Synthesis and biological evaluation of novel AM80 derivatives as antileukemic agents

Article abstract of DOI:10.1007/s00044-012-0019-9

A series of novel AM80 derivatives as antileukemic agents were synthesized and their structures were confirmed by IR, ¹H-NMR, and HR-MS spectra. All the target compounds were evaluated for in vitro antiproliferative activities against human leukemic HL-60, NB4, and K562 cell lines. Among these derivatives, compound 4g showed much stronger antiproliferative activities against all the three human leukemic cell lines than the positive control AM80, and compound 4b exhibited more active antiproliferative effects against HL-60 and K562 cells than AM80. Furthermore, the preliminary SAR analysis suggested that AM80 conjugating with HDAC inhibitors with small steric hindrance could give more effective antileukemic agents. These results would be helpful to design more potent antileukemic drugs for the treatment of human leukemia.

Full text of DOI:10.1007/s00044-012-0019-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:175–185
DOI 10.1007/s00044-012-0019-9
ORIGINAL RESEARCH
Synthesis and biological evaluation of novel AM80 derivatives
as antileukemic agents
•
Haiyong Bian Jinhong Feng Wenfang Xu
•
Received: 22 November 2011 / Accepted: 6 March 2012 / Published online: 21 March 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A series of novel AM80 derivatives as anti-
leukemic agents were synthesized and their structures were
clinically efficacious drug, and drug molecules only
modulating a single target should be not sufficient for the
treatment of complex diseases, such as cancers, cardio-
vascular diseases, and neurodegenerative diseases, which
are involved in multiple pathological pathways (Cavalli
et al., 2005). Today there is a great interest in multi-target
drugs, which are designed as single products to modulate
more than one physiological target simultaneously,
directly or indirectly through metabolites. Compared with
the traditional single-target drugs or a cocktail of drugs,
multi-target drugs have shown many notable benefits,
including enhanced efficacy, reduced side effects, less
drug–drug interactions, improved patient compliance, and
a predictable pharmacokinetic profile (Cavalli et al.,
2005; Csermely et al., 2005; Alberto et al., 2008). In
general, multi-target drugs are obtained by ‘‘medicinal
chemical hybridization’’ approach, namely that two dis-
tinct pharmacophores or drugs are joined into one mole-
cule by cleavable or non-cleavable spacers, and several
classes of multi-target drugs have been carried out
numerous studies, including the hybrids of 5-HT antago-
nists with SERT inhibitors, hybrids of H1 receptor
antagonists with platelet-activating factor receptor (PAF)
antagonists, NO-donor non-steroidal anti-inflammatory
drug hybrids (NO-NSAIDs), and so on (Alberto et al.,
2008; Morphy and Rankovic, 2005; Morphy et al., 2004;
Wermuth, 2004). However, it is rarely reported about
antileukemic hybrids with multi-target action.
1
confirmed by IR, H-NMR, and HR-MS spectra. All the
target compounds were evaluated for in vitro antiprolifer-
ative activities against human leukemic HL-60, NB4, and
K562 cell lines. Among these derivatives, compound 4g
showed much stronger antiproliferative activities against
all the three human leukemic cell lines than the positive
control AM80, and compound 4b exhibited more active
antiproliferative effects against HL-60 and K562 cells than
AM80. Furthermore, the preliminary SAR analysis sug-
gested that AM80 conjugating with HDAC inhibitors with
small steric hindrance could give more effective antileu-
kemic agents. These results would be helpful to design
more potent antileukemic drugs for the treatment of human
leukemia.
Keywords Multi-target drugs ꢀ AM80 ꢀ Synthesis ꢀ
Biological evaluation
Introduction
Over the past few decades, drug research has mainly
placed an emphasis on screening small molecules, which
are able to modulate the biological function of a single
protein target. However, a highly selective ligand for a
specific biological target does not always lead to a
Retinoic acid receptor (RAR) plays a crucial role in
regulating cell differentiation, development and prolifera-
tion, and it has been demonstrated to be associated with
leukemia such as acute promyelocytic leukemia (APL),
which caused by a reciprocal chromosomal translocation
between RARa gene and other partner genes (PML, PLZF,
NPM, NuMA, and STAT5b genes) (Monzon et al., 1997;
H. Bian ꢀ J. Feng ꢀ W. Xu (&)
Institute of Medicinal Chemistry, School of Pharmaceutical
Sciences, Shandong University, Jinan, Shandong 250012, China
e-mail: wfxu@yahoo.cn
123

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Med Chem Res (2013) 22:175–185
Pandolfi, 2001). RAR agonists have been found to show
significant antitumor activities through inducing cell dif-
ferentiation or inhibiting cell proliferation (Altucci et al.,
2007), and some of them have successfully gone into clinic
application to treat leukemia, such as all-trans retinoic acid
(ATRA) and tamibarotene (AM80). Many studies have
shown that the combination therapy with RAR agonists and
HDAC inhibitors (or RXR agonists) can result in syner-
gistic effects to afford improved efficacy, reduced side
effects, and less drug resistance for the treatment of leu-
kemia (Umemiya et al., 1997; Nguyen et al., 2003;
Kitamura et al., 2000; Bellos and Mahlknecht, 2008; He
et al., 2001; Savickiene et al., 2006). These facts construct
a basis for the development of novel hybrids of RAR
agonists with HDAC inhibitors or RXR agonists, which
may exhibit better antileukemic activities.
Results and discussion
Chemistry
The preparation of novel AM80 derivatives 4a–4j and 7a–
7l was outlined in Schemes 1 and 2. Butyryl chloride 2a
and valproyl chloride 2b were obtained in excellent yields
(90.9–93.6 %), respectively, from butyric acid 1a and
valproic acid 1b by the treatment of thionyl chloride under
the catalysis of DMF. Key intermediates 3a–3j were syn-
thesized in moderate yields (48.1–67.1 %) by the reaction
of each of compounds 2a–2b with glycol, 1,3-propanediol,
1,4-butanediol, ethylenediamine, or ethanolamine in
CH2Cl2 under the catalysis of pyridine at room tempera-
ture, and then each of intermediates 3a–3j was reacted
with AM80 in tetrahydrofuran (THF) in the presence of
1,3-dicyclohexylcarbodiimide (DCC) and 4-dimethylami-
nopyridine (DMAP) to generate target compounds 4a–4j in
good yields (81.7–90.2 %). 4-[(5,6,7,8-tetrahydro-3,5,5,
8,8-pentamethyl-2-naphthalenyl)carbonyl]-benzoic acid 5a
and bexarotene 5b were reacted with short chain alkylene
glycols containing two to four carbon atoms on the catal-
ysis of 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide
hydrochloride (EDC) and 1-hydroxybenzotrizole (HOBt)
in THF at room temperature to give intermediates 6a–6f in
73.0–82.8 % yields, and were also, respectively, reacted
with ethylenediamine, 1,6-hexanediamine, or ethanolamine
in the presence of isobutyl chloroformate and N-methyl
morpholine in THF at -15 °C to give intermediates 6g–6l
in 62.9–88.6 % yields. Finally, each of intermediates 6a–6l
was condensated with AM80 in THF at room temperature
by the catalysis of EDC and DMAP to give target com-
pounds 7a–7l in good yields (83.2–93.7 %).
The purpose of this study is to develop a new type of
AM80 derivatives containing HDAC inhibitor (butyric
acid or valproic acid) or RXR agonist (bexarotene or
4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-
naphthalenyl)carbonyl]-benzoic acid) moieties, and it was
expected to find out more potent antileukemic agents with
multi-target mechanism from these derivatives. Novel
AM80 derivatives were synthesized by coupling HDAC
inhibitor or RXR agonist moieties to the carboxyl group of
AM80 through various spacers such as ethylene glycols,
ethanolamine, and ethylenediamine, and in vivo these
hybrid drugs were supposed to be able to release AM80
moieties as a RAR agonist and HDAC inhibitor or RXR
agonist moieties by the enzyme-catalyzed metabolic reac-
tions to exert synergistic antileukemic activities. In this
study, we have examined the antiproliferative activities of
these derivatives based on human leukemic HL-60, NB4,
and K562 cell lines. Furthermore, we have also prelimi-
narily studied the structure–activity relationship (SAR) of
these hybrids to attempt to seek a better paradigm for the
multi-target-directed drug design strategy.
All of the novel AM80 derivatives were purified by
column chromatography techniques, and their structures
were confirmed by IR, 1H-NMR, and High-resolution
mass spectra (HR-MS) spectra, which gave satisfactory
Scheme 1 Reagents and conditions: (a) SOCl2, DMF, reflux; (b) glycol/1,3-propanediol/1,4-butanediol/ethylenediamine/ethanolamine, Py,
CH2Cl2, rt; (c) AM80, DCC, DMAP, THF, rt
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Med Chem Res (2013) 22:175–185
177
Scheme 2 Reagents and conditions: (a) glycol/1,3-propanediol/1,4-butanediol, EDC, HOBt, THF, rt; (b) ethylenediamine/1,6-hexamethylene
diamine/ethanolamine, isobutyl chloroformate, N-methyl morpholine, THF, -15 °C; (c) AM80, EDC, DMAP, THF, rt
spectroscopic data and were completely in accordance with
the depicted structures.
against human leukemic cells of the target compounds than
the RXR agonists coupled to AM80, and the reason might
be that AM80–HDAC inhibitor hybrids could exert more
potent synergistic multi-target actions than AM80–RXR
agonist hybrids after in vivo metabolism, or AM80–HDAC
inhibitor hybrids, which have a smaller steric hindrance,
are easier to be metabolized than AM80–RXR agonist
hybrids. Comparing AM80–butyric acid hybrids (4a–4c,
4g, and 4i) with AM80–valproic acid hybrids (4d–4f, 4h,
and 4j), obviously, AM80–butyric acid hybrids were more
active against three human leukemic cell lines (HL-60,
NB4, and K562) than AM80–valproic acid hybrids, and
that might be due to the small steric hindrance of butyric
acid as a HDAC inhibitor, which could facilitate the
enzyme-catalyzed metabolic reactions for AM80–HDAC
inhibitor hybrids to release AM80 and HDAC inhibitors to
exert synergistic multi-target actions.
Biological evaluation
All of the novel AM80 derivatives were evaluated for the
antiproliferative activities against human leukemic HL-60,
NB4, and K562 cell lines using the MTT cell proliferation
assay and the results are listed in Table 1. The results
showed that most of the target compounds exhibited higher
antiproliferative activities against acute myeloid leukemia
cell lines (HL-60 and NB4) than against chronic myeloid
leukemia cell lines (K562). Compound 4g displayed
remarkably more potent antiproliferative activities against
all the three human leukemic cell lines than the positive
control AM80, and compound 4b exhibited significantly
stronger antiproliferative effects against HL-60 and K562
cells than AM80, while exhibited similar biological
activity against NB4 cells with AM80, as well as two
compounds (4a and 4i) were more active against K562
cells than AM80. In addition, three compounds (4a, 4c, and
7a) exhibited similar antiproliferative activities against
HL-60 cells with AM80, and two compounds (7a and 7g)
exhibited similar biological activity against K562 cells
with AM80. However, the other compounds (4d–4f, 4h, 4j,
7b–7f, and 7h–7l) showed significantly decreasing anti-
proliferative activities against HL-60, NB4, and K562 cell
lines.
Conclusion
In summary, a series of novel AM80 derivatives as multi-
target agents were synthesized and evaluated for the
antileukemic activities in this study. Among the target
compounds, compound 4g showed more potent antipro-
liferative activities against all the three human leukemic
cell lines than the positive control AM80, and compound
4b exhibited much stronger antiproliferative effects
against HL-60 and K562 cells than AM80, as well as two
compounds (4a and 4i) were more active against K562
cells than AM80. Furthermore, the preliminary SAR
analysis for these derivatives suggested that AM80 cou-
pling to HDAC inhibitors with small steric hindrance
could produce more potent antileukemic agents. These
interesting results would be helpful to design more
Comparing compounds 4a–4j (AM80–HDAC inhibitor
hybrids) with compounds 7a–7l (AM80–RXR agonist
hybrids), we found that the types of pharmacophores or
drugs coupled to AM80 moieties had a major impact on the
bioactivity of the target compounds, and it suggested that
HDAC inhibitors coupled to AM80 might be more potent
pharmacophores to improve the antiproliferative activity
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Med Chem Res (2013) 22:175–185
to literature. Solvents and reagents were commercial
materials used and purified by standard procedures when-
ever required.
Table 1 In vitro antiproliferative activities against three human
leukemic cell lines for compounds 4a–4j, 7a–7l, and AM80
Compounds IC50 (lM)a
HL-60
NB4
K562
General procedure for the preparation
of compounds 3a–3j
4a
4b
4c
4d
4e
4f
6.29 1.12
2.99 0.63
7.32 1.58
10.97 2.35
5.75 1.17
23.21 4.59
18.61 1.67
4.57 0.75
92.62 12.16
663.79 42.31
[1,000
Compounds 3a–3j were prepared according to modified
literature procedures (Blunt et al., 1966; Huang and Xu,
1990; Sapozhnikova et al., 1982; Guan et al., 2009; Levi
et al., 1997). General Procedure: A solution of compound
2a or 2b (100 mmol) in dichloromethane (50 mL) was
slowly added dropwise to another stirred solution of glycol,
1,3-propanediol, 1,4-butanediol, ethylenediamine, or etha-
nolamine (100 mmol) in dichloromethane (100 mL) con-
taining triethylamine (150 mmol) in 2 h, and then the
mixture was stirred for additional 5 h at room temperature,
concentrated in vacuum, and purified by column chroma-
tography to give 3a–3j as an oil or solid, which was used
immediately for the next reaction.
256.20 33.15 [1,000
834.93 61.51 [1,000
914.18 50.32 [1,000
[1,000
4g
4h
4i
5.61 1.21
12.41 2.26
36.84 9.23
[1,000
3.26 0.78
5.69 1.35
7.98 1.19
83.68 9.83
212.61 25.36 25.38 2.91
4j
[1,000
66.99 7.13
[1,000
39.88 6.37
7a
7b
7c
7d
7e
7f
6.83 1.86
14.87 2.81
24.66 3.99
30.71 5.92
19.25 2.64
25.09 4.67
14.27 2.38
95.40 8.95
14.79 1.16
70.68 7.63
37.53 9.15
503.5 60.56
8.94 3.16
112.09 15.23 49.14 4.81
147.4 12.65
84.05 9.68
[1,000
504.21 47.92
212.50 36.28 [1,000
650.39 51.67 [1,000
104.25 15.22 39.56 5.49
7g
7h
7i
General procedure for the preparation
of compounds 4a–4j
[1,000 95.39 8.95
569.05 49.39 73.46 7.72
7j
[1,000
294.2 32.53
247.11 27.36
[1,000
A mixture of AM80 (3 mmol), DCC (3 mmol), and DMAP
(1 mmol) in tetrahydrofuran (THF) (50 mL) was stirred at
room temperature for 1 h, and then the mixture was added
dropwise to a stirred solution of each of compounds 3a–3j
(3 mmol) in THF (50 mL) in 1 h. The reaction mixture was
successively stirred for about 2 h at room temperature until
reaction was complete, and the insoluble byproduct was
filtered off, and then the filtrate was concentrated in vac-
uum and purified by column chromatography to give target
compounds 4a–4j in good yields.
7k
7l
AM80b
72.42 8.71
[1,000
4.81 2.03
42.37 5.62
a
All values are mean SD (n = 3)
b
AM80 (tamibarotene) was used as a positive control drug in MTT
assay
effective antileukemic drugs for the treatment of human
leukemia.
2-(Butyryloxy)ethyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahy-
dronaphthalen-2-ylcarbamoyl)benzoate (4a) White cot-
ton-like solid; Yield: 88.3 %; mp 127–128 °C; IR (KBr,
Experimental
cm-1) m: 3298.71 (tNH), 2953.99 (tas ), 2931.43 (t ),
as
CH3
CH2
2858.54 (tsCH ), 1741.63 (tC=O), 1715.67 (tC=O), 1649.44
Chemistry
2
(tC=O), 1619.53 (tC=C), 1594.83 (tC=C), 1494.86 (tC=C),
1456.58 (tC=C); 1H-NMR (300 MHz, DMSO-d6) d:
0.839–0.888 (t, J = 7.2 Hz, 3H, CH3), 1.238 (s, 6H, 29
CH3), 1.250 (s, 6H, 29 CH3), 1.481–1.603 (sext,
J = 7.2 Hz, 2H, CH2), 1.648 (s, 4H, 29 CH2),
2.286–2.334 (t, J = 7.2 Hz, 2H, CO–CH2), 4.391–4.535
(m, 4H, 29 O–CH2), 7.283–7.312 (d, J = 8.7 Hz, 1H, Ph–
H), 7.565–7.600 (dd, J1 = 8.4 Hz, J2 = 2.1 Hz, 1H, Ph–
H), 7.672–7.679 (d, J = 2.1 Hz, 1H, Ph–H), 8.075 (s, 4H,
49 Ph–H), 10.286 (s, 1H, NH); HR-MS (ESI-TOF) (m/z):
466.2574 [M?H]? (calcd for [C28H35NO5?H]?:
466.2588).
Melting points were determined in open capillary tubes on
1
a RY-1 melting point apparatus and are uncorrected. H-
NMR spectra were recorded on a Bruker Avance-300 FT-
NMR instrument with tetramethylsilane (TMS) as an
internal standard in DMSO-d6 as a solvent. IR spectra were
recorded on a Nicolet AVATAR 370 FT-IR spectrometer
in KBr disks. HR-MS were recorded on an Agilent 6520
Accurate-Mass Q-TOF LC–MS spectrometer. Column
chromatography was performed on silica gel (200–300
mesh). AM80 (Kagechika et al., 1988), 5a and 5b (Boehm
et al., 1994; Dawson et al., 1995) were prepared according
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Med Chem Res (2013) 22:175–185
179
(m/z): 522.3198 [M?H]? (calcd for [C32H43NO5?H]?:
522.3214).
3-(Butyryloxy)propyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahy-
dronaphthalen-2-ylcarbamoyl)benzoate (4b) White solid;
Yield: 81.7 %; mp 106–108 °C; IR (KBr, cm-1) m: 3346.10
as
(tNH), 2963.09 (tas ), 2931.76 (t ), 2868.03 (tCs H ),
3-(2-Propylpentanoyloxy)propyl 4-(5,5,8,8-tetramethyl-5,
6,7,8-tetrahydronaphthalen-2-ylcarbamoyl)benzoate (4e)
White solid; Yield: 85.2 %; mp 118–119 °C; IR (KBr,
CH3
CH2
2
1732.67 (tC=O), 1720.08 (tC=O), 1645.12 (tC=O), 1613.89
(tC=C), 1588.54 (tC=C), 1504.00 (tC=C), 1460.13 (tC=C);
1H-NMR (300 MHz, DMSO-d6) d: 0.833–0.882 (t, J =
7.2 Hz, 3H, CH3), 1.238 (s, 6H, 29 CH3), 1.251 (s, 6H, 29
CH3), 1.465–1.587 (sext, J = 7.2 Hz, 2H, CH2), 1.648 (s,
4H, 29 CH2), 2.027–2.110 (quint, J = 6.3 Hz, 2H, CH2),
2.238–2.287 (t, J = 7.2 Hz, 2H, CO–CH2), 4.177–4.218
(t, J = 6.3 Hz, 2H, O–CH2), 4.361–4.403 (t, J = 6.3 Hz,
2H, O–CH2), 7.282–7.311 (d, J = 8.7 Hz, 1H, Ph–H),
7.565–7.600 (dd, J1 = 8.4 Hz, J2 = 2.1 Hz, 1H, Ph–H),
7.678–7.685 (d, J = 2.1 Hz, 1H, Ph–H), 8.087 (s, 4H,
49 Ph–H), 10.285 (s, 1H, NH); HR-MS (ESI-TOF)
(m/z): 480.2724 [M?H]? (calcd for [C29H37NO5?H]?:
480.2745).
cm-1) m: 3388.57 (tNH), 2961.17 (tas ), 2933.96 (t ),
as
CH2
CH3
2874.08 (tsCH ), 1732.23 (tC=O), 1711.45 (tC=O), 1653.59
2
(tC=O), 1610.52 (tC=C), 1585.00 (tC=C), 1500.68 (tC=C),
1462.16 (tC=C); 1H-NMR (300 MHz, DMSO-d6) d:
0.799–0.848 (t, J = 7.2 Hz, 6H, 29 CH3), 1.143–1.218 (m,
4H, 29 CH2), 1.238 (s, 6H, 29 CH3), 1.250 (s, 6H, 29
CH3), 1.313–1.544 (m, 4H, 29 CH2), 1.648 (s, 4H, 29
CH2), 2.033–2.116 (quint, J = 6.3 Hz, 2H, CH2),
2.285–2.379 (m, 1H, CO–CH), 4.184–4.226 (t, J = 6.3 Hz,
2H, O–CH2), 4.351–4.393 (t, J = 6.3 Hz, 2H, O–CH2),
7.282–7.311 (d, J = 8.7 Hz, 1H, Ph–H), 7.561–7.597 (dd,
J1 = 8.7 Hz, J2 = 2.1 Hz, 1H, Ph–H), 7.675–7.682 (d,
J = 2.1 Hz, 1H, Ph–H), 8.081–8.084 (m, 4H, 49 Ph–H),
10.281 (s, 1H, NH); HR-MS (ESI-TOF) (m/z): 536.3352
[M?H]? (calcd for [C33H45NO5?H]?: 536.3371).
4-(Butyryloxy)butyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahy-
dronaphthalen-2-ylcarbamoyl)benzoate (4c) White solid;
Yield: 83.8 %; mp 92–94 °C; IR (KBr, cm-1) m: 3316.62
4-(2-Propylpentanoyloxy)butyl 4-(5,5,8,8-tetramethyl-5,
6,7,8-tetrahydronaphthalen-2-ylcarbamoyl)benzoate (4f)
as
CH2
(tNH), 2960.18 (tas ), 2929.99 (t ), 2873.38 (tCs H ),
CH3
2
1722.76 (tC=O), 1650.92 (tC=O), 1612.22 (tC=C), 1589.38
(tC=C), 1502.03 (tC=C), 1458.27 (tC=C); 1H-NMR
(300 MHz, DMSO-d6) d: 0.849–0.898 (t, J = 7.2 Hz, 3H,
CH3), 1.238 (s, 6H, 29 CH3), 1.251 (s, 6H, 29 CH3),
1.478–1.600 (sext, J = 7.2 Hz, 2H, CH2), 1.647(s, 4H, 29
CH2), 1.686–1.822 (m, 4H, 29 CH2), 2.246–2.295 (t,
J = 7.2 Hz, 2H, CO–CH2), 4.076–4.117 (t, J = 6.3 Hz,
2H, O–CH2), 4.321–4.361 (t, J = 6.0 Hz, 2H, O–CH2),
7.282–7.310 (d, J = 8.4 Hz, 1H, Ph–H), 7.567–7.603 (dd,
J1 = 8.7 Hz, J2 = 2.1 Hz, 1H, Ph–H), 7.681–7.688 (d,
J = 2.1 Hz, 1H, Ph–H), 8.082 (s, 4H, 49 Ph–H), 10.286 (s,
1H, NH); HR-MS (ESI-TOF) (m/z): 494.2899 [M?H]?
(calcd for [C30H39NO5?H]?: 494.2901).
White solid; Yield: 86.6 %; mp 84–86 °C; IR (KBr, cm-1
)
m: 3335.54 (tNH), 2958.46 (tas ), 2932.10 (t ), 2871.63
as
CH2
CH3
(tsCH ), 1726.25 (tC=O), 1651.82 (tC=O), 1612.70 (tC=C),
2
1
1589.57 (tC=C), 1502.92 (tC=C), 1458.10 (tC=C); H-NMR
(300 MHz, DMSO-d6) d: 0.812–0.860 (t, J = 7.2 Hz, 6H,
29 CH3), 1.159–1.208 (m, 4H, 29 CH2), 1.237 (s, 6H, 29
CH3), 1.251 (s, 6H, 29 CH3), 1.316–1.552 (m, 4H, 29
CH2), 1.647 (s, 4H, 29 CH2), 1.745–1.791 (m, 4H, 29
CH2), 2.282–2.376 (m, 1H, CO–CH), 4.091–4.130 (t,
J = 6.0 Hz, 2H, O–CH2), 4.324–4.363 (t, J = 6.0 Hz, 2H,
O–CH2), 7.281–7.309 (d, J = 8.4 Hz, 1H, Ph–H),
7.566–7.601 (dd, J1 = 8.4 Hz, J2 = 2.1 Hz, 1H, Ph–H),
7.679–7.686 (d, J = 2.1 Hz, 1H, Ph–H), 8.075 (s, 4H, 49
Ph–H), 10.286 (s, 1H, NH); HR-MS (ESI-TOF) (m/z):
550.3508 [M?H]? (calcd for [C33H45NO5?H]?:
550.3527).
2-(2-Propylpentanoyloxy)ethyl 4-(5,5,8,8-tetramethyl-5,6,
7,8-tetrahydronaphthalen-2-ylcarbamoyl)benzoate (4d)
White solid; Yield: 87.1 %; mp 131–133 °C; IR (KBr,
cm-1) m: 3314.97 (tNH), 2958.18 (tas ), 2931.06 (t ),
N1-(2-butyramidoethyl)-N4-(5,5,8,8-tetramethyl-5,6,7,8-tet-
rahydronaphthalen-2-yl)terephthalamide (4g) White pow-
der; Yield: 82.5 %; mp 245–246 °C; IR (KBr, cm-1) m:
as
CH2
CH3
2871.22 (tsCH ), 1730.00 (tC=O), 1650.95 (tC=O), 1612.47
2
(tC=C), 1589.58 (tC=C), 1502.33 (tC=C), 1457.40 (tC=C);
1H-NMR (300 MHz, DMSO-d6) d: 0.751–0.799 (t,
J = 7.2 Hz, 6H, 29 CH3), 1.140–1.215 (m, 4H, 29 CH2),
1.238 (s, 6H, 29 CH3), 1.250 (s, 6H, 29 CH3),
1.306–1.544 (m, 4H, 29 CH2), 1.647 (s, 4H, 29 CH2),
2.312–2.407 (m, 1H, CO–CH), 4.420–4.546 (m, 4H, 29
O–CH2), 7.282–7.310 (d, J = 8.4 Hz, 1H, Ph–H),
7.563–7.599 (dd, J1 = 8.7 Hz, J2 = 2.1 Hz, 1H, Ph–H),
7.673–7.681 (d, J = 2.4 Hz, 1H, Ph–H), 8.040–8.103 (m,
4H, 49 Ph–H), 10.282 (s, 1H, NH); HR-MS (ESI-TOF)
as
CH2
3263.70 (tNH), 2959.24 (tas ), 2930.71 (t ), 2860.18
CH3
(tsCH ), 1649.04 (tC=O), 1614.13 (tC=C), 1594.52 (tC=C),
1498.96 (tC=C), 1458.33 (tC=C), 1236.32 (tC–N); H-NMR
2
1
(300 MHz, DMSO-d6) d: 0.819–0.868 (t, J = 7.2 Hz, 3H,
CH3), 1.238 (s, 6H, 29 CH3), 1.252 (s, 6H, 29 CH3),
1.452–1.575 (sext, J = 7.2 Hz, 2H, CH2), 1.648 (s, 4H, 29
CH2), 2.028–2.077 (t, J = 7.2 Hz, 2H, CO–CH2),
3.238–3.337 (m, 4H, 29 N–CH2), 7.277–7.306 (d,
J = 8.7 Hz, 1H, Ph–H), 7.572–7.608 (dd, J1 = 8.7 Hz,
123

180
Med Chem Res (2013) 22:175–185
J2 = 2.1 Hz, 1H, Ph–H), 7.680–7.687 (d, J = 2.1 Hz, 1H,
Ph–H), 7.924 (s, 1H, NH), 7.943–8.047 (m, 4H, 49 Ph–H),
8.638–8.674 (t, J = 5.4 Hz, 1H, NH), 10.193 (s, 1H, NH);
HR-MS (ESI-TOF) (m/z): 464.2895 [M?H]? (calcd for
[C28H37N3O3?H]?: 464.2908).
1.647 (s, 4H, 29 CH2), 2.279–2.373 (m, 1H, CO–CH),
3.520–3.575 (q, J = 5.4 Hz, 2H, N–CH2), 4.183–4.220 (q,
J = 5.4 Hz, 2H, O–CH2), 7.276–7.305 (d, J = 8.7 Hz, 1H,
Ph–H), 7.569–7.604 (dd, J1 = 8.7 Hz, J2 = 2.1 Hz, 1H,
Ph–H), 7.677–7.684 (d, J = 2.1 Hz, 1H, Ph–H),
7.942–8.049 (q, J = 8.4 Hz, 4H, 49 Ph–H), 8.701–8.738
(t, J = 5.4 Hz, 1H, NH), 10.193 (s, 1H, NH); HR-MS
(ESI-TOF) (m/z): 521.3369 [M?H]? (calcd for [C32
H44N2O4?H]?: 521.3374).
N1-(2-(2-propylpentanamido)ethyl)-N4-(5,5,8,8-tetramethyl-
5,6,7,8-tetrahydronaphthalen-2-yl)terephthalamide (4h)
White powder; Yield: 85.7 %; mp 228–229 °C; IR (KBr,
cm-1) m: 3302.76 (tNH), 2955.71 (tas ), 2929.64 (t ),
as
CH2
CH3
2870.08 (tsCH ), 1643.33 (tC=O), 1589.20 (tC=C), 1504.05
General procedure for the preparation
of compounds 6a–6l
2
(tC=C), 1455.23 (tC=C), 1261.28 (tC–N); 1H-NMR
(300 MHz, DMSO-d6) d: 0.775–0.823 (t, J = 7.2 Hz, 6H,
29 CH3), 1.109–1.217 (m, 4H, 29 CH2), 1.238 (s, 6H, 29
CH3), 1.252 (s, 6H, 29 CH3), 1.282–1.497 (m, 4H, 29
CH2), 1.649 (s, 4H, 29 CH2), 2.074–2.150 (m, 1H, CO–
CH), 3.265–3.353 (m, 4H, 29 N–CH2), 7.276–7.305 (d,
J = 8.7 Hz, 1H, Ph–H), 7.569–7.604 (dd, J1 = 8.4 Hz,
J2 = 2.1 Hz, 1H, Ph–H), 7.678–7.685 (d, J = 2.1 Hz, 1H,
Ph–H), 7.934 (s, 1H, NH), 7.962–8.047 (m, 4H, 49 Ph–H),
8.575–8.609 (t, J = 5.1 Hz, 1H, NH), 10.190 (s, 1H, NH);
HR-MS (ESI-TOF) (m/z): 520.3511 [M?H]? (calcd for
[C32H45N3O3?H]?: 520.3534).
A mixture of compound 5a or 5b (15 mmol) with EDC
(25 mmol) and HOBt (25 mmol) in THF (100 mL) was
stirred at room temperature for 1 h, and then the mixture
was added dropwise to a stirred solution of glycol, 1,3-
propanediol, or 1,4-butanediol (500 mmol) in THF
(200 mL) in 2 h. The reaction mixture was successively
stirred for additional 5 h at room temperature, concentrated
in vacuum, and poured into water (300 mL). Finally, the
precipitated solid was filtered, washed with water, and
purified by column chromatography to give compounds
6a–6f in good yields.
2-(4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-
ylcarbamoyl)benzamido)ethyl butyrate (4i) White pow-
der; Yield: 88.3 %; mp 206–208 °C; IR (KBr, cm-1) m:
A mixture of compound 5a or 5b (9 mmol) with iso-
butyl chloroformate (9 mmol) and N-methyl morpholine
(20 mmol) in THF (100 mL) was stirred at -15 °C for
10 min, and then the mixture was added to a vigorously
stirred solution of ethylenediamine, 1,6-hexamethylene
diamine or ethanolamine (300 mmol) to react for 0.5 h at
-15 °C. Subsequently, the reaction mixture was allowed to
warm to room temperature and stirred for additional 2–4 h
until reaction was complete, and then the reaction solution
was concentrated in vacuum and poured into water
(300 mL). Finally, the precipitated solid was filtered out
and washed in turn with saturated sodium bicarbonate
solution, water, 1 mol L-1 hydrochloric acid solution and
again with water, and then the crude products were purified
by column chromatography to give compounds 6g–6l in
various yields.
as
3317.96 (tNH), 2961.53 (tas ), 2928.34 (t ), 2874.31
CH3
CH2
(tsCH ), 1738.86 (tC=O), 1648.54 (tC=O), 1617.48 (tC=C),
2
1
1591.21 (tC=C), 1502.80 (tC=C), 1455.96 (tC=C); H-NMR
(300 MHz, DMSO-d6) d: 0.839–0.889 (t, J = 7.5 Hz, 3H,
CH3), 1.238 (s, 6H, 29 CH3), 1.252 (s, 6H, 29 CH3),
1.446–1.601 (sext, J = 7.2 Hz, 2H, CH2), 1.648 (s, 4H, 29
CH2), 2.261–2.310 (t, J = 7.5 Hz, 2H, CO–CH2),
3.502–3.559 (q, J = 5.7 Hz, 2H, N–CH2), 4.162–4.200 (q,
J = 5.7 Hz, 2H, O–CH2), 7.277–7.306 (d, J = 8.7 Hz, 1H,
Ph–H), 7.570–7.606 (dd, J1 = 8.4 Hz, J2 = 2.1 Hz, 1H,
Ph–H), 7.678–7.685 (d, J = 2.1 Hz, 1H, Ph–H),
7.942–8.049 (q, J = 8.7 Hz, 4H, 49 Ph–H), 8.734–8.771
(t, J = 5.7 Hz, 1H, NH), 10.196(s, 1H, NH); HR-MS (ESI-
TOF) (m/z): 465.2732 [M?H]? (calcd for [C28H36
N2O4?H]?: 465.2748).
2-Hydroxyethyl 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-
naphthalene-2-carbonyl)benzoate (6a) White solid; Yield:
81.9 %; mp 129–130 °C; IR (KBr, cm-1) m: 3512.21 (tOH),
2-(4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-
ylcarbamoyl)benzamido)ethyl 2-propylpentanoate (4j)
White powder; Yield: 90.2 %; mp 193–195 °C; IR (KBr,
as
CH3
as
CH2
2964.32 (t ), 2925.97 (t ), 2854.74 (tsCH ), 1719.26
2
(tC=O), 1653.41 (tC=O), 1607.30 (tC=C), 1568.48 (tC=C),
1501.70 (tC=C), 1460.78 (tC=C); 1H-NMR (300 MHz,
DMSO-d6) d: 1.171 (s, 6H, 29 CH3), 1.291 (s, 6H, 29
CH3), 1.658 (s, 4H, 29 CH2), 2.257 (s, 3H, Ph–CH3),
3.702–3.754 (q, J = 5.7 Hz, 2H, O–CH2), 4.315–4.347 (t,
J = 4.8 Hz, 2H, O–CH2), 4.948–4.986 (t, J = 5.7 Hz, 1H,
OH), 7.261 (s, 1H, Ph–H), 7.335 (s, 1H, Ph–H),
7.802–7.830 (d, J = 8.4 Hz, 2H, 29 Ph–H), 8.128–8.156
cm-1) m: 3291.29 (tNH), 2957.68 (tas ), 2930.70 (t ),
as
CH2
CH3
2870.43 (tsCH ), 1736.44 (tC=O), 1644.69 (tC=O), 1612.73
2
(tC=C), 1589.38 (tC=C), 1500.64 (tC=C), 1458.18 (tC=C);
1H-NMR (300 MHz, DMSO-d6) d: 0.756–0.804 (t,
J = 7.2 Hz, 6H, 29 CH3), 1.129–1.204 (m, 4H, 29 CH2),
1.237 (s, 6H, 29 CH3), 1.251 (s, 6H, 29 CH3),
1.314–1.366 (m, 2H, CH2), 1.384–1.545 (m, 2H, CH2),
123

Med Chem Res (2013) 22:175–185
181
(d, J = 8.4 Hz, 2H, 29 Ph–H); HR-MS (ESI-TOF) (m/z):
395.2200 [M?H]? (calcd for [C25H30O4?H]?: 395.2217).
1H, =CH), 5.921 (s, 1H, =CH), 7.079 (s, 1H, PhH), 7.151
(s, 1H, PhH), 7.354–7.382 (d, J = 8.4 Hz, 2H, 29 PhH),
7.911–7.939 (d, J = 8.4 Hz, 2H, 29 PhH).
3-Hydroxypropyl 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahy-
dronaphthalene-2-carbonyl)benzoate (6b) Viscous solid;
4-Hydroxybutyl 4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetra-
hydronaphthalen-2-yl)vinyl)benzoate (6f) Viscous solid;
1
Yield: 76.2 %; H-NMR (300 MHz, DMSO-d6) d: 1.161
1
(s, 6H, 29 CH3), 1.280 (s, 6H, 29 CH3), 1.647 (s, 4H, 29
CH2), 1.830–1.914 (quint, J = 6.3 Hz, 2H, C–CH2), 2.239
(s, 3H, Ph–CH3), 3.530–3.617 (m, 2H, O–CH2),
4.349–4.392 (t, J = 6.3 Hz, 2H, O–CH2), 4.603–4.638 (t,
J = 5.4 Hz, 1H, OH), 7.249 (s, 1H, Ph–H), 7.324 (s, 1H,
Ph–H), 7.787–7.815 (dd, J1 = 6.6 Hz, J2 = 1.8 Hz, 2H,
29 Ph–H), 8.085–8.113 (dd, J1 = 6.6 Hz, J2 = 1.8 Hz,
2H, 29 Ph–H).
Yield: 73.0 %; H-NMR (300 MHz, DMSO-d6) d: 1.220
(s, 6H, 29 CH3), 1.252 (s, 6H, 29 CH3), 1.486–1.578 (m,
2H, C–CH2), 1.643 (s, 4H, 29 CH2), 1.682–1.776 (m, 2H,
C–CH2), 1.884 (s, 3H, Ph–CH3), 3.410–3.469 (q,
J = 6.3 Hz, 2H, O–CH2), 4.243–4.287 (t, J = 6.6 Hz, 2H,
O–CH2), 4.447–4.482 (t, J = 5.4 Hz, 1H, OH), 5.286 (s,
1H, =CH), 5.915 (s, 1H, =CH), 7.071 (s, 1H, PhH), 7.144
(s, 1H, PhH), 7.347–7.376 (d, J = 8.7 Hz, 2H, 29 PhH),
7.904–7.932 (d, J = 8.7 Hz, 2H, 29 PhH).
4-Hydroxybutyl 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-
naphthalene-2-carbonyl)benzoate (6c) Viscous solid;
N-(2-aminoethyl)-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahy-
dronaphthalene-2-carbonyl)benzamide (6g) White solid;
Yield: 62.9 %; mp 173–175 °C; 1H-NMR (300 MHz,
DMSO-d6) d: 1.169 (s, 6H, 29 CH3), 1.285 (s, 6H, 29
CH3), 1.659 (s, 4H, 29 CH2), 2.249 (s, 3H, Ph–CH3),
2.806–2.850 (t, J = 6.6 Hz, 2H, N–CH2), 3.311–3.375 (q,
J = 6.6 Hz, 2H, N–CH2), 7.256 (s, 1H, Ph–H), 7.342 (s,
1H, Ph–H), 7.786–7.814 (d, J = 8.4 Hz, 2H, 29 Ph–H),
8.091–8.117 (d, J = 8.4 Hz, 2H, 29 Ph–H), 8.703–8.740
(m, 1H, NH).
1
Yield: 80.1 %; H-NMR (300 MHz, DMSO-d6) d: 1.159
(s, 6H, 29 CH3), 1.278 (s, 6H, 29 CH3), 1.487–1.596 (m,
2H, C–CH2), 1.645 (s, 4H, 29 CH2), 1.707–1.809 (m, 2H,
C–CH2), 2.237 (s, 3H, Ph–CH3), 3.422–3.481 (q,
J = 6.3 Hz, 2H, O–CH2), 4.298–4.342 (t, J = 6.6 Hz, 2H,
O–CH2), 4.477–4.512 (t, J = 5.4 Hz, 1H, OH), 7.247 (s,
1H, PhH), 7.321 (s, 1H, PhH), 7.786–7.814 (dd,
J1 = 6.6 Hz, J2 = 1.8 Hz, 2H, 29 PhH), 8.082–8.111 (dd,
J1 = 6.9 Hz, J2 = 1.8 Hz, 2H, 29 PhH).
N-(2-aminoethyl)-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetra-
hydronaphthalen-2-yl)vinyl)benzamide (6i) White solid;
Yield: 71.3 %; mp 167–169 °C; IR (KBr, cm-1) m: 3359.54
2-Hydroxyethyl 4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetra-
hydronaphthalen-2-yl)vinyl)benzoate (6d) White solid;
Yield: 84.6 %; mp 120–121 °C; IR (KBr, cm-1) m: 3424.55
as
(tNH), 3017.86 (t=CH), 2962.09 (tas ), 2921.07 (t ),
CH3
CH2
as
(tOH), 2959.17 (tas ), 2915.01 (t ), 2854.74 (tCs H ),
2855.91 (tsCH ), 1639.55 (tC=O), 1606.21 (tC=C), 1497.40
CH3
CH2
2
2
(tC=C), 1453.98 (tC=C), 1310.11 (tC–N); 1H-NMR
(300 MHz, DMSO-d6) d: 1.226 (s, 6H, 29 CH3), 1.262 (s,
6H, 29 CH3), 1.652 (s, 4H, 29 CH2), 1.900 (s, 3H, Ph–
CH3), 2.664–2.708 (t, J = 6.6 Hz, 2H, N–CH2),
3.231–3.293 (q, J = 6.6 Hz, 2H, N–CH2), 5.228 (s, 1H,
=CH), 5.885 (s, 1H, =CH), 7.064 (s, 1H, Ph–H), 7.147 (s,
1H, Ph–H), 7.277–7.305 (d, J = 8.4 Hz, 2H, 29 Ph–H),
7.785–7.813 (d, J = 8.4 Hz, 2H, 29 Ph–H), 8.388–8.426
(m, 1H, NH); HR-MS (ESI-TOF) (m/z): 391.2733 [M?H]?
(calcd for [C26H34N2O?H]?: 391.2744).
1719.86 (tC=O), 1699.87 (tC=O), 1607.14 (tC=C), 1561.56
(tC=C), 1496.44 (tC=C), 1456.38 (tC=C); 1H-NMR
(300 MHz, DMSO-d6) d: 1.229 (s, 6H, 29 CH3), 1.261 (s,
6H, 29 CH3), 1.652 (s, 4H, 29 CH2), 1.894 (s, 3H, Ph–
CH3), 3.669–3.721 (q, J = 5.7 Hz, 2H, O–CH2),
4.258–4.291 (t, J = 4.8 Hz, 2H, O–CH2), 4.897–4.935 (t,
J = 5.7 Hz, 1H, OH), 5.297 (s, 1H, =CH), 5.928 (s, 1H,
=CH), 7.082 (s, 1H, Ph–H), 7.152 (s, 1H, Ph–H),
7.351–7.392 (m, 2H, 29 Ph–H), 7.937–7.979 (m, 2H, 29
Ph–H); HR-MS (ESI-TOF) (m/z): 393.2410 [M?H]?
(calcd for [C26H32O3?H]?: 393.2425).
N-(2-hydroxyethyl)-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetra-
hydronaphthalene-2-carbonyl)benzamide (6k) Viscous
3-Hydroxypropyl 4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetra-
hydronaphthalen-2-yl)vinyl)benzoate (6e) White solid;
Yield: 82.8 %; mp 82–83 °C; 1H-NMR (300 MHz,
DMSO-d6) d: 1.228 (s, 6H, 29 CH3), 1.260 (s, 6H, 29
CH3), 1.651 (s, 4H, 29 CH2), 1.804–1.867 (q, J = 6.3 Hz,
2H, C–CH2), 1.891 (s, 3H, Ph–CH3), 3.517–3.576 (q,
J = 6.3 Hz, 2H, O–CH2), 4.300–4.343 (t, J = 6.3 Hz, 2H,
O–CH2), 4.571–4.606 (t, J = 5.4 Hz, 1H, OH), 5.293 (s,
1
solid; Yield: 82.3 %; mp 83–85 °C; H-NMR (300 MHz,
DMSO-d6) d: 1.177 (s, 6H, 29 CH3), 1.291 (s, 6H, 29
CH3), 1.660 (s, 4H, 29 CH2), 2.243 (s, 3H, Ph–CH3),
3.327–3.385 (q, J = 5.4 Hz, 2H, N–CH2), 3.504–3.564 (t,
J = 5.7 Hz, 2H, O–CH2), 4.738–4.775 (t, J = 5.7 Hz, 1H,
OH), 7.247 (s, 1H, Ph–H), 7.324 (s, 1H, Ph–H),
7.742–7.770 (d, J = 8.4 Hz, 2H, 29 Ph–H), 7.972–8.001
123

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Med Chem Res (2013) 22:175–185
3-(4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalene-
2-carbonyl)benzoyloxy)propyl 4-(5,5,8,8-tetramethyl-5,6,7,
(d, J = 8.7 Hz, 2H, 29 Ph–H), 8.624–8.661 (t, J =
5.7 Hz, 1H, NH).
8-tetrahydronaphthalen-2-ylcarbamoyl)benzoate
(7b)
)
White solid; Yield: 86.6 %; mp 96–98 °C; IR (KBr, cm-1
N-(2-hydroxyethyl)-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tet-
rahydronaphthalen-2-yl)vinyl)benzamide (6l) White flaky
crystal; Yield: 88.6 %; mp 171–172 °C; IR (KBr, cm-1) m:
3383.27 (tOH), 3295.42 (tNH), 3014.70 (t=CH), 2961.56
as
CH2
m: 3336.89 (tNH), 2959.42 (tas ), 2925.43 (t ), 2860.20
CH3
(tsCH ), 1725.53 (tC=O), 1655.37 (tC=O), 1612.14 (tC=C),
2
1
1589.09 (tC=C), 1502.84 (tC=C), 1457.53 (tC=C); H-NMR
as
CH3
as
CH2
(t ), 2925.21 (t ), 2854.44 (tsCH ), 1635.29 (tC=O),
(300 MHz, DMSO-d6) d: 1.157 (s, 6H, 29 CH3), 1.237 (s,
6H, 29 CH3), 1.246 (s, 6H, 29 CH3), 1.276 (s, 6H, 29
CH3), 1.644 (s, 8H, 49 CH2), 2.223 (s, 3H, Ph–CH3),
2.245–2.266 (m, 2H, C–CH2), 4.475–4.530 (q, J = 5.7 Hz,
4H, 29 O–CH2), 7.249–7.307 (m, 3H, 39 Ph–H),
7.558–7.594 (dd, J1 = 8.7 Hz, J2 = 2.1 Hz, 1H, Ph–H),
7.674–7.681 (d, J = 2.1 Hz, 1H, Ph–H), 7.764–7.792 (d,
J = 8.4 Hz, 2H, 29 Ph–H), 8.011–8.120 (m, 6H, 69
Ph–H), 10.262 (s, 1H, NH); HR-MS (ESI-TOF) (m/z):
742.4073 [M?H]? (calcd for [C48H55NO6?H]?:
742.4103).
2
1603.16 (tC=C), 1504.71 (tC=C), 1455.18 (tC=C), 1325.85
(tC–N), 1068.17 (tCO); H-NMR (300 MHz, DMSO-d6) d:
1
1.227 (s, 6H, 29 CH3), 1.262 (s, 6H, 29 CH3), 1.651 (s,
4H, 29 CH2), 1.900 (s, 3H, Ph–CH3), 3.293–3.353 (m, 2H,
N–CH2), 3.475–3.535 (q, J = 6.3 Hz, 2H, O–CH2),
4.715–4.753 (t, J = 5.7 Hz, 1H, OH), 5.227–5.230 (d,
J = 0.9 Hz, 1H, =CH), 5.884–5.887 (d, J = 0.9 Hz, 1H,
=CH), 7.070 (s, 1H, Ph–H), 7.147 (s, 1H, Ph–H),
7.282–7.310 (d, J = 8.4 Hz, 2H, 29 Ph–H), 7.796–7.825
(d, J = 8.7 Hz, 2H, 29 Ph–H), 8.405–8.442 (t, J =
5.7 Hz, 1H, NH); HR-MS (ESI-TOF) (m/z): 392.2570
[M?H]? (calcd for [C26H33NO2?H]?: 392.2585).
4-(4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalene-
2-carbonyl)benzoyloxy)butyl 4-(5,5,8,8-tetramethyl-5,6,7,8-
tetrahydronaphthalen-2-ylcarbamoyl)benzoate (7c) White
solid; Yield: 83.2 %; mp 89–90 °C; IR (KBr, cm-1) m:
General procedure for the preparation
of compounds 7a–7l
as
CH2
3336.89 (tNH), 2959.03 (tas ), 2926.08 (t ), 2861.38
CH3
A mixture of AM80 (3 mmol), EDC (5 mmol), and DMAP
(1 mmol) in THF (30 mL) was stirred at room temperature
for 2 h, and then the mixture was added dropwise to a
stirred solution of each of compounds 6a–6l (3 mmol) in
THF (50 mL) in 0.5 h. Subsequently, the reaction mixture
was stirred for additional 4 h at room temperature until
reaction was complete, and then the resulting mixture was
concentrated in vacuum and poured into water (300 mL).
Finally, the precipitated solid was filtered out, washed with
water, and purified by column chromatography to give
target compounds 7a–7l in good yields.
(tsCH ), 1723.19 (tC=O), 1660.08 (tC=O), 1611.80 (tC=C),
1589.26 (tC=C), 1501.96 (tC=C), 1458.06 (tC=C); H-NMR
2
1
(300 MHz, DMSO-d6) d: 1.158 (s, 6H, 29 CH3), 1.237 (s,
6H, 29 CH3), 1.250 (s, 6H, 29 CH3), 1.281 (s, 6H, 29
CH3), 1.643 (s, 8H, 49 CH2), 1.919–1.995 (m, 4H, 29 C–
CH2), 2.245 (s, 3H, Ph–CH3), 4.399–4.408 (m, 4H, 29 O–
CH2), 7.254 (s, 1H, Ph–H), 7.278–7.307 (m, 1H, Ph–H),
7.324 (s, 1H, Ph–H), 7.578–7.607 (m, 1H, Ph–H),
7.686–7.692 (d, J = 1.8 Hz, 1H, Ph–H), 7.787–7.814 (d,
J = 8.1 Hz, 2H, 29 Ph–H), 8.043–8.129 (m, 6H, 69 Ph–
H), 10.281 (s, 1H, NH); HR-MS (ESI-TOF) (m/z):
756.4216 [M?H]? (calcd for [C49H57NO6?H]?:
756.4259).
2-(4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalene-
2-carbonyl)benzoyloxy)ethyl 4-(5,5,8,8-tetramethyl-5,6,7,8-
tetrahydronaphthalen-2-ylcarbamoyl)benzoate (7a) White
solid; Yield: 85.4 %; mp 108–110 °C; IR (KBr, cm-1) m:
2-(4-(1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphtha-
len-2-yl)vinyl)benzoyloxy)ethyl 4-(5,5,8,8-tetramethyl-5,6,
7,8-tetrahydronaphthalen-2-ylcarbamoyl)benzoate (7d)
White solid; Yield: 88.7 %; mp 103–105 °C; IR (KBr,
3325.93 (tNH), 2959.08 (tas ), 2926.01 (t ), 2861.47
as
CH2
CH3
(tsCH ), 1728.49 (tC=O), 1660.35 (tC=O), 1611.64 (tC=C),
2
1
1589.19 (tC=C), 1501.68 (tC=C), 1457.43 (tC=C); H-NMR
cm-1) m: 3320.45 (tNH), 2958.70 (tas ), 2924.13 (t ),
as
CH2
(300 MHz, DMSO-d6) d: 1.146 (s, 6H, 29 CH3), 1.234 (s,
6H, 29 CH3), 1.244 (s, 6H, 29 CH3), 1.274 (s, 6H, 29
CH3), 1.643 (s, 8H, 49 CH2), 2.239 (s, 3H, Ph–CH3), 4.702
(s, 4H, 29 O–CH2), 7.239 (s, 1H, Ph–H), 7.276 (s, 1H, Ph–
H), 7.305–7.319 (d, J = 4.2 Hz, 1H, Ph–H), 7.559–7.594
(dd, J1 = 8.4 Hz, J2 = 2.1 Hz, 1H, Ph–H), 7.666–7.673
(d, J = 2.1 Hz, 1H, Ph–H), 7.792–7.820 (d, J = 8.4 Hz,
2H, 29 Ph–H), 8.038–8.133 (m, 6H, 69 Ph–H), 10.266 (s,
1H, NH); HR-MS (ESI-TOF) (m/z): 728.3986 [M?H]?
(calcd for [C47H53NO6?H]?: 728.3946).
CH3
2860.36 (tsCH ), 1725.94 (tC=O), 1652.73 (tC=O), 1609.17
2
(tC=C), 1589.43 (tC=C), 1499.06 (tC=C), 1456.67 (tC=C);
1H-NMR (300 MHz, DMSO-d6) d: 1.212 (s, 6H, 29 CH3),
1.236 (s, 6H, 29 CH3), 1.246 (s, 12H, 49 CH3),
1.636–1.645 (m, 8H, 49 CH2), 1.878 (s, 3H, Ph–CH3),
4.656 (s, 4H, 29 O–CH2), 5.289 (s, 1H, =CH), 5.921 (s,
1H, =CH), 7.062 (s, 1H, PhH), 7.138 (s, 1H, PhH),
7.277–7.306 (d, J = 8.7 Hz, 1H, PhH), 7.353–7.382 (d,
J = 8.7 Hz, 2H, 29 PhH), 7.560–7.596 (dd, J1 = 8.7 Hz,
123

Med Chem Res (2013) 22:175–185
183
J2 = 2.1 Hz, 1H, PhH), 7.662–7.669 (d, J = 2.1 Hz, 1H,
PhH), 7.923–7.952 (d, J = 8.7 Hz, 2H, 29 PhH),
8.028–8.095 (m, 4H, 49 PhH), 10.260 (s, 1H, NH); HR-
MS (ESI-TOF) (m/z): 726.4131 [M?H]? (calcd for
[C49H57NO6?H]?: 726.4153).
6H, 29 CH3), 1.250 (s, 6H, 29 CH3), 1.288 (s, 6H, 29
CH3), 1.650 (s, 8H, 49 CH2), 2.241 (s, 3H, Ph–CH3), 3.493
(br.s, 4H, 29 N–CH2), 7.244–7.324 (m, 3H, 39 PhH),
7.569–7.605 (dd, J1 = 8.7 Hz, J2 = 2.1 Hz, 1H, PhH),
7.675–7.682 (d, J = 2.1 Hz, 1H, PhH), 7.750–7.777 (d,
J = 8.1 Hz, 2H, 29 PhH), 7.956–8.045 (m, 6H, 69 PhH),
8.780–8.836 (m, 2H, 29 NH), 10.187 (s, 1H, NH); HR-MS
(ESI-TOF) (m/z): 726.4234 [M?H]? (calcd for
[C47H55N3O4?H]?: 726.4266).
3-(4-(1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-
2-yl)vinyl)benzoyloxy)propyl 4-(5,5,8,8-tetramethyl-5,6,7,8-
tetrahydronaphthalen-2-ylcarbamoyl)benzoate (7e) White
solid; Yield: 86.5 %; mp 92–94 °C; IR (KBr, cm-1) m:
3325.93 (tNH), 2959.34 (tas ), 2924.33 (t ), 2860.33
N1-(6-(4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtha-
lene-2-carbonyl)benzamido)hexyl)-N4-(5,5,8,8-tetramethyl-
5,6,7,8-tetrahydronaphthalen-2-yl)terephthalamide (7h)
White solid; Yield: 86.1 %; mp 163–165 °C; IR (KBr,
as
CH2
CH3
(tsCH ), 1722.56 (tC=O), 1652.35 (tC=O), 1609.47 (tC=C),
1589.48 (tC=C), 1499.02 (tC=C), 1457.07 (tC=C); H-NMR
2
1
(300 MHz, DMSO-d6) d: 1.211 (s, 6H, 29 CH3),
1.240–1.249 (m, 18H, 69 CH3), 1.637–1.644 (m, 8H, 49
CH2), 1.864 (s, 3H, Ph–CH3), 2.170–2.256 (m, 2H, C–
CH2), 4.437–4.499 (q, J = 6.3 Hz, 4H, 29 O–CH2), 5.266
(s, 1H, =CH), 5.902 (s, 1H, =CH), 7.067 (s, 1H, PhH),
7.120 (s, 1H, PhH), 7.279–7.335 (t, J = 8.7 Hz, 3H, 39
PhH), 7.572–7.608 (dd, J1 = 8.7 Hz, J2 = 2.1 Hz, 1H,
PhH), 7.684–7.691 (d, J = 2.1 Hz, 1H, PhH), 7.899–7.928
(d, J = 8.7 Hz, 2H, 29 PhH), 8.001–8.084 (m, 4H, 49 Ph–
H), 10.265 (s, 1H, NH); HR-MS (ESI-TOF) (m/z):
740.4281 [M?H]? (calcd for [C49H57NO5?H]?:
740.4310).
cm-1) m: 3287.85 (tNH), 2958.33 (tas ), 2927.68 (t ),
as
CH2
CH3
2859.13 (tsCH ), 1637.74 (tC=O), 1611.49 (tC=C), 1591.01
2
(tC=C), 1499.44 (tC=C), 1457.56 (tC=C), 1318.24 (tC–N);
1H-NMR (300 MHz, DMSO-d6) d: 1.152 (s, 6H, 29 CH3),
1.237 (s, 6H, 29 CH3), 1.250 (s, 6H, 29 CH3), 1.287 (s, 6H,
29 CH3), 1.367 (br.s, 4H, 29 C–CH2), 1.560 (br.s, 4H, 29
C–CH2), 1.650 (s, 8H, 49 CH2), 2.237 (s, 3H, Ph–CH3),
3.256–3.320 (q, J = 6.3 Hz, 4H, 29 N–CH2), 7.246–7.320
(m, 3H, 39 PhH), 7.569–7.605 (dd, J1 = 8.7 Hz,
J2 = 2.1 Hz, 1H, PhH), 7.680–7.687 (d, J = 2.1 Hz, 1H,
PhH), 7.740–7.768 (d, J = 8.4 Hz, 2H, 29 PhH),
7.952–8.038 (m, 6H, 69 PhH), 8.594–8.679 (m, 2H, 29 NH),
10.186 (s, 1H, NH); HR-MS (ESI-TOF) (m/z): 782.4846
[M?H]? (calcd for [C51H63N3O4?H]?: 782.4892).
4-(4-(1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphtha-
len-2-yl)vinyl)benzoyloxy)butyl 4-(5,5,8,8-tetramethyl-5,6,
7,8-tetrahydronaphthalen-2-ylcarbamoyl)benzoate (7f)
White solid; Yield: 87.9 %; mp 88–89 °C; IR (KBr, cm-1
)
N1-(2-(4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaph-
thalen-2-yl)vinyl)benzamido)ethyl)-N4-(5,5,8,8-tetramethyl-
m: 3331.41 (tNH), 2958.55 (tas ), 2924.14 (t ), 2860.10
as
CH2
CH3
(tsCH ), 1721.32 (tC=O), 1652.62 (tC=O), 1609.55 (tC=C),
5,6,7,8-tetrahydronaphthalen-2-yl)terephthalamide
(7i)
2
1
1589.38 (tC=C), 1499.23 (tC=C), 1457.20 (tC=C); H-NMR
White solid; Yield: 90.3 %; mp 262–264 °C; IR (KBr,
cm-1) m: 3278.38 (tNH), 2959.78 (tas ), 2925.30 (t ),
as
CH2
(300 MHz, DMSO-d6) d: 1.219 (s, 6H, 29 CH3), 1.237 (s,
6H, 29 CH3), 1.251 (s, 12H, 49 CH3), 1.644 (s, 8H, 49
CH2), 1.886 (s, 7H, 29 C–CH2?Ph–CH3), 4.352–4.382 (m,
4H, 29 O–CH2), 5.288 (s, 1H, =CH), 5.916 (s, 1H, =CH),
7.074 (s, 1H, Ph–H), 7.141 (s, 1H, Ph–H), 7.279–7.308 (d,
J = 8.7 Hz, 1H, Ph–H), 7.341–7.369 (d, J = 8.4 Hz, 2H,
29 Ph–H), 7.579–7.608 (d, J = 8.7 Hz, 1H, Ph–H),
7.684–7.691 (d, J = 2.1 Hz, 1H, Ph–H), 7.917–7.945 (d,
J = 8.4 Hz, 2H, 29 Ph–H), 8.034–8.099 (m, 4H, 49 Ph–H),
10.278 (s, 1H, NH); HR-MS (ESI-TOF) (m/z): 754.4436
[M?H]? (calcd for [C50H59NO5?H]?: 754.4466).
CH3
2859.48 (tsCH ), 1634.87 (tC=O), 1612.80 (tC=C), 1592.39
2
(tC=C), 1502.41 (tC=C), 1456.99 (tC=C); 1H-NMR
(300 MHz, DMSO-d6) d: 1.225 (s, 6H, 29 CH3), 1.238 (s,
6H, 29 CH3), 1.251 (s, 6H, 29 CH3), 1.260 (s, 6H, 29
CH3), 1.650 (br.s, 8H, 49 CH2), 1.902 (s, 3H, Ph–CH3),
3.461 (br.s, 4H, 29 N–CH2), 5.232 (s, 1H, =CH), 5.892(s,
1H, =CH), 7.065 (s, 1H, PhH), 7.146 (s, 1H, PhH),
7.276–7.318 (dd, J1 = 8.4 Hz, J2 = 4.2 Hz, 3H, 39 PhH),
7.569–7.605 (m, 1H, PhH), 7.673–7.680 (d, J = 2.1 Hz,
1H, PhH), 7.799–7.828 (d, J = 8.7 Hz, 2H, 29 PhH),
7.949–8.040 (m, 4H, 49 PhH), 8.618–8.763 (m, 2H, 29
NH), 10.182 (s, 1H, NH); HR-MS (ESI-TOF) (m/z):
724.4443 [M?H]? (calcd for [C48H57N3O3?H]?:
724.4473).
N1-(2-(4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtha-
lene-2-carbonyl)benzamido)ethyl)-N4-(5,5,8,8-tetramethyl-
5,6,7,8-tetrahydronaphthalen-2-yl)terephthalamide (7g)
White solid; Yield: 88.2 %; mp 225–227 °C; IR (KBr,
cm-1) m: 3269.05 (tNH), 2959.51 (tas ), 2926.86 (t ),
N1-(6-(4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaph-
thalen-2-yl)vinyl)benzamido)hexyl)-N4-(5,5,8,8-tetramethyl-
as
CH2
CH3
2861.56 (tsCH ), 1634.51 (tC=O), 1612.43 (tC=C), 1592.13
2
(tC=C), 1501.86 (tC=C), 1457.93 (tC=C); 1H-NMR
5,6,7,8-tetrahydronaphthalen-2-yl)terephthalamide
(7j)
(300 MHz, DMSO-d6) d: 1.174 (s, 6H, 29 CH3), 1.238 (s,
White solid; Yield: 89.6 %; mp 229–231 °C; IR (KBr,
123

184
Med Chem Res (2013) 22:175–185
cm-1) m: 3287.56 (tNH), 2960.52 (tas ), 2925.02 (t ),
2H, 29 Ph–H), 8.037–8.121 (q, J = 8.7 Hz, 4H, 49 Ph–
H), 8.703–8.740 (t, J = 5.7 Hz, 1H, NH), 10.259 (s, 1H,
NH); HR-MS (ESI-TOF) (m/z): 725.4285 [M?H]? (calcd
for [C48H56N2O4?H]?: 725.4313).
as
CH2
CH3
2860.82 (tsCH ), 1627.71 (tC=O), 1502.45 (tC=C), 1469.48
2
(tC=C), 1305.48 (tC–N); 1H-NMR (300 MHz, DMSO-d6) d:
1.223 (s, 6H, 29 CH3), 1.237 (s, 6H, 29 CH3), 1.251 (s,
6H, 29 CH3), 1.259 (s, 6H, 29 CH3), 1.352 (br.s, 4H, 29
C–CH2), 1.532–1.553 (br.s, 4H, 29 C–CH2), 1.648 (s, 8H,
49 CH2), 1.901 (s, 3H, Ph–CH3), 3.219–3.315 (m, 4H, 29
N–CH2), 5.223 (s, 1H, =CH), 5.879 (s, 1H, =CH),
7.274–7.303 (d, J = 8.7 Hz, 2H, 29 Ph–H), 7.569–7.605
(dd, J1 = 8.7 Hz, J2 = 2.1 Hz, 1H, Ph–H), 7.679–7.687
(d, J = 2.4 Hz, 1H, Ph–H), 7.772–7.801 (d, J = 8.7 Hz,
2H, 29 Ph–H), 7.941–8.036 (m, 6H, 69 Ph–H),
8.408–8.446 (t, J = 5.7 Hz, 1H, NH), 8.588–8.625 (t,
J = 5.7 Hz, 1H, NH), 10.185 (s, 1H, NH); HR-MS (ESI-
TOF) (m/z): 780.5058 [M?H]? (calcd for [C52H65
N3O3?H]?: 780.5095).
Biological activity evaluation
MTT cell proliferation assay (Denizot and Lang, 1986) was
performed to evaluate the in vitro antiproliferative activi-
ties against human leukemic HL-60, NB4, and K562 cell
lines for the target compounds. HL-60, NB4, and K562
cells were cultured in a complete RPMI-1640 medium with
10 % fetal bovine serum at 37 °C in a humidified incubator
with atmosphere of 5 % CO2, and the cell cultures were
maintained in drug-free medium for 1–2 weeks. After that,
the cells of the exponential growth phase were seeded in
96-well cell culture plates at 10,000 cells per 100 lL per
well and incubated for 4 h at 37 °C, 5 % CO2 in a
humidified incubator (Bayazit and Khan, 2005). The test
compounds were prepared as concentrated stock solutions
and diluted in RPMI-1640 medium, and then test com-
pound solutions were added to triplicate wells at various
concentrations (final concentration at 0.01, 0.1, 1, 10,
100 lM), and incubated for 48 h. Subsequently, 20 lL of
MTT solution (5 mg mL-1 within complete RPMI-1640
medium) was added to each well, followed by an additional
incubation for 4 h, and then centrifugal separations were
performed and the medium was gently removed from the
wells. Finally, DMSO (100 lL) was added to each well and
was vibrated gently on a swing bed for 10 min to dissolve
the formazan crystals completely, and then the optical
density was determined at 570 nm on the enzyme-linked
immunosorbent assay (ELISA) reader. The half inhibitory
concentration (IC50) values of all the test compounds on
three human leukemic cell lines were calculated by SPSS
software.
2-(4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalene-
2-carbonyl)benzamido)ethyl 4-(5,5,8,8-tetramethyl-5,6,7,8-
tetrahydronaphthalen-2-ylcarbamoyl)benzoate (7k) White
solid; Yield: 92.5 %; mp 139–141 °C; IR (KBr, cm-1) m:
as
CH2
3335.16 (tNH), 2959.11 (tas ), 2925.62 (t ), 2861.04
CH3
(tsCH ), 1726.39 (tC=O), 1651.81 (tC=O), 1611.77 (tC=C),
2
1
1589.72 (tC=C), 1498.30 (tC=C), 1457.47 (tC=C); H-NMR
(300 MHz, DMSO-d6) d: 1.161 (s, 6H, 29 CH3), 1.236 (s,
6H, 29 CH3), 1.247 (s, 6H, 29 CH3), 1.280 (s, 6H, 29
CH3), 1.645 (s, 8H, 49 CH2), 2.236 (s, 3H, Ph–CH3),
3.704–3.722 (m, 2H, N–CH2), 4.445–4.479 (t, J = 5.1 Hz,
2H, O–CH2), 7.240–7.316 (m, 3H, 39 Ph–H), 7.559–7.595
(dd, J1 = 8.7 Hz, J2 = 2.1 Hz, 1H, Ph–H), 7.671–7.679
(d, J = 2.4 Hz, 1H, Ph–H), 7.754–7.783 (d, J = 8.7 Hz,
2H, 29 Ph–H), 7.965–7.993 (d, J = 8.4 Hz, 2H, 29 Ph–
H), 8.042–8.126 (q, J = 8.7 Hz, 4H, 49 Ph–H),
8.924–8.962 (t, J = 5.7 Hz, 1H, NH), 10.263 (s, 1H, NH);
HR-MS (ESI-TOF) (m/z): 727.4087 [M?H]? (calcd for
[C47H54N2O5?H]?: 727.4106).
Acknowledgments The authors are grateful to the National Nature
Science Foundation of China (Grant No.90713041) and National
Science and Technology Major Project of the Ministry of Science and
Technology of China (Grant No.2009ZX09103-118) for financial
support for this research.
2-(4-(1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphtha-
len-2-yl)vinyl)benzamido)ethyl 4-(5,5,8,8-tetramethyl-5,
6,7,8-tetrahydronaphthalen-2-ylcarbamoyl)benzoate (7l)
White solid; Yield: 93.7 %; mp 140–142 °C; IR (KBr,
cm-1) m: 3321.22 (tNH), 2959.12 (tas ), 2924.54 (t ),
as
CH3
CH2
2860.11 (tsCH ), 1726.68 (tC=O), 1649.81 (tC=O), 1610.76
2
References
(tC=C), 1590.07 (tC=C), 1500.23 (tC=C), 1457.20 (tC=C);
1H-NMR (300 MHz, DMSO-d6) d: 1.217 (s, 6H, 29 CH3),
1.237 (s, 6H, 29 CH3), 1.250 (s, 12H, 49 CH3), 1.643 (s,
8H, 49 CH2), 1.899 (s, 3H, Ph–CH3), 3.648–3.709 (q,
J = 6.3 Hz, 2H, N–CH2), 4.419–4.454 (t, J = 5.1 Hz, 2H,
O–CH2), 5.230 (s, 1H, =CH), 5.888 (s, 1H, =CH), 7.059 (s,
1H, Ph–H), 7.138 (s, 1H, Ph–H), 7.279–7.323 (dd,
J1 = 8.7 Hz, J2 = 4.8 Hz, 3H, 39 Ph–H), 7.565–7.601
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(d, J = 2.1 Hz, 1H, Ph–H), 7.793–7.822 (d, J = 8.7 Hz,
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