Synthesis and Anticancer Activity of 5-(1,2-Diselenolan-3-Yl)pentanoic Acid and its Derivatives

Article abstract of DOI:10.1080/10426507.2013.765425

A green and high-yielding synthetic route for the preparation of 5-(1,2-diselenolan-3-yl)pentanoic acid (SeA) was reported. Some SeA derivatives, N′-substituted benzylidene-5-(1,2-diselenolan-3-yl)pentanehydrazide, were prepared, and they were screened for their anticancer activity against human breast MCF-7, leukemia HL-60, cervixuterus Hela, and placental villus Bewo cancer cell lines. The minimum inhibitory concentrations (MICs) of the synthetic compounds showed moderate anticancer activity at low concentrations (0.5-5 μg/mL).

Full text of DOI:10.1080/10426507.2013.765425

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Synthesis and Anticancer Activity of 5-
(1,2-Diselenolan-3-Yl)pentanoic Acid and
its Derivatives
Feng Xu a , Zhen-Zhen Yang a & Shi-Jie Zhang b
a Biopharmaceutical Research and Development Centre , Taizhou
Vocational & Technical College , Taizhou , 318000 , P. R. China
b Graduate School , Zhejiang Chinese Medical University ,
Hangzhou , 310053 , P. R. China
Accepted author version posted online: 25 Feb 2013.Published
online: 06 Sep 2013.
To cite this article: Feng Xu , Zhen-Zhen Yang & Shi-Jie Zhang (2013) Synthesis and Anticancer
Activity of 5-(1,2-Diselenolan-3-Yl)pentanoic Acid and its Derivatives, Phosphorus, Sulfur, and Silicon
and the Related Elements, 188:10, 1312-1319, DOI: 10.1080/10426507.2013.765425
To link to this article: http://dx.doi.org/10.1080/10426507.2013.765425
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Phosphorus, Sulfur, and Silicon, 188:1312–1319, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.765425
SYNTHESIS AND ANTICANCER ACTIVITY
OF 5-(1,2-DISELENOLAN-3-YL)PENTANOIC
ACID AND ITS DERIVATIVES
Feng Xu,1 Zhen-Zhen Yang,1 and Shi-Jie Zhang2
1Biopharmaceutical Research and Development Centre, Taizhou Vocational &
Technical College, Taizhou 318000, P. R. China
2Graduate School, Zhejiang Chinese Medical University, Hangzhou 310053,
P. R. China
GRAPHICAL ABSTRACT
Abstract A green and high-yielding synthetic route for the preparation of 5-(1,2-diselenolan-3-
yl)pentanoic acid (SeA) was reported. Some SeA derivatives, Nꢁ-substituted benzylidene-5-(1,2-
diselenolan-3-yl)pentanehydrazide, were prepared, and they were screened for their anticancer
activity against human breast MCF-7, leukemia HL-60, cervixuterus Hela, and placental
villus Bewo cancer cell lines. The minimum inhibitory concentrations (MICs) of the synthetic
compounds showed moderate anticancer activity at low concentrations (0.5–5 μg/mL).
Keywords 5-(1,2-Diselenolan-3-yl)pentanoic acid; anticancer; synthesis; minimum inhibitory
concentrations
INTRODUCTION
In recent years, compounds containing selenium have become a research focus due
to their physiological activities. For example, Ebselen, which is being tested in the stage of
Received 18 November 2012; accepted 8 January 2013.
The authors are indebted to the Taizhou Science and Technology Program of China (grant no. 111KY01)
for financial support.
Address correspondence to Feng Xu, Biopharmaceutical Research and Development Centre, Taizhou Voca-
tional & Technical College, Taizhou 318000, P. R. China. E-mail: xufeng901@126.com; xufeng@tzvtc.com
1312

SYNTHESIS AND ANTICANCER ACTIVITY
1313
phase III clinical trials, has been found to show anticancer,1 antioxidative,2 and antimicrobial
activity3; BXT-51072 has been reported to exhibit antioxidative4 and anti-inflammatory5
activity; selenocysteine, a common amino acid in living systems, has characteristic features
as the active sites of several enzymes,6,7 and as the 21st amino acid genetically coded in
the DNA.8
5-(1,2-Dithiolan-3-yl)pentanoic acid (LA) is a sulfur-containing coenzyme found in
a wide variety of organisms, which is often used as a drug with cancer-preventative,9 antiox-
idative,10 and radiation-resistant11 activities. 5-(1,2-diselenolan-3-yl)pentanoic acid (SeA)
is an analogue of LA, which has been found to show antihyperlipidemic,12 antioxidative,13
and antibacterial activities.14 So far, although some synthesis and biological activity studies
of SeA have been published, no report refers to the anticancer activity of SeA and its deriva-
tives. The traditional synthetic method of SeA reported in the literature15–17 is illustrated
as follows: first, ethyl 6,8-dichlorooctanoate is reacted with sodiumdiselenide or potassium
diselenide to produce ethyl 5-(1,2-diselenolan-3-yl)pentanoate (4), then 4 is hydrolyzed
with alkali to yield the corresponding SeA salt, which is finally acidified and extracted
with a lot of chloroform to get SeA (3). The above synthetic method has the disadvantages
of a low molar yield (<35%) and the consumption of a large number of organic solvents.
Therefore, it is necessary to explore a green and high-yielding synthetic route of SeA.
Herein, we present an improved synthetic method of SeA with water as a solvent and a
molar yield of 69%, on the basis of which, some SeA derivatives were synthesized and
their anticancer activities were evaluated.
RESULTS AND DISCUSSION
Chemistry
The reaction for synthesis of SeA (3) and its derivatives 6a–6o are shown in
Scheme 1. The improved synthetic route of SeA (3) was developed via three steps
(hydrolysis, selenylation, and acidification) with water as a solvent and a small amount
of ethanol as a co-solvent. SeA (3) was then esterified by acetylchloride and anhydrous
ethanol to yield ethyl 5-(1,2-diselenolan-3-yl)pentanoate (4), which was then converted to
5-(1,2-diselenolan-3-yl)pentanehydrazide (5) in the presence of hydrazine hydrate. When
benzaldehyde, 4-nitrobenzaldehyde, 2,4-dichlorobenzaldehyde, 4-fluorobenzaldehyde, 4-
chlorobenzaldehyde, salicylaldehyde, 4-methylbenzaldehyde, furfural, 2-chlorobenzal-
dehyde, vanillin, 3-hydroxy-4-methoxybenzaldehyde, 4-(dimethylamino)benzaldehyde,
4-methyloxybenzaldehyde, 4-hydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde were
added to 5, respectively, 6a–6o were obtained.
The yields of 6b–6g were high, and the reaction rate was rapid (5–10 h) at room
temperature. One reason could be the lack of conjugation between acylhydrazine, and
the aromatic ring, which has an electron-withdrawing group in intermediate compounds
of 6b–6g. On the other hand, the yields of 6h–6o were relatively low, and their reaction
rate was very slow even under refluxing temperature (10–20 h) because of an effective
conjugation they have with the aromatic ring, which has an electron-donating group in
intermediate compounds of 6h–6o.
In the infrared (IR) spectra of 6a–6o, the most characteristic absorptions are at
3182–3252 cm−1 (NH), 3023–3089 cm−1 ( CH), 1644–1679 cm−1 (C O), and 725–
1
789 cm−1 (C–Se). In the H NMR spectra, all compounds 6a–6o have stereoisomerism
because of the presence of C N bonds. Characteristic signals due to the ( CH) protons

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F. XU ET AL.
Scheme 1 Synthesis of SeA and its derivatives 6a–6o.
appeared at 8.88–11.59 ppm for E-isomers and 8.55–10.12 ppm for Z-isomers, respec-
tively, and signals due to the (NH) protons appeared at 7.95–9.89 ppm for Z-isomers and
7.67–9.85 ppm for E-isomers, respectively. The data for all compounds are given in the
1
Experimental section. Selected H NMR spectra (Figures S1–S5) can be found in the
Supplemental Materials available online.
Biological Screening
The synthesized compounds, 3 and 6a–6o, were tested in vitro for the anticancer
activity by the MTT method18 at three different concentrations (0.5 μg/mL, 5 μg/mL, and
50 μg/mL) against human breast MCF-7, leukemia HL-60, cervixuterus Hela, and placental
villus Bewo cancer cell lines, in comparison with cisplatin. Dimethyl sulfoxide (DMSO)
was used as solvent control. The results are reported in Table S1 (available online in the
Supplemental Materials).
Table S1 showed that all compounds exhibited a certain anticancer activity at a
concentration of 0.5–5 μg/mL for MCF-7, HL-60, Hela, and Bewo cell lines. Compounds
6a–6o showed more effective activity than compound 3. Compound 6h exhibits the highest
anticancer activity at a concentration of 50 μg/mL among all tested compounds.
CONCLUSION
A green and high-yielding process for the synthesis of 6,8-diselenooctanoic acid
(SeA) has been developed and its derivatives first reported. The anticancer activities of the
newly synthesized compounds exhibited moderate activities at low concentration. Com-
pound 6h possessed an activity equivalent to that of cisplatin, and is worthy of further
research. The introduction of (substituted benzylidene) hydrazide group improved the bio-
logical activities comparable with the starting material SeA.

SYNTHESIS AND ANTICANCER ACTIVITY
1315
EXPERIMENTAL
Melting points were determined using an XRC-1 apparatus and are uncorrected
(Beijing Technical Instrument Co.). Infrared spectra were recorded, from KBr discs of
1
solid materials, on a Nicolex FI-IR-170 instrument. The H NMR spectra were run on
a Bruker AC500 (500 MHz). Compounds were dissolved in CDCl3 or DMSO-d6, and
chemical shifts were referenced to tetramethylsilane (TMS). High-resolution mass spectra
(HRMS) were obtained on an Agilent 6210 TOF LC/MS. Mass spectra were obtained on
a Agilent 1260 lon Trap LC/MS 500 analysis system. Elemental analyses were performed
on a Thermo-Finnigan Flash EA 1112 instrument. Thin-layer chromatography (TLC) was
carried out on silica gel UV-254 plates.
Synthesis of 6,8-Diselenooctanoic Acid (3)
To a solution of ethyl 6,8-dichlorooctanoate (6.01 g, 25 mmol) in 95% ethanol (10 mL)
was added sodium hydroxide (2 g, 50 mmol) and water (38 mL). The mixture was heated
to 50◦C for 1.5 h and the aqueous disodium diselenide (prepared from 3.95 g selenium
powder19) was then added dropwise at 65◦C. After stirring for 2 h, the mixture was cooled
to 40◦C and activated carbon (8 g) was then added. After stirring for 0.5 h, the mixture was
filtered, and the ethanol was distilled off under reduced pressure (caution: the temperature
of the filtrate must not exceed 50◦C). Water (400 mL) was added to the residue and the
mixture was cooled to 0◦C. A solution of 10% hydrochloric acid was then added dropwise
till pH = 1, resulting in the formation of a solid product. The solid was filtered and washed
thoroughly with water.
6,8-Diselenooctanoic acid (3): Brown solid, yield 69%, mp 88–90◦C (Lit.
89–90.5◦C17). IR(KBr, cm−1)υ: 3024 (OH), 1697 (C O), 730 (C Se). 1H NMR(CDCl3):
δ10.68 (bs, 1H, OH), 3.92 (m, 1H, Se CH ), 3.34 (t, 2H, J = 6.0 Hz, Se CH2-),
2.53 (sext, 1H, J = 7.0 Hz, Se CH2 CH ), 2.39 (t, 2H, J = 7.0 Hz, CH2 CO ),
1.47–1.87 (m, 7H, (CH2)3 CH2 CO , Se CH2 CH ). APCI-MS (atmospheric
pressure chemical ionization-mass spectrometry): m/z (%):303.0 ([M+H]+, 43).
Synthesis of 6,8-Diselenooctanehydrazine (5)
A mixture of acetylchloride (1 mL, 14 mmol) and anhydrous ethanol (250 mL) was
stirred at room temperature for 2 h and 3 (10 g, 33 mmol) was then added. The mixture
was stirred at room temperature for 24–30 h, during which time the progress of the reaction
was monitored by TLC (ethyl acetate). To the solution was added dropwise 80% hydrazine
hydrate (10 g, 160 mmol) and the mixture was heated to reflux for 40–50 h, during which
time the progress of the reaction was also monitored by TLC (ethyl acetate). The solvent
was removed under reduced pressure and water (100 mL) was added to the residue. The
mixture was extracted with ethylacetate (3 × 30 mL), and the organic layer was combined
and washed with water (3 × 20 mL), then dried and filtered. The solvent was removed
under reduced pressure to give the crude product that was recrystallized from ethyl acetate
to give a pure product.
6,8-Diselenooctanehydrazine (5): Brown solid, yield 80%, mp 67–69◦C. IR(KBr,
1
cm−1)υ: 3420 (NH), 3302 (NH), 1650 (C O), 799 (C-Se). H NMR(CDCl3): δ8.95 (s,
1H, NH), 4.14 (brs, 2H, NH2), 3.90–3.95 (m, 1H, Se CH ), 3.31 (t, 2H, J = 5.7 Hz,
Se CH2 ), 2.84–2.90 (m, 1H, Se CH2 CH ), 2.01 (t, 2H, J = 7.4 Hz, CH2 CO ),

1316
F. XU ET AL.
1.78 (m, 1H, Se CH2 CH ), 1.28–1.64 (m, 6H, CH2 CH2 CH2 CH2 CO ).
APCI-MS: m/z (%):317.0 ([M+H]+, 2.5).
General Procedure for the Synthesis of SeA Derivatives 6a–6o
To a solution of 5 (0.95 g, 3 mmol) and anhydrous ethanol (30 mL) was added the
corresponding aromatic aldehyde (3 mmol). The mixture was stirred for 5–20 h at room
temperature for 6a–6g or at refluxing temperature for 6h–6o. After the starting material 5
was completely consumed (the reaction was monitored by TLC with methylene chloride
as the elution solvent), evaporation of the solvent left crude SeA derivatives 6a–6o. They
were purified by preparative TLC over silica gel PF254 (2 mm)(dichloromethane/cyclohex-
ane = 1/1).
Nꢁ-Benzylidene-5-(1,2-diselenolan-3-yl)pentanehydrazide (6a): Brown solid, yi-
eld 75%, mp 101–103◦C. IR(KBr, cm−1)υ: 3198 (NH), 3067 ( CH), 1657 (C O), 760
1
(C Se). H NMR(CDCl3): δ9.96 (s, 0.94H, N CH), 8.84 (s, 0.06H, N CH), 8.19 (s,
0.06H, NH), 7.85 (s, 0.94H, NH), 7.73 (m, 0.12H, ArH), 7.69 (m, 1.88H, ArH), 7.42 (m,
3H, ArH), 3.94–3.97 (m, 1H, Se CH ), 3.32 (t, 2H, J = 6.0 Hz, Se CH2 ), 2.98 (m,
1H, J = 6.0 Hz, Se CH2 CH ), 2.81 (t, 2H, J = 7.5 Hz, CH2 CO ), 1.54–1.92 (m,
7H, (CH2)3 CH2 CO , Se CH2 CH ). APCI-MS: m/z (%):405.0 ([M+H] +, 44).
Anal. calculated for C15H20N2OSe2: C, 44.79; H, 5.01; N, 6.96; O, 3.98; Found C, 44.85;
H, 5.00; N, 6.94; O, 3.97.
Nꢁ-(4-Nitrobenzylidene)-5-(1,2-Diselenolan-3-yl)pentanehydrazide (6b): Brown
solid, yield 86%, mp 159–161◦C. IR(KBr, cm−1)υ: 3182 (NH), 3089 ( CH), 1679
(C O), 749 (C-Se). 1H NMR(CDCl3): δ9.35 (s, 0.86H, N CH), 8.73 (s, 0.14H, N CH),
8.36 (s, 0.14H, NH), 7.90 (d, 2H, J = 8.9 Hz, ArH), 7.90 (d, 0.28H, J = 8.6 Hz, ArH), 7.84
(d, 1.72H, J = 8.8 Hz, ArH), 7.84 (s, 0.86H, NH), 3.93–3.99 (m, 1H, Se CH ), 3.34 (t,
2H, J = 6.1 Hz, Se CH2 ), 2.98–3.03 (m, 1H, J = 6.0 Hz, Se CH2 CH ), 2.82 (t, 2H,
J = 7.5 Hz, CH2 CO ), 1.54–1.95 (m, 7H, (CH2)3 CH2 CO , Se CH2 CH ).
APCI-MS: m/z (%):450.0 ([M+H] +, 78). Anal. calculated for C15H19N3O3Se2: C, 40.28;
H, 4.28; N, 9.40; O, 10.73; Found C, 40.30; H, 4.27; N, 9.43; O, 10.72.
Nꢁ-(2,4-Chlorobenzylidene)-5-(1,2-Diselenolan-3-yl)pentanehydrazide (6c): Br-
own solid, yield 84%, mp 135–136◦C. IR(KBr, cm−1)υ: 3182 (NH), 3083 ( CH),
1
1668 (C O), 774 (C Se). H NMR(CDCl3): δ9.19 (s, 0.87H, N CH), 8.83 (s, 0.13H,
N CH), 8.48 (s, 0.13H, NH), 8.11 (s, 0.87H, NH), 8.10 (d, 0.13H, J = 8.5 Hz, ArH), 7.92
(d, 0.87H, J = 8.5 Hz, ArH), 7.43 (s, 1H, ArH), 7.30 (d, 1H, J = 8.5 Hz, ArH), 3.92–3.97
(m, 1H, Se CH ), 3.33 (t, 2H, J = 6.0 Hz, Se CH2 ), 2.99 (m, 1H, J = 5.5 Hz,
Se CH2 CH ), 2.78 (t, 2H, J = 7.5 Hz, CH2 CO ), 1.53–1.90 (m, 7H, (CH2)3
CH2 CO , Se CH2 CH ). APCI-MS: m/z (%): 472.8 ([M+H] +, 67). Anal. calcu-
lated for C15H18Cl2N2OSe2: C, 38.24; H, 3.85; N, 5.95; O, 3.40; Found C, 38.29; H, 3.86;
N, 5.93; O, 3.39.
Nꢁ-(4-Fluorobenzylidene)-5-(1,2-Diselenolan-3-yl)- pentanehydrazide (6d): Br-
own solid, yield 88%, mp 108–110◦C. IR(KBr, cm−1)υ: 3198 (NH), 3067 ( CH), 1660
(C O), 789 (C Se). 1H NMR(CDCl3): δ10.00 (s, 0.92H, N CH), 8.85 (s, 0.08H, N CH),
8.17 (s, 0.08H, NH), 7.82 (s, 0.92H, NH), 7.67 (q, 2H, J1 = 8.5 Hz, J2 = 5.5 Hz, ArH), 7.11 (t,
2H, J = 8.5 Hz ArH), 3.92–3.98 (m, 1H, Se CH ), 3.32 (t, 2H, J = 6.0 Hz, Se CH2 ),
2.98 (m, 1H, J = 6.0 Hz, Se CH2 CH ), 2.79 (t, 2H, J = 7.5 Hz, CH2 CO ),
1.54–1.91 (m, 7H, (CH2)3 CH2 CO , Se CH2 CH ). APCI-MS: m/z (%):422.2

SYNTHESIS AND ANTICANCER ACTIVITY
1317
([M+H] +, 17). Anal. calculated for C15H19FN2OSe2: C, 42.87; H, 4.56; N, 6.67; O, 3.81;
Found C, 42.89; H, 4.56; N, 6.68; O, 3.80.
Nꢁ-(4-Chlorobenzylidene)-5-(1,2-diselenolan-3-yl)- pentanehydrazide (6e): Br-
own solid, yield 82%, mp 124–126◦C. IR(KBr, cm−1)υ: 3182 (NH), 3083 ( CH),
1
1671 (C O), 789 (C-Se). H NMR(CDCl3): δ9.73 (s, 0.91H, N CH), 8.75 (s, 0.09H,
N CH), 8.16 (s, 0.09H, NH), 7.78 (s, 0.91H, NH), 7.67 (d, 0.18H, J = 8.5 Hz, ArH), 7.61
(d, 1.82H, J = 8.5 Hz, ArH), 7.39 (d, 2H, J = 8.5 Hz ArH), 3.93–3.97 (m, 1H, Se CH ),
3.33 (t, 2H, J = 6.0 Hz, Se CH2 ), 2.98 (m, 1H, J = 6.0 Hz, Se CH2 CH ), 2.78 (t, 2H,
J = 7.5 Hz, CH2 CO ), 1.52–1.91 (m, 7H, (CH2)3 CH2 CO , Se CH2 CH ).
APCI-MS: m/z (%):438.9 ([M+H] +, 100). Anal. calculated for C15H19ClN2OSe2: C, 41.26;
H, 4.39; N, 6.41; O, 3.66; Found C, 41.24; H, 4.40; N, 6.43; O, 3.65.
Nꢁ-(furan-2-ylmethylene)-5-(1,2-diselenolan-3-yl)- pentanehydrazide (6f): Br-
own solid, yield 75%, mp 107–109◦C. IR(KBr, cm−1)υ: 3193 (NH), 3023 ( CH), 1660
1
(C O), 744 (C-Se). H NMR(CDCl3): δ10.52 (s, 0.07H, N CH), 10.33 (s, 0.26H,
N CH), 9.96 (s, 0.60H, N CH), 9.17 (s, 0.07H, N CH), 8.39 (s, 0.07H, NH), 7.73
(s, 0.60H, NH), 7.68 (s, 0.07H, NH), 7.61 (s, 0.26H, NH), 7.53 (s, 0.60H, OCH), 7.50 (s,
0.07H, OCH), 7.27 (s, 0.07H, OCH), 7.02 (s, 0.26H, OCH), 6.79 (d, 0.07H, J = 3.5 Hz,
O C CH), 6.75 (d, 0.07H, J = 3.5 Hz, O C CH), 6.71 (d, 0.60H, J = 3.5 Hz, O
C CH), 6.69 (d, 0.26H, J = 3.5 Hz, O C CH), 6.60 (q, 0.07H, J = 2.0 Hz, O CH CH),
6.55 (q, 0.26H, J = 2.0 Hz, O CH CH), 6.50 (q, 0.67H, J = 2.0 Hz, O CH CH),
3.92–3.96 (m, 1H, Se CH ), 3.32 (t, 2H, J = 6.0 Hz, Se CH2 ), 2.99 (m, 1H, J =
6.0 Hz, Se CH2 CH ), 2.75 (t, 2H, J = 7.5 Hz, CH2 CO ), 1.50–1.92 (m, 7H,
(CH2)3 CH2 CO , Se CH2 CH ). APCI-MS: m/z (%):395.0 ([M+H] +, 100).
Anal. calculated for C13H18N2O2Se2: C, 39.81; H, 4.63; N, 7.14; O, 8.16; Found C, C,
39.88; H, 4.62; N, 7.16; O, 8.14.
Nꢁ-(2-Chlorobenzylidene)-5-(1,2-diselenolan-3-yl)- pentanehydrazide (6g): Br-
own oil, yield 79%. IR(KBr, cm−1)υ: 3193 (NH), 3045 ( CH), 1655 (C O), 756 (C Se).
1H NMR(CDCl3): δ9.87 (s, 0.90H, N CH), 9.58 (s, 0.10H, N CH), 8.54 (s, 0.10H,
NH), 8.25 (s, 0.90H, NH), 7.96–7.98 (m, 1H, ArH), 7.31–7.40 (m, 3H, ArH), 3.91–3.96
(m, 1H, Se CH ), 3.31 (t, 2H, J = 6.0 Hz, Se CH2 ), 2.98 (m, 1H, J = 5.0 Hz,
Se CH2 CH ), 2.78 (t, 2H, J = 7.5 Hz, CH2 CO ), 1.52–1.89 (m, 7H, (CH2)3
CH2 CO , Se CH2 CH ). HRMS(APCI): Calculatedfor C15H19ClN2OSe2 (M+H):
438.9595; found 438.9592.
Nꢁ-(2-Hydroxybenzylidene)-5-(1,2-diselenolan-3-yl)- pentanehydrazide (6h): Br-
own solid, yield 51%, mp 126–128◦C. IR(KBr, cm−1)υ: 3182 (NH), 3067 ( CH),
1663 (C O), 746 (C Se). 1H NMR(DMSO-d6): δ11.59 (s, 0.64H, N CH), 11.21
(s, 0.36H, OH), 11.19 (s, 0.64H, OH), 10.12 (s, 0.36H, N CH), 8.35 (s, 0.64H,
NH), 8.34 (s, 0.36H, NH), 7.62 (d, 0.36H, J = 7.5 Hz, ArH), 7.49 (d, 0.64H,
J = 7.5 Hz, ArH), 7.28 (t, 0.64H, J = 7.5 Hz, ArH), 7.23 (t, 0.36H, J = 7.5 Hz,
ArH), 6.85–6.92 (m, 2H, ArH), 3.93–3.99 (m, 1H, Se CH ), 3.32 (t, 2H, J = 6.0 Hz,
Se CH2 ), 2.87 (m, 1H, J = 5.0 Hz, Se CH2 CH ), 2.59 (t, 0.72H, J = 7.5 Hz,
CH2 CO ), 2.33 (t, 1.28H, J = 7.5 Hz, CH2 CO ), 1.36–1.85 (m, 7H, (CH2)3
CH2 CO , Se CH2 CH ). APCI-MS: m/z (%). 420.9 ([M+H] +, 50). Anal.
calculated for C15H20N2O2Se2: C, 43.07; H, 4.82; N, 6.70; O, 7.65; Found C, 43.09; H,
4.81; N, 6.68; O, 7.64.
Nꢁ-(4-Methylbenzylidene)-5-(1,2-diselenolan-3-yl)- pentanehydrazide (6i): Br-
own solid, yield 68%, mp 100–102◦C. IR(KBr, cm−1)υ: 3182 (NH), 3083 ( CH),
1
1665 (C O), 774 (C-Se). H NMR(CDCl3): δ9.21 (s, 0.90H, N CH), 8.58 (s, 0.10H,
N CH), 8.10 (s, 0.10H, NH), 7.74 (s, 0.90H, NH), 7.63 (d, 0.2H, J = 8.0 Hz, ArH),7.56

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F. XU ET AL.
(d, 1.8H, J = 8.0 Hz, ArH), 7.23 (d, 2H, J = 8.0 Hz, ArH), 3.93–3.98 (m, 1H, Se CH ),
3.32 (t, 2H, J = 6.0 Hz, Se CH2 ), 2.98 (m, 1H, J = 5.0 Hz, Se CH2 CH ), 2.79
(t, 2H, J = 7.0 Hz, CH2 CO ), 2.40 (s, 3H, CH3), 1.53–1.92 (m, 7H, (CH2)3
CH2 CO , Se CH2 CH ). APCI-MS: m/z (%):419.0 ([M+H] +, 98). Anal. calcu-
lated for C16H22N2OSe2: C, 46.16; H, 5.33; N, 6.73; O, 3.84; Found C, 46.33; H, 5.32; N,
6.75; O, 3.85.
Nꢁ-(3-Methoxy-4-hydroxybenzylidene)-5-(1,2-diselenolan-3-yl)-pentanehydra-
zide (6j): Brown solid, yield 48%, mp 136–138◦C. IR(KBr, cm−1)υ: 3416 (OH), 3253
(NH), 3078 ( CH), 1655 (C O), 748 (C-Se). 1H NMR(CDCl3): δ8.88 (s, 0.82H, N CH),
8.55 (s, 0.18H, N CH), 8.01 (s, 0.18H, NH), 7.67 (s, 0.82H, NH), 7.52 (s, 0.18H, ArH),
7.26 (s, 0.82H, ArH), 7.11 (d, 0.82H, J = 8.0 Hz, ArH), 7.01 (d, 0.18H, J = 8.0 Hz, ArH),
6.95 (d, 0.82H, J = 8.0 Hz, ArH), 6.92 (d, 0.18H, J = 8.0 Hz, ArH), 5.89 (bs, 1H, OH),
3.93–3.99 (m, 1H, Se CH ), 3.98 (s, 3H, OCH3), 3.33 (t, 2H, J = 6.0 Hz, Se CH2 ),
2.98 (m, 1H, J = 5.0 Hz, Se CH2 CH ), 2.78 (t, 2H, J = 7.5 Hz, CH2 CO ),
1.53–1.93 (m, 7H, (CH2)3 CH2 CO , Se CH2 CH ). APCI-MS: m/z (%):450.9
([M+H] +, 26). Anal. calculated for C16H22N2O3Se2: C, 42.87; H, 4.95; N, 6.25; O, 10.71;
Found C, 42.84; H, 4.93; N, 6.25; O, 10.69;
Nꢁ-(3-Hydroxy-4-methoxybenzylidene)-5-(1,2-diselenolan-3-yl)- pentanehydr-
azide (6k): Brown oil, yield 45%, IR(KBr, cm−1)υ: 3384 (OH), 3193 (NH), 3045 ( CH),
1
1657 (C O), 761 (C Se). H NMR(CDCl3): δ9.35 (s, 0.91H, N CH), 8.72 (s, 0.09H,
N CH), 8.05 (s, 0.09H, NH), 7.69 (s, 0.91H, NH), 7.46 (s, 0.09H, ArH), 7.34 (s, 0.91H,
ArH), 7.22 (d, 0.09H, J = 8.4 Hz, ArH), 7.09 (d, 0.91H, J = 8.4 Hz, ArH), 6.87 (d,
0.91H, J = 8.0 Hz, ArH), 6.85 (d, 0.09H, J = 8.0 Hz, ArH), 5.87 (s, 0.09H, OH), 5.78
(s, 0.91H, OH), 3.92–3.98 (m, 1H, Se CH ), 3.95 (s, 3H, OMe), 3.32 (t, 2H, J =
6.2 Hz, Se CH2 ), 2.98 (m, 1H, J = 5.0 Hz, Se CH2 CH ), 2.77 (t, 2H, J = 7.5 Hz,
CH2 CO ), 1.51–1.91 (m, 7H, (CH2)3 CH2 CO , Se CH2 CH ). HRMS
(APCI): Calculated for C16H22N2O3Se2 (M+H): 451.0039; Found 451.0050.
Nꢁ-(4-(Dimethylamino)benzylidene)-5-(1,2-diselenolan-3-yl)pentanehydrazide
(6l): Brown oil, yield 42%, IR(KBr, cm−1)υ: 3198 (NH), 3040 ( CH), 1652 (C O), 735
(C-Se). 1H NMR(CDCl3): δ9.82 (s, 0.9H, N CH), 9.24 (s, 0.1H, N CH), 8.00 (s, 0.1H,
NH), 7.69 (s, 0.9H, NH), 7.58 (d, 0.2H, J = 8.9 Hz, ArH), 7.53 (d, 1.8H, J = 8.9 Hz,
ArH), 6.71 (d, 0.2H, J = 8.9 Hz, ArH), 6.64 (d, 1.8H, J = 8.9 Hz, ArH), 3.91–3.96 (m, 1H,
Se CH ), 3.30 (t, 2H, J = 6.4 Hz, Se CH2 ), 3.02 (s, 6H, 2CH3), 2.88–3.02 (m, 1H,
Se CH2 CH ), 2.76 (t, 2H, J = 7.6 Hz, CH2 CO ), 1.51–1.90 (m, 7H, (CH2)3
CH2 CO , Se CH2 CH ). HRMS (APCI): Calculated for C17H25N3OSe2 (M+H):
448.0406; Found 448.0415.
Nꢁ-(4-Methoxybenzylidene)-5-(1,2-diselenolan-3-yl)pentanehydrazide (6m): Br-
own oil, yield 48%, IR(KBr, cm−1)υ: 3193 (NH), 3034 ( CH), 1660 (C O), 772 (C Se).
1H NMR(CDCl3): δ10.13 (s, 0.92H, N CH), 9.12 (s, 0.08H, N CH), 8.10 (s, 0.08H, NH),
7.81 (s, 0.92H, NH), 7.65 (d, 0.16H, J = 8.8 Hz, ArH), 7.62 (d, 1.84H, J = 8.8 Hz, ArH),
6.94 (d, 1.84H, J = 8.8 Hz, ArH), 6.88 (d, 0.16H, J = 8.8 Hz, ArH), 3.94–3.96 (m, 1H,
Se CH ), 3.85 (s, 3H, OCH3), 3.30 (t, 2H, J = 6.3 Hz, Se CH2 ), 2.95–3.01 (m, 1H,
Se CH2 CH ), 2.74 (t, 2H, J = 7.6 Hz, CH2 CO ), 1.53–1.82 (m, 7H, (CH2)3
CH2 CO , Se CH2 CH ). HRMS (APCI): Calculated for C16H22N2O2Se2 (M+H):
435.0090; Found 435.0105.
Nꢁ-(4-Hydroxybenzylidene)-5-(1,2-diselenolan-3-yl)pentanehydrazide (6n): Bro-
wn solid, yield 42%, mp 127–129◦C. IR(KBr, cm−1)υ: 3285 (OH), 3209 (NH), 3056
( CH), 1644 (C O), 725 (C Se). 1H NMR(DMSO-d6): δ11.12 (s, 0.44H, N CH), 11.01
(s, 0.56H, N CH), 9.89 (s, 0.44H, OH), 9.85 (s, 0.56H, OH), 8.04 (s, 0.44H, NH), 7.87

SYNTHESIS AND ANTICANCER ACTIVITY
1319
(s, 0.56H, NH), 7.47–7.51 (m, 2H, J = 8.7 Hz, ArH), 6.81 (d, 2H, J = 8.7 Hz, ArH),
3.92–3.98 (m, 1H, Se CH ), 3.31 (t, 2H, J = 5.9 Hz, Se CH2 ), 2.85–2.91 (m, 1H,
Se CH2 CH ), 2.59 (t, 1.12H, J = 7.4 Hz, CH2 CO ),2.18 (t, 0.88H, J = 7.4 Hz,
CH2 CO ), 1.36–1.82 (m, 7H, (CH2)3 CH2 CO , Se CH2 CH ). APCI-MS:
m/z (%):420.9 ([M+H] +, 29). Anal. calculated for C15H20N2O2Se2: C, 43.07; H, 4.82; N,
6.70; O, 7.65; Found C, 43.10; H, 4.83; N, 6.69; O, 7.65.
Nꢁ-(3,4-Dihydroxybenzylidene)-5-(1,2-diselenolan-3-yl)pentanehydrazide (6o):
Brown oil, yield 35%. IR(KBr, cm−1)υ: 3372 (OH), 3215 (NH), 3051 ( CH), 1650
1
(C O), 760 (C Se). H NMR(DMSO-d6): δ11.09 (s, 0.46H, N CH), 11.01 (s, 0.54H,
N CH), 9.29 (brs, 2H, OH), 7.95 (s, 0.46H, NH), 7.79 (s, 0.54H, NH), 7.17 (s, 0.46H,
ArH), 7.11 (s, 0.54H, ArH), 6.72 (tt, 1H, J = 8.1 Hz, Ar) 6.75 (dd, 1H, J = 8.1 Hz, ArH),
3.92–3.97 (m, 1H, Se CH ), 3.31 (t, 2H, J = 5.8 Hz, Se CH2 ), 2.85–2.90 (m, 1H,
Se CH2 CH ), 2.59 (t, 1.08H, J = 7.3 Hz, CH2 CO ),2.16 (t, 0.92H, J = 7.3 Hz,
CH2 CO ), 1.35–1.82 (m, 7H, (CH2)3 CH2 CO , Se CH2 CH ). HRMS
(APCI): Calculated for C15H20N2O3Se2 (M+H): 436.9883; Found 436.9896.
Supplementary Data
Figures S1–S5 and Table S1 are available online in Supplemental Materials.
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