Concise syntheses and antitumor activities of a-hydroxy(mercapto)amide derivatives

Article abstract of DOI:10.14233/ajchem.2014.15894

A novel process for preparing a-hydroxy(mercapto)-N-[6-(3-phenylureido) hexyl]amide derivatives was described and three new compounds 8-10 were synthesized. The antitumor activities on Hut102, MCF7 and HepG2 of the compounds 7-10 were assayed. The results showed that the target compounds 7-10 exhibited some antitumor activities against tumor cell lines.

Full text of DOI:10.14233/ajchem.2014.15894

Asian Journal of Chemistry; Vol. 26, No. 11 (2014), 3219-3223
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.15894
Concise Syntheses and Antitumor Activities of α-Hydroxy(mercapto)amide Derivatives
*
Y.X. LI and Z. QIU
Chemistry and Chemical Engineering Department, Huaihua University, 612 Yingfeng Road, Huaihua 418008, P.R. China
*Corresponding author: E-mail: hhxyyxli@163.com
Received: 11 June 2013;
Accepted: 17 October 2013;
Published online: 25 May 2014;
AJC-15217
A novel process for preparing α-hydroxy(mercapto)-N-[6-(3-phenylureido)hexyl]amide derivatives was described and three new compounds
8-10 were synthesized. The antitumor activities on Hut102, MCF7 and HepG2 of the compounds 7-10 were assayed. The results showed
that the target compounds 7-10 exhibited some antitumor activities against tumor cell lines.
Keywords: Histone deacetylase inhibitors, α-Hydroxy(mercapto)amide, Drug design, Antitumor activity.
deacetylase inhibitors have become promising anticancer
agents in recent years. They have shown ability to block
angiogenesis and cell cycling, as well as initiate differentiation
and apoptosis5-6. At present, many of the histone deacetylases
inhibitors such as suberoylanilide hydroxamic acid (SAHA),
trichostatin A (TSA), Panobinostat (LBH 589) and MC 1568
have been reported (Fig. 1a) and the histone deacetylases
inhibitors have potent anticancer effects in vitro and in vivo7-8.
Among them, in 2006, Zolinza (SAHA, vorinostat) became
the first histone deacetylases inhibitor to acquire FDA approval
and is used for the management of the cutaneous manifestations
of T-cell lymphoma9. On the whole, the classic pharmacophore
INTRODUCTION
Histone acetylation and histone deacetylation are essential
for chromatin remodeling and regulation of gene transcription
in eukaryotic cells. Histone deacetylases and histone acetyl-
transferases are two classes of enzymes that catalyze the
deacetylation and acetylation of lysine residues located in the
NH2 terminal tails of core histones1,2. Perturbations of this
balance in the form of histone deacetylation are often observed
in human tumors3.Aberrant activation of histone deacetylases
results in the transcriptional repression of oncoprotein and is
linked to the malignant phenotypes of tumors4. Thus, Histone
O
O
O
a
b
H
N
OH
OH
N
H
Linker
N
H
O
N
SAHA
TSA
HN
O
Surface recognition
group
Zinc binding
group (ZBG)
HN OH
O
N
H
H
N
N
OH
F
O
LBH 589
MC 1568
c
S
O
O
S
S
O
N
N
N
H
N
H
SH
NCH-3 1
NCH-51
Fig. 1. Small molecule histone deacetylases inhibitors; (a) Selected examples of histone deacetylases inhibitors; (b) Pharmacophoric model of histone
deacetylases inhibitors; (c) Structures of NCH-31 and NCH-51

3220 Li et al.
Asian J. Chem.
for histone deacetylases inhibitors consists of three distinct
structural motifs: the zinc-binding group (enzyme binding), a
hydrophobic linker and a surface recognition group10,11 (Fig.
1b). Typically, the common zinc-binding group of histone
deacetylases inhibitors is the hydroxamate moiety. Study on
the structural modifications of the hydro-xamate zinc-binding
group of histone deacetylases inhibitors has recently attracted
extensive attention. Kozikowski and coworkers reveals that
mercaptoacetamide-based histone deacetylases inhibitors, in
which the hydroxamate moieties of SAHA enzyme binding
domain were replaced by mercaptomethyl amide, would probably
avoid the dose-dependent toxicity associated with the hydro-
xamate-based inhibitors12. Compounds containing a sulfydryl
or isobutyryl sulfydryl in enzyme binding domain were both
potent histone deacetylases inhibitors13 (Fig. 1c). To search
for novel antitumor hits, our research was initially based on
the structure of SAHA.According to the strategy of bioisosteric
replacement, the surface recongnition and enzyme binding
domain were modified with phenylureido and α-hydroxy-
(mercapto), respectively. Herein we wish to disclose our preli-
minary efforts on this subject.
spectrometer. Elemental analyses were performed on a Vario
EL III elemental analysis instrument. Melting points were
measured on a Buchi B-545 melting point apparatus and are
uncorrected. Purity of all compounds was checked by TLC on
precoated silica gel G plates (Kiesel gel 0.25 mm, 60G F254,
Qingdao, China).
Synthesis of α-hydroxy(mercapto)amides: The title
compounds were synthesized by a convenient five-steps proce-
dure as outlined in Scheme-I.
Preparation of tert-butyl 6-aminohexylcarbamate
(2)14,15: To a solution of hexane-1,6-diamine (60 g, 0.516 mol)
1 in CH2Cl2 (200 mL) was added (Boc)2O (22.5 g, 0.103 mol)
during 0.5 h at 0 °C, then the mixture was stirred at room
temperature for 5 h, extracted with CH2Cl2 (150 mL × 3), dried
with anhydrous magnesium sulfate, filtered off with suction.
The combined organic layer was concentrated on a rotary
evaporator to give colourless oil 2 in yield 96 % (21.5 g). The
product was used directly for next reaction without purification.
Preparation of tert-butyl 6-(3-phenylureido)hexyl-
carbamate (3)16,17: To a solution of intermediate 2 (0.5 g, 2.31
mmol) in CH2Cl2 (6 mL) was added isocyanatobenzene (0.33
g, 2.77 mmol) at 0 °C, then the mixture was stirred at room
temperature for 4 h, extracted with CH2Cl2 (50 mL × 3), dried
with anhydrous magnesium sulfate, filtered off with suction.
The combined organic layer was concentrated on a rotary
evaporator, purified by chromatography on silica using
petroleum ether/ethyl acetate (15:1, v/v) as eluent to give white
solid 3 in yield 95 % (0.73 g). m.p. 97-99 °C. 1H NMR (400
MHz, CDCl3) δ (ppm): 1.26 (s, 4H, CCCH2CH2CC), 1.36 (s,
9H, 3 × CH3), 1.41(s, 4H, CCH2CCCH2C), 2.88 (dd, J1 = 6.4
EXPERIMENTAL
Unless otherwise noted, reagents were purchased from
commercial suppliers and used without further purification,
as all solvents were redistilled before use. NMR spectra were
recorded on a Mercury-Plus 400 spectrometer in CDCl3 or
DMSO-d6 with TMS as the internal reference, the chemical
shifts were reported in δ ppm. MS spectra were determined
using a TraceMS 2000 or Waters 2Q4000 LC/MS organic mass
H
N
O
(Boc)2O
CH2Cl2
NH2
Ph NCO
CH2Cl2
H2N
H2N
O
1
2
O
O
O
H
HCl (gas)
AcOEt
N
O
NH2·HCl
N
H
N
H
N
H
N
H
O
3
4
R
O
CH2Cl2
Cl
Cl
O
R
H
N
H
N
NaSH
N
H
N
H
Cl
N
H
N
H
SH MeOH
O
O
5: R = H; 6: R = CH3
7: R = H; 8: R = CH3
1) AcONa
2) NaOH, H+
O
R
H
N
N
H
N
H
OH
O
9: R = H; 10: R = CH3
Scheme-I: Synthetic route of α-hydroxy(mercapto) amide derivatives

Vol. 26, No. 11 (2014)
Concise Syntheses and Antitumor Activities of α-Hydroxy(mercapto)amide Derivatives 3221
Hz, J2 = 10.6 Hz, 2H, N(CO)NCH2), 3.04 (dd, J1 = 6.4 Hz, J2
= 10.6 Hz, 2H, O(CO)NCH2), 6.08 (t, J = 5.6 Hz, 1H,
PhN(CO)NH), 6.76 (t, J = 5.6 Hz, 1H, O(CO)NH), 6.85-7.37
(m, 5H, PhH), 8.35 (s, 1H, PhNH); EI MS: m/z (%) 336 ([M + 1]+,
1), 335 (M+, 4), 279 (10), 206 (3), 143 (12), 119 (2), 93 (100).
Preparation of 1-(6-aminohexyl)-3-phenylurea hydro-
chloride (4)18: In a 250 mL three neck round bottom flask,
intermediate 3 (5.5 g, 0.016 mol) and ethyl acetate (150 mL)
were added. HCl (gas) was passed in reaction mixture at room
temperature, the mixture was stirred for 5 h, which was concen-
trated on a rotary evaporator to give white solid 4, yield 97 %
2H, CH2S), 6.10 (t, J = 5.4 Hz, 1H, PhN(CO)NH), 6.87-7.37
(m, 5H, PhH), 7.97 (t, J = 5.4 Hz, 1H, NH(CO)C), 8.37 (s,
1H, PhNH). 13C NMR (100 MHz, DMSO-d6) δ (ppm): 169.42,
155.20, 140.61, 128.62, 120.89, 117.51, 38.96, 38.79, 29.7,
29.0, 27.1, 26.1. LC MS calcd. 309.4, found 309.7 [M], 332.6
[M + Na]+. Anal. calcd. for C15H23N3O2S (%): C, 58.22; H,
7.49; N, 13.58. Found (%): C, 58.17; H, 7.32; N, 13.37.
Preparation of 2-mercapto-N-[6-(3-phenylureido)hexyl]-
propanamide (8): In the same way as compound 7, the target
compound 8 was synthesized. white solid, Yield: 69 %, m.p.
1
128-130 °C. H NMR (400 MHz, DMSO-d6) δ (ppm): 1.28
1
(4.35 g). m.p. 154-156 °C. H NMR (400 MHz, CDCl3) δ
(m, 4H, CCCH2CH2CC), 1.32 (d, J = 6.8 Hz, 3H, CH3), 1.41
(m, 4H, CCH2CCCH2C), 2.79 (d, J = 8.5 Hz, 1H, SH), 3.02
(m, 4H, CH2CCCCCH2), 3.41 (dd, J1 = 7.0 Hz, J2 = 8.5 Hz,
1H, SCH), 6.09 (t, J = 4.0 Hz, 1H, PhN(CO)NH), 6.85-7.38
(m, 5H, PhH), 7.91 (t, J = 5.1 Hz, 1H, NH(CO)C), 8.35 (s,
1H, PhNH); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 172.98,
155.74, 141.13, 129.13, 121.42, 118.11, 40.08, 39.17, 36.83,
30.26, 29.45, 26.60, 22.69; LC-MS calcd. for [C16H25N3O2S +
1]+, 324, found, 324.1. [2 × C16H25N3O2S + Na]+, 669, found,
669.3. Anal. calcd. for C16H25N3O2S: C, 59.41; H, 7.79; N,
12.99. Found: C, 59.37; H, 7.72; N, 13.07.
(ppm): 1.32 (s, 4H, CCCH2CH2CC), 1.41 (s, 2H, NCCH2),
1.55 (s, 2H, (CO)NCCH2), 2.77 (dd, J1 = 13.2 Hz, J2 = 6.8 Hz,
2H, NCH2), 3.06 (dd, J1 = 13.2 Hz, J2 = 6.8 Hz, 2H,
(CO)NCH2), 6.41 (t, J = 5.2 Hz, 1H, PhN(CO)NH), 6.84-7.39
(m, 5H, PhH), 7.87 (s, 2H, NH2), 8.76(s, 1H, PhNH); EI MS:
m/z (%) 236 ([M + 1]+, 1), 235 (M+, 3), 219(1), 183(10), 149(4),
143(12), 93(100).
Preparation of 2-chloro-N-[6-(3-phenylureido)hexyl]
acetamide (5)19: To a solution of intermediate 4 (2.0 g, 7.36
mmol) in CH2Cl2 (50 mL) was added Et3N (2.23 g, 22.1 mmol).
The mixture was stirred at room temperature for 1 h, then 2-
chloroacetyl chloride (1.0 g, 8.85 mmol) was dropwise added
at 0 °C. The resulting mixture was stirred at room temperature
for 5 h, extracted with CH2Cl2 (60 mL × 3), dried with anhy-
drous magnesium sulfate, filtered off with suction. The combined
organic layer was concentrated on a rotary evaporator, tritu-
rated with ethyl acetate (5 mL). The precipitate was filtrated
and dried with vacuum to give white solid 5, yield 73 % (1.67 g).
m.p. 139-141 °C. 1H NMR (400 MHz, CDCl3) δ (ppm): 1.29
(s, 4H, CCCH2CH2CC), 1.43 (s, 4H, CCH2CCCH2C), 1.51 (d,
J = 6.8 Hz, 3H, CH3), 3.99 (dd, J1 = 11.6 Hz, J2 = 5.6 Hz, 4H,
CH2CCCCCH2), 4.43 (dd, J1 = 12.6 Hz, J2 = 6.8 Hz, 1H, ClCH),
6.08 (t, J = 5.6 Hz, 1H, PhN(CO) NH), 6.84-7.37 (m, 5H,
PhH), 8.18 (s, 1H, NH(CO)C), 8.35 (s, 1H, PhNH); EI MS:
m/z (%) 313([M + 2]+, 1), 311 (M+, 3), 219(6), 174(12),
162(13), 128(21), 119(25), 106(22), 98(16), 93(100).
Preparation of 2-chloro-N-[6-(3-phenylureido)hexyl]
propanamide (6): In the same way as compound 5, intermediate
compound 6 was synthesized. white solid, Yield: 71 %, m.p.
Preparation of 2-hydroxy-N-[6-(3-phenylureido)hexyl]-
acetamide (9)21: To a solution of 5 (0.5 g, 1.6 mmol) in DMF
(10 mL) was added CH3COONa (0.26 g, 3.2 mmol). The mixture
was stirred at 100 °C for 4 h, cooled to room temperature and
extracted with ethyl acetate (50 mL × 3), dried with anhydrous
magnesium sulfate, filtered off with suction. The combined
organic layer was concentrated on a rotary evaporator to give
residue. Therein NaOH (0.13 g, 3.2 mmol), H2O (5 mL), acetone
(5 mL) were added, the mixture was stirred at room tempera-
ture for 4 h. The resulting mixture was evaporated in vacuum
to remove acetone, then H2O (10 mL) was added, acidification
by HCl to pH = 3, the precipitate was filtered and dried with
vacuum to give white solid 9 in yield 80 % (0.37 g). m.p. 103-
1
105 °C. H NMR (400 MHz, DMSO-d6) δ (ppm): 1.28 (m,
4H, CCCH2CH2CC), 1.42 (m, 4H, CH2CCCH2), 3.11 (m, 4H,
CH2CCCCCH2), 3.78 (s, 2H, CH2O), 5.44 (s, 1H, OH), 6.11
(t, J = 5.6 Hz, 1H, PhN (CO)NH), 6.85-7.23 (m, 5H, PhH),
7.70 (s, 1H, NH(CO)C), 8.37 (s, 1H, PhNH). 13C NMR (100
MHz, DMSO-d6) δ (ppm): 171.54, 155.18, 140.54, 128.58,
120.87, 117.54, 61.40, 38.93, 37.93, 29.68, 29.21, 26.08. LC
MS calcd. 294.3, found 294.2 [M], 316.2 [M + Na]+. Anal.
calcd. for C15H23N3O3: C, 61.41; H, 7.90; N, 14.32. Found: C,
61.38; H, 7.82; N, 14.27.
1
142-144 °C. H NMR (400 MHz, CDCl3) δ (ppm): 1.29 (s,
4H, CCCH2CH2CC), 1.43 (s, 4H, CCH2CCCH2C), 1.51(d, J =
6.8 Hz, 3H, CH3), 3.99 (dd, J1 = 11.6 Hz, J2 = 5.6 Hz, 4H,
CH2CCCCCH2), 4.43 (dd, J1 = 12.6 Hz, J2 = 6.8 Hz, 1H, ClCH),
6.08 (t, J = 5.6 Hz, 1H, PhN(CO)NH), 6.84-7.37 (m, 5H, PhH),
8.18 (s, 1H, NH(CO)C), 8.35 (s, 1H, PhNH); EI MS: m/z (%)
313 ([M + 2]+, 1), 311 (M+, 3), 219(6), 174(12), 162(13),
128(21), 119(25), 106(22), 98(16), 93(100).
Preparation of 2-hydroxy-N-[6-(3-phenylureido)hexyl]-
propanamide (10): In the same way as compound 9, the target
compound 10 was synthesized. white solid,Yield: 76 %, m.p.
1
102-103 °C. H NMR (400 MHz, DMSO-d6) δ (ppm): 1.21
Preparation of 2-mercapto-N-[6-(3-phenylureido)-
hexyl]acetamide (7)20: To a solution of intermediate 5 (0.2 g,
0.64 mmol) in MeOH (15 mL) was added NaSH (54 mg, 0.96
mmol), the mixture was refluxed for 3 h. The reaction mixture
was cooled to room temperature, evaporated in vacuum, purified
by chromatography on silica using chloroform/methanol (10:1,
v/v) as eluent to give white solid 7 in yield 75 % (0.15 g). m.p.
127-129 °C. H NMR (400 MHz, DMSO-d6) δ (ppm): 1.28
(m, 4H, CCCH2CH2CC), 1.41 (m, 4H, CCH2CCCH2C), 2.72
(t, J = 7.8 Hz, 1H, SH), 3.05 (m, 4H, CH2CCCCCH2), 3.58 (s,
(d, J = 6.8, 3H, CH3), 1.28 (m, 4H, CCCH2CH2CC), 1.44 (m,
4H, CCH2CCCH2C), 3.08 (m, 4H, CH2CCCCCH2), 3.94 (dd,
J1 = 6.0, J2 = 12.0 Hz, 1H, COCH), 5.42 (s, 1H, OH), 6.11 (t,
J = 5.2 Hz, 1H, PhN(CO)NH), 6.86-7.39 (m, 5H, PhH), 7.67
(s, 1H, NH(CO)C), 8.37 (s, 1H, PhNH). 13C NMR (100 MHz,
DMSO-d6) δ (ppm): 174.27, 155.17, 140.55, 128.58, 120.87,
117.54, 67.23, 38.92, 38.00, 29.68, 29.15, 26.03, 21.11. LC
MS calcd. 308.4, found 308.2 [M], 330.2 [M + Na]+. Anal.
calcd. for C16H25N3O3: C, 62.52; H, 8.20; N, 13.67. Found: C,
62.48; H, 8.15; N, 13.63.
1

3222 Li et al.
Asian J. Chem.
Assay of antitumor activities: The cytotoxic activity of
three determinations and calculated by Bliss method. The
results were illustrated in Table-1 with Sorafenib as the positive
control.
synthesized α-hydroxy (mercapto)-N-[6-(3-phenylureido)-
hexyl]amide compounds 7-10 were evaluated against a panel
of human cell lines, with SAHA and 5-Fu as the reference
control. The cancer cell lines were cultured in Dulbecco's modi-
fied Eagle's medium (DMEM) supplement with 10 % fetal
bovine serum (FBS). Approximately 4 × 103 cells, suspended
in DMEM medium, were plated onto each well of a 96-well
plate and incubated in 5 % CO2 at 37 °C for 24 h. The subject
compounds at indicated final concentrations were added to
the culture medium and the cell cultures were continued for
72 h. Fresh MTT was added to each well at a terminal concen-
tration of 0.5 mg/mL and incubated with cells at 37 °C for 4 h.
The formazan crystals were dissolved in 100 µL DMSO each
well and the absorbency at 492 nm (for absorbance of MTT
formazan) and 630 nm (for the reference wavelength) was
measured with the ELISA reader. All of the compounds were
tested three times in each of the cell lines. The results expressed
as IC50 (inhibitory concentration 50 %) were the averages of
RESULTS AND DISCUSSION
In the deprotection of 3, typically methods including TFA
and hydrochloric acid led to inconvenient workup and low
yields (26 %). However, hydrogen chloride gas gave a clean
ammonium salt 4 with 97 % yield. To obtain α-mercapto-N-
[6-(3-phenylureido)hexyl]amides, a route involved rigorous
conditions using expensive triphenylmethanol, TFA and Et3SiH,
was reported12,22. As outlined in Scheme-I, the mercaptopro-
pionamide 7-8 are synthesized from 1,6-hexanediamine in this
paper, obviating the need of fetid thioglycolic derivatives.
There were three methods for α-sulfhydrylation of α-chloro-
amides: deacylation of acetylthio substituted intermediate23,
deamidination of carbamimidothioate24 and reduction of disulfides
which were obtained with sodium disulfide25,26 (Scheme-II).
However, all have failed in the preparation of 7-8 after we
tried the three routes. It worked well when treated with NaSH
in refluxing methanol. Direct sulfhydrylation of our method
has a superiorities of mild conditions, convenient operations
and higher yields (the overall yield of 7 increase to 48 % from
16 % reported in literature), which provides a concise and
efficient improvement. On the other hand, hydroxylations step-
by-step afforded a rapid preparation of 9 or 10 using
CH3COONa and NaOH, subsequently.
TABLE 1
ANTITUMOR ACTIVITIES OF THE COMPOUNDS 7-10
AGAINST THREE TUMOR CELL LINES in vitro
IC50/nM
Compound
Hut102
43.6
56.9
57.0
94.6
MCF7
28.3
24.4
37.1
26.4
20.1
15.5
HepG2
31.2
25.1
29.7
43.8
22.3
16.2
7
8
9
Antitumor activity: The in vitro antitumor activities of
the synthesized title compounds 7-10 against three human
cancer cell lines, including Hut102, MCF7 and HepG2, were
evaluated by MTT method. As shown in Table-1, the results
10
SAHA
5-Fu
aNot tested
10.0
a
-
O
O
O
KSAc, N2
Thiourea
AcCl, MeOH
R
N
H
S
O
R
R
SH
SH
R
N
H
Cl
N
H
or NaOH; H3O+
R'
R'
R'
R'
O
O
O
O
Na2SO3
R
S
NH2
R
N
H
Cl
N
H
N
H
R'
S
NH
R'
R'
R'
O
O
H
N
Zn, H2O
Na2S, S
S
R
R
SH
R
Cl
R
N
H
N
H
N
H
O
R'
R'
This paper
O
O
NaSH, MeOH
reflux, 3h
R
Cl
R
SH
N
H
N
H
R'
R'
7-8
Scheme-II: Sulfhydrylation of α-chloroamides
69-75% yield

Vol. 26, No. 11 (2014)
Concise Syntheses and Antitumor Activities of α-Hydroxy(mercapto)amide Derivatives 3223
4. M.F. Fraga, E. Ballestar, A. Villar-Garea, M. Boix-Chornet, J. Espada,
indicated that title compounds 7-10 displayed a broad spectrum
of antitumor activity.Although compounds 7-10 showed slightly
weaker antitumor activity against Hut102, MCF7 and HepG2,
they were in the same order of magnitude as the positive control.
Nevertheless, replacement of the hydroxamate moieties with
α-hydroxy(mercapto) amide led to a distinct decrease in activity.
It could be concluded that the hydroxamate moieties played a
crucial role in the antitumor activity. Probably the hydroxamate
moieties can interact much more efficiently with a Hut102
Zn2+ ion. The structural optimization of SAHA was worth to
further research.
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Conclusion
In summary, four α-hydroxy(mercapto)-N-[6-(3-pheny-
lureido)hexyl]amide derivatives were designed according to
the strategy of bioisosteric replacement. Except 7 the other
title compounds were newly synthesized. The titled compounds
7-10 were synthesized through a novel synthetic procedure
with wild conditions and acceptable yields. Direct sulfhydry-
lation using NaSH from α-chloroamide will become an extremely
useful synthetic method for α-mercaptoamides. The preliminary
bioassay showed that all of the target compounds exhibited
certain antitumor activities against Hut102, MCF7 and HepG2
cell lines.
ACKNOWLEDGEMENTS
This work was supported by Project supported by the
Planned Science and Technology Project of Hunan Province,
China (No. 2012NK3098) and Scientific Research Fund of
Hunan Provincial Education Department of China (No.
11A092).
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