
Zhao
To cite this article: Jisong Wang, Fuli Yang, Liang Zheng, Gang Ren, Jiude Qi, Zhijun Wang &
Liwei Zhao (2016) Novel selenium-containing acenaphtho[1,2-b]pyrrole derivatives: Synthesis
and bioactivity, Phosphorus, Sulfur, and Silicon and the Related Elements, 191:5, 715-718, DOI:
10.1080/10426507.2015.1072187
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1072187
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Date: 07 May 2016, At: 01:32

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
, VOL. , NO. , –
http://dx.doi.org/./..
Novel selenium-containing acenaphtho[,-b]pyrrole derivatives: Synthesis and
bioactivity
Jisong Wanga, Fuli Yanga, Liang Zhengb, Gang Rena, Jiude Qia, Zhijun Wangc, and Liwei Zhaoc
aDepartment of Oncology, Laiwu City People’s Hospital, Shandong, P. R. China; bDepartment of Respiration, Laiwu City People’s Hospital, Shandong,
P. R. China; cShandong Wego Pharmaceutical Co. Limited, Shandong, P. R. China
ABSTRACT
ARTICLE HISTORY
Received  April 
Accepted  July 
Seven novel selenium-containing acenaphtho[1,2-b]pyrrole derivatives were designed and synthesized and
their cytotoxic effects were evaluated by the MTT tetrazolium dye assay. Two compounds presented good
anticancer activities.
KEYWORDS
Selenium;
acenaphtho[,-b]pyrrole;
cytotoxicity; cancer
GRAPHICAL ABSTRACT
replacement of oxygen or sulfur atoms in known bioactive com-
pounds with selenium, is promising. Several reports9–12 and our
research13 have indicated that selenium-containing compounds
had higher activity than their sulfur analogues.
Herein we prepared the selenium analogue 4a of compound
1a after the successful bioisosteric exchange of thiomorpholine
to selenomorpholine; other derivatives 4b–g were synthesized
to improve anticancer activity or selectivity (Figure 2).
Introduction
Apoptosis is a physiological cell-death process, and plays
an important role during the development and mainte-
nance of tissue homeostasis. Apoptosis induction is arguably
the most potent defense against cancer. Recently, 8-Oxo-
8H-acenaphtho[1,2-b] pyrrolecarbonitrile derivative 1a1 was
synthesized, which showed high antitumor properties. Later
several derivatives2,3 were designed and synthesized, such as
compound 24 exhibited nanomolar IC50 against diverse cancer
cell lines through the inhibition of anti-apoptotic protein Bcl-
2/Mcl-1, and compound 35 was a potent and selective inhibitor
of tyrosine kinase fibroblast growth factor receptor 1 (FGRI1)
(Figure 1).
Interest in selenium compounds, especially organoselenium
compounds, in cancer prevention and treatment is a fascinating
field. These compounds have been proven as potent anticarcino-
genic agents in different models, such as spontaneous, chemi-
cally induced, transplanted tumors or in culture.6–8 The applica-
tion of organoselenium compounds, particularly the bioisosteric
Results and discussion
Synthesis
The intermediates 8-Oxo-8H-acenaphtho[1,2-b]pyrrol-9-
carbonitrile 714 or its derivates 2 and corresponding amines
815,16 were prepared according to published procedures.
Products 4 were prepared in dry CH3CN; all reactions were
monitored by thin-layer chromatography (Scheme 1). The
solvent was removed under reduced pressure and the residue
CONTACT Liwei Zhao
pauling_zlw@.com
Shandong Wego Pharmaceutical Co., Limited, Xingshan Road , Weihai, Shandong, P. R. China.
Supplemental data for this article can be accessed on the publisher’s website at http://dx.doi.org/./..
© Shandong Wego Pharmaceutical Co., Limited

716
J. WANG ET AL.
Figure . Structural formulas of -Oxo-H-acenaphtho[,-b] pyrrolecarbonitrile derivatives 1–3.
was subjected to column chromatography on silica gel. Products than its sulfur analogue 1a, and compound 4d presented good
were separated with CH2Cl2/EtOH 50:1 (v/v) as a dark purple cytotoxic activity against K562 and MCF-7 cell lines.
powder.
Experimental
Cytotoxic evaluation in vitro
Synthesis
The in vitro antitumor activities of the target com-
All chemical reagents and solvents were purchased from com-
mercial sources and used without further purification. Thin
layer chromatography (TLC) was performed on silica gel plate.
Column chromatography was performed using silica gel 300–
400 mesh. 1H NMR was obtained with a Bruker AV-400 spec-
trometer with chemical shifts reported as ppm (in dimethyl
sulfoxide (DMSO), tetramethylsilane (TMS) as internal stan-
dard). IR spectra were obtained using a Perkin–Elmer 2000
FT-IR instrument. High-resolution mass spectra (HRMS) were
obtained on an HPLC-Q-Tof MS (micro) spectrometer. Melt-
ing points were determined using a Büchi melting point B-540
apparatus, and were uncorrected.
pounds were evaluated by examining their cytotoxic
effects using the MTT tetrazolium dye assay against Hela
(human cervical carcinoma cell line), HCT116 (human
colon cancer cell line), K562 (chronic myelogenous
leukemia cell line), A549 (human lung cancer cell line),
and MCF-7 (human Caucasian breast adenocarcinoma
cell line). The IC50 values representing the drug concen-
tration (μM) required to inhibit cell growth by 50% are
summarized in Table S1 (available online in Supplemental
Materials).
The selenium analogue 4a showed better cytotoxicity than
1a, especially against MCF-7 cell lines. But the functional group
modification of esters to nitrile was not successful. Interest-
ingly, among compounds containing 2-aryl-selanyl-ethylamino
group, only 4d presented bioactivity against K562 and MCF-7
cell lines, and the IC50 value was 12.4 μM and 6.2 μM respec-
tively.
Characterization
8-oxo-3-selenomorpholino-8H-acenaphtho[1,2-b]pyrrole-9-
carbonitrile (4a)
Conclusions
Herein we prepared seven novel seleninm-containing
acenaphtho[1,2-b]pyrrole derivatives, and evaluated their
cytotoxic effects. Compound 4a had better cytotoxic effects
1
Yield 41%, dark purple powder, mp > 300°C. H NMR
(400 MHz, DMSO-d6): δ = 8.68–8.65 (m, 2H), 8.17 (d, 1H, J
= 8.8 Hz), 7.97 (t, 1H, J = 7.9 Hz), 7.43 (d, 1H, J = 8.8 Hz),
4.07 (t, 4H, J = 4.2 Hz, N(CH2CH2)2Se), 3.02 (t, 4H, J =
4.2 Hz, N(CH2CH2)2Se) ppm; HRMS (EI) m/z [M]+ calcd for
C19H13N3O80Se 379.0224, found 379.0234; IR (KBr): ν 2219,
1624, 1572, 1499 cm−1
Methyl
b]pyrrole-9-carboxylate (4b)
.
8-oxo-3-selenomorpholino-8H-acenaphtho[1,2-
Figure . Selenium bioisosteric exchange and modification of sulfur.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
717
Scheme . Synthesis of 4a–g.
8-oxo-3-((2-(phenylselanyl)ethyl)amino)-8H-
acenaphtho[1,2-b]pyrrole-9-carbonitrile (4d)
Yield 32%, dark purple powder, mp: 238.2–237.6°C. 1H NMR
(400 MHz, DMSO-d6): δ = 9.04 (d, 1H, J = 8.3 Hz), 8.79 (d, 1H,
J = 7.4 Hz), 8.52 (d, 1H, J = 7.3 Hz), 7.75 (t, 1H, J = 7.8 Hz), 7.23
(d, 1H, J = 8.3 Hz), 3.87–3.84(m, 4H), 3.20 (s, 3H), 3.05–3.03 (m,
4H) ppm; HRMS (EI) m/z [M+H]+ calcd for C20H17N2O380Se
413.0404, found 413.0406; IR(KBr): ν 2916, 1786,1785, 1653,
1
Yield 27%, dark purple powder, mp > 300°C, H NMR
(400 MHz, DMSO-d6): δ = 9.64 (s, 1H), 8.85 (d, 1H, J = 7.9 Hz),
8.65 (d, 1H, J = 7.4 Hz), 8.01 (d, 1H, J = 9.1 Hz), 7.93 (t, 1H, J
= 7.9 Hz), 7.53 (dd, 2H, J1 = 1.1 Hz, J2 = 8.1 Hz), 7.26–7.17(m,
3H), 7.02 (d, 1H, J = 9.1 Hz), 3.92 (t, 2H, J = 6.9 Hz), 3.36–3.35
(m, 2H) ppm; HRMS (EI) m/z [M]+ calcd for C23H15N3O80Se
429.0380, found 429.0425; IR(KBr): ν 3284, 2217, 1619, 1562,
1607, 1511 cm−1
.
Ethyl 8-oxo-3-selenomorpholino-8H-acenaphtho[1,2-b]py-
rrole-9-carboxylate (4c)
1529 cm−1
.
8-oxo-3-((2-(p-tolylselanyl)ethyl)amino)-8H-
acenaphtho[1,2-b]pyrrole-9-carbonitrile (4e)
Yield 33%, dark purple powder, mp: 245.2–246.9°C, 1H NMR
(400 MHz, DMSO-d6): δ = 9.03 (d, 1H, J = 8.3 Hz), 8.77 (d, 1H,
J = 7.4 Hz), 8.46 (d, 1H, J = 8.2 Hz), 7.82 (t, 1H, J = 7.8 Hz),
7.22 (d, 1H, J = 8.3 Hz), 3.84 (m, 4H), 3.76 (q, 2H, J = 7.1 Hz),
3.04 (m, 4H), 1.31 (t, 3H, J = 7.2 Hz) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 178.18, 169.20, 166.97, 165.48, 160.02, 144.57,
142.51, 135.34, 132.31, 132.15, 131.13, 127.66, 126.66, 116.34,
115.45, 56.67, 32.86, 18.16, 13.63 ppm; HRMS (EI) m/z [M]+
calcd for C21H18N2O380Se 426.0483, found 426.0485; IR: ν 2922,
1816,1779, 1658, 1627, 1501 cm−1
.

718
J. WANG ET AL.
Yield 31%, dark purple powder, mp > 300°C,1H NMR
7.9 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.18 (d, 2H, J = 8.3 Hz), 7.01 (d,
1H, J = 9.1 Hz), 3.92–3.94 (m, 2H), 3.39 (t, 2H, J = 6.8 Hz) ppm;
HRMS (EI) m/z [M]+ calcd for C24H14F3N3O280Se 513.0203,
(400 MHz, DMSO-d6): δ = 9.62 (s, 1H), 8.82 (d, 1H, J = 8.0 Hz),
8.64 (d, 1H, J = 7.6 Hz), 7.98 (d, 1H, J = 9.0 Hz), 7.92 (t, 1H, J =
7.9 Hz), 7.39 (d, 2H, J = 8.0 Hz), 7.00–6.97 (m, 3H), 3.90 (s, br,
2H), 3.31–3.28 (m, 2H), 2.15 (s, 3H) ppm; HRMS (EI) m/z [M]+
calcd for C24H17N3O80Se 443.0537, found 443.0541; IR(KBr): ν
found 513.0208; IR(KBr): ν 3317, 2258, 1637, 1526 cm−1
.
Evaluation of in vitro cell proliferation by MTT colorimetric
assay
3328, 2217, 1629, 1580, 1545 cm−1
.
3-((2-((4-methoxyphenyl)selanyl)ethyl)amino)-8-oxo-8H-
Growth inhibitory effects on the cell lines (Hela, HCT116, K562,
A549, and MCF-7) were measured by using MTT assay.
acenaphtho[1,2-b]pyrrole-9-carbonitrile (4f)
Acknowledgment
The authors would like to thank Professor Zhong Li, from East China Uni-
versity of Science and Technology, for his help and valuable suggestions.
Funding
This work was financially supported by the Shandong Wego Pharmaceutical
Co. Limited.
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(400 MHz, DMSO-d6): δ = 9.62 (s, 1H), 8.82 (d, 1H, J = 8.0 Hz),
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Yield 35%, dark purple powder, mp > 300°C, H NMR
(400 MHz, DMSO-d6): δ = 9.61 (s, 1H), 8.82 (d, 1H, J = 8.1 Hz),
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