Convenient synthesis and evaluation of biological activity of benzyl (2S)-2-[(R)-1-hydroxy-2-oxo-(1-phenethyl)prop-3-ylcarbamoyl]-4-oxopiperidine- (or -4-oxopyrrolidine)-1-carboxylate as novel histone deacetylase inhibitors

Article abstract of DOI:10.1515/znb-2008-1108

A simple synthesis, involving a key coupling reaction, and the biological activity of the title compounds 16 and 17 are described. The key fragments are the amine·HCl salt 6 and the acids 9 and 13, which were smoothly coupled by using ethyl(dimethylaminopropyl)carbodiimide (EDCI) and 1- hydroxybenzotriazole (HOBt) in high yield. We have found that the in vitro growth inhibitory potency of the new compounds 16 and 17 exhibits good histone deacetylase (HDAC) activity.

Full text of DOI:10.1515/znb-2008-1108

Convenient Synthesis and Evaluation of Biological Activity of
Benzyl (2S)-2-[(R)-1-hydroxy-2-oxo-(1-phenethyl)prop-3-ylcarbamoyl]-
4-oxopiperidine- (or -4-oxopyrrolidine)-1-carboxylate as Novel Histone
Deacetylase Inhibitors
Seikwan Oha, Hyung-In Moonb, and Jae-Chul Junga, and Mitchell A. Averyc
a Department of Neuroscience and Medical Research Institute, School of Medicine, Ewha Womans
University, Seoul 158-710, South Korea
b Department of Neuroscience and Inam Neuro Science Research Center, Wonkwang University
Sanbon Medical Center, Sanbondong, Gunpocity, Kyunggido, 435-040, South Korea
c Department of Medicinal Chemistry, School of Pharmacy, National Center for Natural Products
Research & Department of Chemistry, University of Mississippi, University, MS 38677-1848, USA
Reprint requests to Dr. Jae-Chul Jung. Fax: +82-02-2650-5791. E-mail: jcjung10@yahoo.co.kr
Z. Naturforsch. 2008, 63b, 1300 – 1304; received June 11, 2008
A simple synthesis, involving a key coupling reaction, and the biological activity of the title com-
pounds 16 and 17 are described. The key fragments are the amine·HCl salt 6 and the acids 9 and
13, which were smoothly coupled by using ethyl(dimethylaminopropyl)carbodiimide (EDCI) and 1-
hydroxybenzotriazole (HOBt) in high yield. We have found that the in vitro growth inhibitory potency
of the new compounds 16 and 17 exhibits good histone deacetylase (HDAC) activity.
Key words: 4-Oxopiperidine-1-carboxylate, 4-Oxopyrrolidine-1-carboxylate, Acetylation,
Coupling Synthesis
Introduction
as new potent HDAC inhibitors with good in vitro
and in vivo activities. Pankiewicz et al. [7] described
the synthesis of dual inhibitors of inosine monophos-
phate dehydrogenase and HDAC inhibitors for cancer
treatment.
As a part of our ongoing medicinal chemistry pro-
gram dealing with the development of new HDAC in-
hibitors, we report herein an efficient synthesis of the
title compounds 16 and 17 starting from N-Boc-L-
homophenylalanine (1) and the evaluation of their in
vitro growth inhibitory potency.
The naturally occurring anticancer substances and
various synthetic agents for cancer treatment have
evoked a great deal of interest in recent years due
to their characteristic therapeutic effects [1]. Histone
deacetylase (HDAC) inhibitors are a new class of po-
tential therapeutic cancer agents. They are categorized
into two classes according to the enzymes respon-
sible for reversible acetylation or deacetylation pro-
cesses as histone acetyltransferases (HAT) and his-
tone deacetylases (HDAC), respectively [2]. It is well
known that the HATs act as transcriptional coactiva-
tors, and HDACs are part of transcriptional corepres-
sor complexes [3]. Recently, the Schaefer group [4]
reported the synthesis of biarylalanine-containing hy-
droxamic acids and investigated their action on im-
munoprecipitated HDAC1 and HDAC6; a subtype se-
lectivity for HDAC6 was confirmed in cells by West-
ern blot. The Angibaud group [5] developed the syn-
thesis of a series of pyrimidyl-5-hydroxamic acids as
potent HDAC inhibitors, which can be used as a linker
to provide HDAC inhibitors of good enzymatic po-
tency. The Delorme group [6] reported the synthe-
sis and evaluation of sulfonamide hydroxamic acids
Results and Discussion
To generate the key fragment 6 [8], diazoketone 2
was prepared in quantitative yield from commercially
available N-Boc-L-homophenylalanine (1) by react-
ing it with freshly prepared diazomethane in the pres-
ence of N-methylmorpholine and isobutyl chlorofor-
mate [9]. Compound 2 was submitted without purifica-
tion to a treatment with sodium hydroxide in THF/H2O
to yield primary alcohol 3 in 33 % two steps yield.
Bromination of alcohol 3 with phosphorus tribromide
in diethyl ether gave bromide 4 in 84 % yield. Treat-
ment of 4 with sodium acetate and 18-crown-6 as a
c
0932–0776 / 08 / 1100–1300 $ 06.00 ꢀ 2008 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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S. Oh et al. · Benzyl (2S)-2-[(R)-1-hydroxy-2-oxo-(1-phenethyl)prop-3-ylcarbamoyl]-4-oxopiperidine-1-carboxylate 1301
Scheme 1. (a) ClCO2i-
Bu, N-methylmorphol-
◦
ine, CH2N2, 20 C, 2 h;
(b) NaOH, THF/H2O
(8 : 2, v/v), r. t., 24 h
(33 %); (c) PBr3, Et2O,
◦
0 C to r. t., 2 h (84 %);
(d) NaOAc, 18-crown-6,
DMF, r. t., 1 h (82 %);
(e) 4 M HCl, 1,4-dioxane,
0
◦C, 30 min, r. t., 4 h
(85 %).
Table 1. HDAC and growth inhibiting potency of novel com-
phase transfer catalyst afforded acetate 5 in 82 % yield
[10], which was deprotected with 4 M aqueous HCl so-
lution in 1,4-dioxane to give amine · HCl salt 6 in 85 %
yield (Scheme 1).
pounds 16 and 17.
Compound
IC50 cells (µM)a
14
15
16
17
NDb
ND
16.3
> 100
140
c
In order to generate compounds 16 and 17, trans-
4-hydroxy-L-proline (7) was protected with benzyl-
oxycarbonyl chloride (Cbz-Cl) in the presence of
chlorotrimethylsilane (TMS-Cl) to generate the Cbz-
protected acid 8 in 95 % two steps yield. Oxidation of
8 was accomplished by using Jones reagent at 0 ◦C in
acetone to afford keto acid 9 in 92 % yield, which was
subsequently treated with catalytic amounts of isobuty-
lene and sulfuric acid in dichloromethane to give keto
ester 10 [11] in 80 % yield. Ring expansion of keto es-
ter 10 was performed with ethyl diazoacetate (EDA)
and boron trifluoride-diethyl etherate (BF3 · Et2O) in
diethyl ether to yield β-keto ester 11 (K : E = 9 : 1)
[12], which was subsequently treated with sodium
chloride in DMSO to give 4-oxopiperidine 12 and the
regioisomeric 5-ketone (isolated ratio = 2 : 3) in 75 %
combined yield.
Ketone 12 was hydrolyzed by using trifluoroacetic
acid in dichloromethane to give acid 13 in high yield.
Acids 9 and 13 were then coupled with amine · HCl
salt 6 by using ethyl(dimethylaminopropyl)carbodi-
imide (EDCI) and 1-hydroxybenzotriazole (HOBt) in
the presence of triethylamine to give amides 14 and 15
in 80 and 83 % yield, respectively [13]. To explore the
reaction scope and generality, we investigated several
coupling agents such as DCC, HOAt, HATU, TATU,
and BOP-Cl [14]. Although the latter were more con-
venient in handling, the HOBt/EDCI method afforded
a favorable yield. Deacetylation of compounds 14
and 15 was accomplished with K2CO3 · 1.5 H2O in
MeOH/CH2Cl2/H2O (8 : 1 : 1, v/v) to afford esters 16
and 17 in 70 and 75 % yield, respectively (Scheme 2).
Sodium butyratec
a
b
Values are means of three experiments; not detected; substance
for comparison.
The in vitro histone deacetylase (HDAC) activity of
16 and 17 was evaluated in human leukemia K562 cells
(2.5 ×108). These compounds exhibited good efficacy
(IC50: 16.3 µM for 16, > 100 µM for 17) comparable to
sodium butyrate in vitro histone deacetylase (HDAC)
activity, while compounds 14 and 15 were not detected
(Table 1).
Conclusion
In conclusion, a simple preparation of the title
compounds 16 and 17 as novel histone deacetylase
(HDAC) inhibitors has been described. The key frag-
ments were the amine · HCl salt 6, prepared from N-
Boc-L-homophenylalanine (1), and acids 9 and 13. We
found that compounds 16 and 17 exhibited good effi-
cacy comparable to sodium butyrate as a reference ma-
terial for in vitro HDAC activity. We expect that sim-
ple syntheses of new 4-oxopiperidine (or 4-oxopyrrol-
idine)-1-carboxylates and key fragments will be useful
for the modification of histone deacetylase (HDAC) in-
hibitors.
Experimental Section
Reactions requiring anhydrous conditions were performed
with the usual precautions for rigorous exclusion of air and
moisture. Tetrahydrofuran was distilled from sodium ben-
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1302 S. Oh et al. · Benzyl (2S)-2-[(R)-1-hydroxy-2-oxo-(1-phenethyl)prop-3-ylcarbamoyl]-4-oxopiperidine-1-carboxylate
Scheme 2. (a) TMS-Cl, DIPEA, CH2Cl2, reflux, 2 h; then Cbz-Cl, 0 ◦C to r. t., 16 h (95 %); (b) CrO3, H2SO4, acetone, 0 ◦C,
10 min (92 %); (c) isobutylene, H2SO4 (cat.), CH2Cl2, r. t., 16 h (80 %); (d) EDA, BF3 · Et2O, Et2O, r. t., 1 h (90 %); (e) NaCl,
DMSO, H2O (cat.), 140 ◦C, 4 h (75 %); (f) TFA, CH2Cl2, r. t., 2 h (97 %); (g) 6, HOBt, EDCI, TEA, CH2Cl2, r. t., 16 h (80 %
for 14, 83 % for 15); (h) K2CO3 · 1.5 H2O, MeOH : CH2Cl2 : H2O (8 : 1 : 1, v/v), −10 to 10 ◦C, 30 min (70 % for 16, 75 %
for 17).
zophenone ketyl prior to use. Thin layer chromatography Q HR 5/5 column (Pharmacia) equilibrated with buffer-A
(TLC) was performed on precoated silica gel G and GP and eluted with a linear gradient of 0.1 M NaCl in buffer-
uniplates from Analtech and visualized with 254 nm UV A (30 mL). A single peak of histone deacetylase activity
light. Flash chromatography was carried out on silica gel 60 was eluted with 0.4 M NaCl, and the fraction was stored at
◦
[Scientific Adsorbents Incorporated (SAI), particle size 32 – −80 C until use. Inhibition of histone deacetylase was es-
63 µm, pore size 60 A]. 1H NMR and 13C NMR spectra timated as described by Yoshida et al. with slight modifica-
˚
were recorded on a Bruker DPX 500 instrument at 500 MHz tions. [3H1]-labeled histone was prepared by the method of
and 125 MHz, respectively. The chemical shifts are reported Yoshida et al.: 3 K562 cells (108 cells) were incubated in
in parts per million (ppm) downfield from tetramethylsilane, growth medium (25 mL) containing 0.5 mCi mL−1 sodium
and J values are in Hz. Infrared (IR) spectra were obtained [3H1]acetate (152.8 GBq mmol−1; NEN) and 5 mM sodium
on an ATI Mattson FT/IR spectrometer. Mass spectra were butyrate at 37 ◦C [17]. Histone deacetylase inhibitory activ-
recorded with a Waters Micromass ZQ LC-Mass system, and ity of a test compound was measured as follows: the mixture
high-resolution mass spectra (HRMS) were measured with (total volume 50 µL) containing the above histone deacety-
a Bruker BioApex FTMS system by direct injection using lase fraction (2 µL), [3H1]-labeled histone (100 µg mL−1),
an electrospray interface (ESI). When necessary, chemicals and the test compound (5 µL) was incubated for 10 min at
were purified according to the reported procedures [15].
37 ◦C. [3H1]acetate, which was liberated from [3H1]-labeled
histone, was extracted with ethyl acetate, and radioactivity
was measured by a liquid scintillation counter.
Inhibition of histone deacetylase in vitro
Histone deacetylase fraction was prepared as described by
theYoshida group [16], human leukemia K562 cells (2.5 ×
108) were disrupted in buffer-A [15 mM potassium phos-
N-Benzyloxycarbonyl-4-oxo-(S)-pipecolic acid (13)
To a stirred solution of 12 [18] (0.13 g, 0.38 mmol)
phate buffer (pH 7.5) containing 5 % glycerol and 0.2 mM in dichloromethane (3 mL) was added trifluoroacetic acid
EDTA] (15 mL). The nuclei were collected by centrifugation (0.3 mL) at 5 ◦C, and the mixture was stirred at r. t. for
(35000 g, 10 min) and resuspended with buffer-A (15 mL) 2 h. The reaction mixture was evaporated in vacuo, and
containing 1 M (NH4)2SO4. After sonication, the supernatant the residue was diluted with dichloromethane (20 mL) and
was collected by centrifugation, and ammonium sulfate was washed with 2.5 % aqueous NaHCO3 solution (12 mL) and
added to ma◦ke the final concentration 3.5 M. After stirring brine (12 mL). The organic layer was separated, dried over
for 1 h at 0 C, the precipitate was collected by centrifuga- anhydrous MgSO4, filtered and concentrated under reduced
tion, dissolved with buffer-A (4 mL), and dialyzed against pressure. The residue was purified by flash column chro-
buffer-A (2000 mL). The dialysate was loaded onto a mono matography (silica gel, 50 % ethyl acetate in n-hexanes)
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S. Oh et al. · Benzyl (2S)-2-[(R)-1-hydroxy-2-oxo-(1-phenethyl)prop-3-ylcarbamoyl]-4-oxopiperidine-1-carboxylate 1303
to give 13 (0.085 g, 97 %) as an oil. Rf = 0.2 (ethyl v = 3031, 2976, 1718 (CO), 1696 (COO), 1527, 1458,
1
acetate/n-hexanes = 1 : 1, v/v). – [α]2D4 = −19.6 (c = 1.0, 1218, 1115, 825 cm−1. – H NMR (CDCl3, 500.14 MHz):
CHCl3). – IR (neat, NaCl): v = 3433 (OH), 3034, 2961, δ = 7.51 – 7.03 (m, 11H, Ar-H, NH), 5.21 – 5.01 (m, 2H,
1727 (CO), 1704 (COO), 1542, 1423, 1317, 1251, 1186, CH2Ph), 4.68 – 4.32 (m, 3H, CH2, CH), 4.20 – 3.68 (m,
1057, 865 cm−1. – 1H NMR (CDCl3, 500.14 MHz): δ = 2H, CH2), 2.98 – 2.42 (m, 5H, CH2, CH), 2.30 – 2.11 (m,
9.30 (brs, 1H, OH), 7.42 – 7.24 (m, 5H, Ar-H), 5.23 – 4.98 2H, CH2), 2.09 (s, 3H, CH3), 1.98 – 1.61 (m, 2H, CH2). –
(m, 3H, CH2Ph, CH), 4.10 (t, J = 6.0 Hz, 1H, CH), 4.68 13C NMR (CDCl3, 125.76 MHz): δ = 206.8, 205.1, 170.7,
(t, J = 6.0 Hz, 1H, CH), 2.92 – 2.71 (m, 2H, CH2), 2.55 – 169.9, 154.5, 140.1, 136.0, 128.5, 128.4, 128.1, 127.0, 126.1,
2.43 (m, 2H, CH2). – 13C NMR (CDCl3, 125.76 MHz): δ = 67.9, 66.4, 54.9, 54.1, 51.8, 41.2, 40.4, 40.2, 34.9, 32.1, 31.9,
206.0, 174.1, 156.0, 155.4, 135.8, 128.6, 128.4, 128.0, 68.3, 30.9, 20.9. – HRMS: m/z = 495.2131 (calcd. 495.2145 for
54.3, 53.5, 40.8, 40.3, 39.4. – HRMS: m/z = 278.1032 (calcd. C27H31N2O7, [M+H]+).
278.1028 for C14H16NO5, [M+H]+).
General procedure for the preparation of compounds 16 and
General procedure for the preparation of compounds 14 and
17 via deacetylation of esters 14 and 15
15 via coupling reaction of amine · HCl salt 6 and acids 9
To a stirred solution of keto esters 14 or 15 (0.13 mmol)
or 13
in MeOH : CH2Cl2 : H2O (5.4 mL, 8 : 1 : 1, v/v) was added
To a stirred solution of acids 9 [19] or 13 [20] (0.20 mmol)
◦
K2CO3 · 1.5 H2O (0.26 mmol) in H2O (0.7 mL) at −10 C,
in dichloromethane (8 mL) was added EDCI (0.24 mmol)
and HOBt (0.24 mmol) at 0 ◦C under argon atmosphere, and
then the mixture was stirred at 0 ◦C for 1.5 h. Triethylamine
(0.22 mmol) was added by a syringe to the reaction mix-
ture, followed by addition of amine · HCl salt 6 (0.20 mmol).
Then the resulting mixture was stirred at r. t. for 1.5 h, di-
luted with dichloromethane (10 mL) and washed with 50 %
aqueous NH4Cl solution (10 mL) and brine (10 mL). The
aqueous phase was extracted with dichloromethane (6 mL).
The combined organic layers were washed with saturated
aqueous NH4Cl solution (15 mL), and the organic phase was
separated, dried over anhydrous MgSO4, filtered and con-
centrated under reduced pressure. The residue was purified
by flash column chromatography (silica gel, ethyl acetate/n-
hexanes/methanol = 22 : 70 : 8, v/v) to afford esters 14 and 15
as viscous oils, respectively.
and the mixture was stirred at −10 ◦C to 0 ◦C for 30 min. The
mixture was evaporated in vacuo, and the residue was treated
with dichloromethane (15 mL). The mixture was washed
with saturated aqueous NH4Cl solution (6 mL), and the aque-
ous phase was extracted with dichloromethane (5 mL). The
combined organic layers were washed with saturated aque-
ous NH4Cl solution (10 mL), and the organic phase was
separated, dried over anhydrous MgSO4, filtered and con-
centrated under reduced pressure. The residue was purified
by flash column chromatography (silica gel, ethyl acetate/n-
hexanes/methanol = 22 : 70 : 8, v/v) to afford primary alco-
hols 16 and 17 as viscous foams, respectively.
Benzyl-(2S)-2-[(R)-1-hydroxy-2-oxo-1-(phenethyl)prop-3-
ylcarbamoyl]-4-oxopiperidine-1-carboxylate (16)
Rf = 0.3 (ethyl acetate/n-hexanes/methanol = 22 : 70 : 8,
v/v). – [α]2D4 = −16.0 (c = 0.5, CHCl3). – IR (neat, NaCl):
v = 3327 (OH), 3063, 3029, 2926, 1727 (CO), 1695 (COO),
1531, 1454, 1321, 1216, 1061, 752 cm−1. – 1H NMR
(CDCl3, 500.14 MHz): δ = 7.49 – 6.99 (m, 11H, Ar-H, NH),
6.08 (brs, 1H, OH), 5.32 – 4.98 (m, 2H, CH2Ph), 4.81 – 4.20
(m, 3H, CH2, CH), 4.12 – 3.51 (m, 2H, CH2), 2.82 – 2.36 (m,
3H, CH2, CH), 2.34 – 2.03 (m, 2H, CH2), 2.00 – 1.65 (m,
2H, CH2). – 13C NMR (CDCl3, 125.76 MHz): δ = 207.9,
204.9, 170.9, 155.5, 139.9, 135.4, 128.6, 128.4, 128.2, 128.0,
126.4, 68.6, 66.7, 55.2, 54.4, 52.0, 40.6, 40.1, 35.8, 32.9,
31.9, 30.0. – HRMS: m/z = 439.4525 (calcd. 439.4810 for
C24H27N2O6, [M+H]+).
Benzyl-(2S)-2-[(R)-1-acetoxy-2-oxo-1-(phenethyl)prop-3-
ylcarbamoyl]-4-oxopiperidine-1-carboxylate (14)
Rf = 0.4 (ethyl acetate/n-hexanes/methanol = 20 : 75 : 5,
v/v). – [α]2D4 = −28.4 (c = 0.3, CHCl3). – IR (neat, NaCl):
ν = 3024, 2971, 1715 (CO), 1684 (COO), 1520, 1376,
1
1265, 1112, 728 cm−1. – H NMR (CDCl3, 500.14 MHz):
δ = 7.58 – 7.12 (m, 11H, Ar-H, NH), 5.25 – 5.08 (m, 2H,
CH2Ph), 4.71 – 4.45 (m, 3H, CH2, CH), 4.31 – 3.75 (m,
2H, CH2), 2.95 – 2.45 (m, 3H, CH2, CH), 2.38 – 2.21 (m,
2H, CH2), 2.12 (s, 3H, CH3), 2.00 – 1.72 (m, 2H, CH2). –
13C NMR (CDCl3, 125.76 MHz): δ = 206.8, 205.1, 170.7,
170.1, 154.5, 140.1, 136.0, 128.5, 128.4, 128.1, 127.0, 126.1,
67.9, 66.4, 54.9, 54.1, 51.8, 41.2, 40.2, 34.9, 32.1, 31.9,
30.9, 21.2. – HRMS: m/z = 481.1975 (calcd. 481.1956 for
C26H29N2O7, [M+H]+).
Benzyl-(2S)-2-[(R)-1-hydroxy-2-oxo-1-(phenethyl)prop-3-
ylcarbamoyl]-4-oxopyrrolidine-1-carboxylate (17)
Benzyl-(2S)-2-[(R)-1-acetoxy-2-oxo-1-(phenethyl)prop-3-
ylcarbamoyl]-4-oxopyrrolidine-1-carboxylate (15)
Rf = 0.3 (ethyl acetate/n-hexanes/methanol = 22 : 70 : 8,
v/v). – [α]2D4 = −33.8 (c = 2.0, CHCl3). – IR (neat, NaCl):
Rf = 0.4 (ethyl acetate/n-hexanes/methanol = 20 : 75 : 5, ν = 3331 (OH), 3062, 3029, 2925, 2856, 1725 (CO), 1690
v/v). – [α]2D4 = −21.8 (c = 0.3, CHCl3). – IR (neat, NaCl): (COO), 1531, 1454, 1357, 1245, 1059, 752 cm−1. – 1H NMR
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1304 S. Oh et al. · Benzyl (2S)-2-[(R)-1-hydroxy-2-oxo-(1-phenethyl)prop-3-ylcarbamoyl]-4-oxopiperidine-1-carboxylate
(CDCl3, 500.14 MHz): δ = 7.48 – 7.00 (m, 11H, Ar-H, NH), HRMS: m/z = 453.2005 (calcd. 453.2026 for C25H29N2O6,
6.11 (brs, 1H, OH), 5.31 – 5.10 (m, 2H, CH2Ph), 5.50 – 4.89 [M+H]+).
(m, 1H, CH2), 4.65 – 4.49 (m, 1H, CH), 4.38 – 4.23 (m, 2H,
CH2), 4.08 – 3.90 (m, 1H, CH), 3.79 – 3.56 (m, 1H, CH2),
Acknowledgement
This work has been supported by the KOSEF Brain Neu-
robiology Grant (2007), by the Ewha Global Challenge
(BK21) grant, and in part by Cooperative Agreement Num-
ber 1-U01 C1000211 from the Centers for Disease Control
and Prevention (M. A. A.).
3.34 – 3.03 (m, 1H, CH), 2.82 (d, J = 8.0 Hz, 1H, CH2),
2.70 – 2.41 (m, 4H, CH2), 2.20 – 2.01 (m, 1H, CH2), 1.97 –
1.74 (m, 1H, CH2). – 13C NMR (CDCl3, 125.76 MHz): δ =
208.2, 205.1, 170.6, 155.6, 140.0, 135.6, 128.7, 128.6, 128.5,
128.3, 126.5, 68.4, 66.6, 55.0, 40.3, 39.9, 38.4, 32.6, 31.5. –
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