Synthesis and characterization of novel bile-acid - heteroaryl conjugates with N-(2-aminoethyl)amido linker

Article abstract of DOI:10.1016/j.molstruc.2008.04.057

Four novel bile acid conjugates N-[2-([2,2′]-bithiophen-5-ylmethyl)aminoethyl]-3α-hydroxy-5β-cholan-24-amide (1), N-[2-([2,2′]-bithiophen-5-ylmethyl)aminoethyl]-3α,7α,12α-trihydroxy-5β-cholan-24-amide (2), N-[2-(1H-pyrrol-2-ylmethyl)aminoethyl]-3α-hydroxy-5β-cholan-24-amide (3), N-[2-(pyridin-2-ylmethyl)aminoethyl]-3α-hydroxy-5β-cholan-24-amide (4) have been synthesized in moderate to good yields, and their structures have been characterized by ¹H, ¹³C, ¹³C DEPT-135, PFG ¹H,¹³C HMQC, and PFG ¹H,¹³C HMBC NMR spectra. Their molecular weights and elemental compositions have been determined by ESI-TOF mass spectrometry and elemental analyses. Crystal structure of 1 characterized with orthorhombic P2₁2₁2₁ space group has also been determined.

Full text of DOI:10.1016/j.molstruc.2008.04.057

Journal of Molecular Structure 892 (2008) 53–57
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis and characterization of novel bile-acid – heteroaryl conjugates
with N-(2-aminoethyl)amido linker
*
Juha Koivukorpi , Arto Valkonen, Manu Lahtinen, Erkki Kolehmainen
Department of Chemistry, University of Jyväskylä, P.O. Box 35, FIN-40014, Finland
a r t i c l e i n f o
a b s t r a c t
0
Article history:
Received 17 April 2008
Received in revised form 25 April 2008
Accepted 25 April 2008
Available online 11 May 2008
Four novel bile acid conjugates N-[2-([2,2 ]-bithiophen-5-ylmethyl)aminoethyl]-3
a
-hydroxy-5b-cholan-
0
2
4-amide (1), N-[2-([2,2 ]-bithiophen-5-ylmethyl)aminoethyl]-3
a
,7
-hydroxy-5b-cholan-24-amide (3), N-[2-(pyri-
-hydroxy-5b-cholan-24-amide (4) have been synthesized in moderate
a
,12
a
-trihydroxy-5b-cholan-24-
amide (2), N-[2-(1H-pyrrol-2-ylmethyl)aminoethyl]-3
din-2-ylmethyl)aminoethyl]-3
to good yields, and their structures have been characterized by H, C, C DEPT-135, PFG 1H, C HMQC,
a
a
1
13
13
13
1
13
and PFG H, C HMBC NMR spectra. Their molecular weights and elemental compositions have been
determined by ESI-TOF mass spectrometry and elemental analyses. Crystal structure of 1 characterized
Keywords:
Bile acids
with orthorhombic P2
1
2
1
2
1
space group has also been determined.
Ó 2008 Elsevier B.V. All rights reserved.
Heteroaromatics
13
C NMR chemical shifts
X-ray diffraction
Thermal analysis
1
. Introduction
Bile acids are natural surfactants, which assist in solubilization,
the NMR acquisition and processing parameters are available from
E.K. on request. Mass spectrometric measurements were performed
using a Micromass LCT time of flight (TOF) mass spectrometer with
electrospray ionization (ESI). Elemental analysis was performed
using a VarioEL III elemental analyzer.
digestion and resorption of lipids and lipid soluble vitamins. In
addition, bile acids and their derivatives are potential carriers for
liver specific drugs and some of them can be used as cholesterol
lowering agents [1] and in treatment of bile acid deficiency and li-
ver diseases [2]. Recently, many pharmaceutical and supramolecu-
lar applications of bile acid derivatives have also been reported [3].
Preparation and characterization of bile acid conjugates with vari-
ous heteroaromatic compounds such as nitrogen and sulfur hetero-
cycles are reported earlier by us [4–8]. Among them thiophene in
addition to its pharmaceutical applications [9], has been frequently
used in electronic and optoelectronic devices [10].
2.2. X-ray crystallography
The single crystal X-ray structural data of compound 1, crystal-
lized from methanol, was collected with Bruker–Nonius Kappa
APEX-IIdiffractometerat123.0 ± 0.1 K usinggraphitemonochroma-
a
tized MoK radiation (k = 0.71073 Å) and COLLECT [11] data collec-
tion software. Data was processed with DENZO-SMN [12]. The
structure was solved by direct methods, using SIR2002 [13], and re-
fined on F2, using SHELXL-97 [14]. The reflections were corrected for
Lorenz polarization effects and absorption correction was not used.
The hydrogen atoms were calculated to their idealized positions
with isotropic temperature factors (1.2 or 1.5 times the C tempera-
ture factor) and refined as riding atoms. The figures were drawn with
ORTEP-3 [15] and MERCURY [16]. Other experimental X-ray data are
shown in Table 1. Crystallographic data (excluding structure factors)
has been deposited with the Cambridge Crystallographic Data Cen-
tre as supplementary publication number CCDC-684960. Copies of
the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK.
2
. Experimental
2.1. Spectroscopy
NMR experiments were run on a Bruker Avance DRX 500 FT NMR
spectrometer equipped with a z-gradient accessory and a 5 mm
diameter inverse detection probehead working at 500.13 MHz for
1
H and 125.77 MHz for 13C, respectively. The H NMR chemical shifts
1
1
are referenced to the resonance of CHCl
TMS]. C NMR chemical shifts are referenced to the center peak of
CDCl triplet [d( C) = 77.00 ppm from int. TMS]. Complete lists of
3
3
[d( H) = 7.26 ppm from int.
1
3
1
3
2.3. Differential scanning calorimetry
Thermal transitions of the compounds were determined on
power compensation type Perkin Elmer PYRIS DIAMOND DSC.
*
Corresponding author. Tel.: +358 14 260 2684; fax: +358 14 260 2501.
E-mail address: jkkorpi@jyu.fi (J. Koivukorpi).
0
022-2860/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2008.04.057

5
4
J. Koivukorpi et al. / Journal of Molecular Structure 892 (2008) 53–57
Table 1
of 10 °C/min. The heating–cooling cycle was repeated once. The
sample was held at ꢀ40 °C for 5 min before initiation of a next cy-
cle. The melting temperature (T ), was obtained as an extrapolated
onset. The glass transition temperature (T ) was obtained at a half-
step temperature of a change. Uncertainty for measured tem-
peratures was less than 0.7 °C for all measurements. Sample
weights of ꢁ1–4 mg were used on the measurements. The sample
weight was checked afterwards to monitor a weight loss that may
have occurred during the scans.
Crystal data and structure refinement parameters of 1
1
m
g
Empirical formula
Formula weight
Crystal system
Space group
a (Å)
b (Å)
c (Å)
a,b,c (°)
Volume (Å )
C
35 52 2 2 2
H N O S
596.91
Orthorhombic
P2
7.05300 (10)
15.6665(4)
29.8895(7)
90
3302.66(12)
4
1.200
DC
p
1 1 1
2 2
3
2.4. Synthesis
Z
Densitycalc (Mg/m3)
Abs. coefficient (mmꢀ1)
Bile acid methyl esters were synthesized according to the previ-
0.194
F(000)
h Range (°)
1296
1.88–25.00
ously reported procedure [17]. Amides 5 and 6 were synthesized
from methyl esters using 10-fold excess of 1,2-diaminoethane
[18]. Synthetic route to 1 starting from lithocholic acid is presented
in Scheme 1. All reagents and solvents (purity P96% or better)
were purchased from Sigma–Aldrich or Fluka and used without
further purification.
Index ranges
ꢀ8 6 h 6 0
ꢀ
ꢀ
18 6 k 6 18
35 6 l 6 35
Reflections collected
Internal consistency
11585
0.1648
Data/restraints/parameters
3341/18/371
1.084
Goodness-of-fit on F2
0
2.4.1. N-[2-([2,2 ]-bithiophen-5-ylmethyl)aminoethyl]-3
a-hydroxy-
5b-cholan-24-amide 1
Final R indices [I > 2r(I)]
R
1
0.0719
0.1266
N-(2-aminoethyl)-3
1.19 mmol) and 2,2 -bithiophenyl-5-carbaldehyde 250 mg
1.29 mmol) were dissolved in 20 mL of methanol, and the solution
was stirred at rt for 1d. Formed Schiff base was reduced by NaBH
150 mg (3.96 mmol) added during 5 min and stirring was contin-
ued for 30 min. Then another 150 mg of NaBH was added and
the mixture was stirred for additional 1.5 h. Solvent was evapo-
rated and the product was dissolved in CH Cl and transferred into
a
-hydroxy-5b-cholan-24-amide 5 500 mg
wR
R indices (all data)
R
wR
Largest diffraction
2
0
(
(
1
0.1050
0.1400
4
2
ꢀ
3
Peak (eÅ
)
0.39
ꢀ0.31
4
Hole (eÅꢀ3)
2
2
separatory funnel with water. About 2 M aq. HCl was added until
the water layer was neutralized. Organic layer was washed with
The measurements were carried out under nitrogen atmosphere
water and dried over anhyd. Na
umn chromatography (silica gel, 0.040–0.063 mm; eluents: CH
and CH Cl :MeOH 95:5). Recrystallization from CH CN gave pure
product 235 mg (33%). H NMR in CDCl : d = 0.62 (3H, s), 0.91
2
SO
4
. Product was purified by col-
ꢀ1
(
flow rate 50 mL min ) using 50
lL sealed aluminum sample
2
Cl
2
pans. The sealing was made by using a 30
lL aluminum pan with
2
2
3
1
capillary holes to ascertain good thermal contact between the sam-
ple and pan, and to minimize the free volume inside the pan. The
temperature calibration was made using two standard materials
3
(3H, s), 0.91 (3H, d), 0.93–1.90 (28H), 2.03–2.12 (1H, m), 2.20–
2.29 (1H, m), 2.81 (2H, t), 3.35 (2H, q), 3.61 (1H, m), 3.95 (2H, d),
6.00 (1H, t), 6.81 (1H, d), 6.99 (1H, t), 7.00 (1H, d), 7.12 (1H, dd),
(
(
n-decane, In) and energy calibration by an indium standard
28.45 J g ). Typically, following temperature profile was used
ꢀ1
+
+
7.19 (1H, dd). MS: m/z = 597 [M+H] , 619 [M+Na] . MW
) = 596.94. Elemental analysis: calcd. (%) for
: C, 70.42; H, 8.78; N, 4.69. Found C, 70.23; H, 8.91;
for each sample: a sample was heated from 0 to either 160 or
80 °C with a heating rate of 10 °C/min, followed by 1 min hold
at the end temperature, and cooled down to ꢀ40 °C with a rate
(C35H
52
N
2
O
S
2 2
1
C H
35 52
N
2
O
S
2 2
N, 4.08.
0
2 4
SO , reflux overnight; (ii) 1,2-diaminoethane, MeOH, reflux 48 h; (iii) 2,2 -bithiophenyl-5-
Scheme 1. Synthetic route to 1. Reagents and condition: (i) MeOH, conc. H
carbaldehyde, CHCl , rt 1 day; (iv) NaBH , MeOH, rt 2 h. Insert: structure of intermediate 6.
3
4

J. Koivukorpi et al. / Journal of Molecular Structure 892 (2008) 53–57
55
Fig. 1. Structures and numbering of 1–4.
Table 2
1
3C NMR chemical shifts of 1–4 (ppm from int. TMS) in CDCl
0
3
at 303 K
2
.4.2. N-[2-([2,2 ]-bithiophen-5-ylmethyl)aminoethyl]-3
trihydroxy-5b-cholan-24-amide. 2
N-(2-aminoethyl)-3 ,7 ,12
a,7a,12a-
Carbon
1
2
3
4
a
a
a
-trihydroxy-5b-cholan-24-amide 6
1
2
3
4
5
6
7
8
9
35.4
30.6
71.8
36.5
42.1
27.2
26.4
35.9
40.5
34.6
20.8
40.2
42.7
56.5
24.2
28.2
56.0
12.0
23.4
35.5
18.4
31.8
33.7
34.7
30.5
71.8
39.7
41.5
35.3
68.4
39.5
26.4
34.7
28.2
73.0
46.4
41.7
23.3
27.6
46.5
12.4
22.4
35.4
17.5
31.6
33.1
35.4
30.6
71.8
36.5
42.1
27.2
26.4
35.9
40.5
34.6
20.8
40.2
42.7
56.5
24.2
28.2
56.0
12.0
23.4
35.5
18.4
31.8
33.6
35.4
30.6
71.7
36.5
42.1
27.2
26.4
35.9
40.5
34.6
20.8
40.2
42.8
56.5
24.2
28.2
56.1
12.1
23.4
35.5
18.4
31.9
33.7
0
5
2
00 mg (1.11 mmol) and 2,2 -bithiophenyl-5-carbaldehyde
30 mg (1.18 mmol) were dissolved in 20 mL of methanol. Synthesis
was continued as described for 1. Product was purified by column
chromatography (silica gel, 0.040–0.063 mm; eluents:
CH Cl :MeOH 95:5, 90:10, 80:20). Yield 460 mg (66%). H NMR in
CDCl : d = 0.64 (3H, s), 0.85 (3H, s), 0.94 (1H, m), 0.97 (3H, d), 1.00–
.93 (23H), 2.05–2.28 (4H), 2.80 (2H, t), 3.34 (2H, t), 3.36 (1H, m),
.80 (1H, d), 3.92 (1H, s), 3.94 (2H, s), 6.52 (1H, br), 6.81 (1H, d),
.98 (1H, t), 6.99 (1H, d), 7.11 (1H, dd), 7.18 (1H, dd). MS:
m/z = 629 [M+H] , 651 [M+Na] . M.W. (C35
Elemental analysis: calcd. (%) for C35
N, 4.45. Found C, 66.94; H, 8.47; N, 4.08.
1
2
2
3
1
3
6
1
1
1
13
14
1
1
1
1
0
1
2
+
+
H
52
N
2
O
4
S
2
) = 628.94.
52 2 4 2
H N O S : C, 66.84; H, 8.33;
5
6
7
8
2
.4.3. N-[2-(1H-pyrrol-2-ylmethyl)aminoethyl]-3
cholan-24-amide. 3
N-(2-aminoethyl)-3
1.19 mmol) and pyrrole-2-carbaldehyde 130 mg (1.37 mmol)
were dissolved in 20 mL of methanol. Synthesis was continued as
a-hydroxy-5b-
19
2
2
2
2
0
1
2
3
a-hydroxy-5b-cholan-24-amide 5 500 mg
(
described for 1. Product was purified by column chromatography
24
25
26
173.7
39.0
47.8
48.2
143.4
125.6
123.3
136.5
137.6
123.4
127.7
124.2
–
–
–
–
–
–
–
–
–
174.3
39.0
47.8
48.0
142.9
125.8
123.3
136.5
137.5
123.4
127.7
124.2
–
–
–
–
–
–
–
–
–
174.1
38.9
48.1
45.8
–
–
–
–
–
–
–
–
129.7
108.1
106.7
117.6
–
–
–
–
–
173.8
39.0
48.4
54.4
–
–
–
–
–
–
–
–
–
–
–
–
(
2
0
silica gel, 0.040–0.063 mm; eluent: CH
26 mg (38%). H NMR in CDCl
3
2
Cl
: d = 0.64 (3H, s), 0.92 (3H, s),
.92 (3H, d), 0.93–2.00 (28H), 2.02–2.13 (1H, m), 2.19–2.27 (1H,
2
:MeOH 70:30). Yield
1
2
2
2
7
8
9
m), 2.76 (2H, t), 3.34 (2H, q), 3.61 (1H, m), 3.80 (2H, s), 6.00 (1H,
t), 6.04 (1H, br), 6.12 (1h, q), 6.74 (1H, m), 8.93 (1H, br). MS:
30
31
+
+
m/z = 498 [M+H] , 520 [M+Na] . M.W. (C31
Elemental analysis: calcd. (%) for C31
3.64; H, 10.40; N, 8.18. Found C, 73.75; H, 10.11; N, 7.75.
H
51
N
3
O
2
) = 497.77.
3
3
3
3
2
3
4
5
H
51
N
3
O
2
ꢂ0.5 CH OH: C,
3
7
2
2
.4.4. N-[2-(pyridin-2-ylmethyl)aminoethyl]-3
4-amide. 4
a-hydroxy-5b-cholan-
36
37
38
39
40
N-(2-aminoethyl)-3a-hydroxy-5b-cholan-24-amide 5 500 mg
(
1.19 mmol)andpyridine-2-carbaldehyde120
lL (1.26 mmol)were
159.1
122.4
136.6
122.2
149.3
dissolved in 20 mL of methanol. Synthesis was continued as de-
scribed for 1. Product was purified by column chromatography (sil-
41
4
4
4
2
3
4
ica gel, 0.040–0.063 mm; eluents: CH
2
Cl
2
:MeOH 98:2, 80:20). Yield
: d = 0.61 (3H, s), 0.89
1
3
60 mg (59%); mp. 161 °C. H NMR in CDCl
3

5
6
J. Koivukorpi et al. / Journal of Molecular Structure 892 (2008) 53–57
NMR reference data of bile acids [19], 13C DEPT-135, PFG 1H,13
C
1
13
HMQC [20], and PFG H, C HMBC [21] spectra.
Steroidal parts in 1, 3, and 4, which all contain a lithocholamide
1
3
fragment, show very similar C NMR chemical shifts whereas
those in 2 being a cholamide derivative differ owing to two addi-
1
3
tional hydroxyls at carbons 7 and 12. The C shifts of these steroi-
dal parts are in agreement with those reported previously [19].
Carbon-27 bearing in both 1 and 2 a bithiophenyl moiety possesses
very similar chemical shift (48.2 and 48.0 ppm), whereas in 3 and 4
the chemical shift of C-27 differs significantly due to the presence
of pyrrole (45.8 ppm) and pyridine (54.4 ppm) substituent, respec-
tively. The effect of different substituents on the shifts of more dis-
tal carbons 25 and 26 is minimal.
3.2. X-ray crystallography
The quality of single crystal X-ray data of 1 is only moderate
(
see Table 1), due to weak crystallinity and scattering effects of
the compound. The absolute structure parameter (Flack parame-
ter) [22] of this chiral compound in chiral space group was mean-
ingless (ꢁ0.5) after last refinement and was removed from the
results. There is also small disorder in the second thiophene ring,
which can be seen from the thermal ellipsoids of C32–C35 and
S2 (Fig. 2). The use of weak restraints (SIMU 0.01) gave better re-
sult than finding the secondary possible positions of atoms in han-
dling this disorder, most probably of static kind in low temperature
data collection.
Fig. 2. Crystal structure of 1, showing thermal ellipsoids drawn with 50%
probability level.
(
(
(
3H, s), 0.90 (3H, d), 0.92–1.96 (28H), 2.01–2.10 (1H, m), 2.19–2.27
1H, m), 2.78 (2H, t), 3.35 (2H, q), 3.58 (1H, m), 3.89 (2H, s), 6.43
1H, t), 7.17 (1H, m), 7.24 (1H, d), 7.63 (1H, dt), 8.54 (1H, qd). MS:
Three classical intermolecular hydrogen bonds were found from
+
+
m/z = 510 [M+H] , 532 [M+Na] . M.W. (C32
mental analysis: calcd. (%) for C32 : C, 75.40; H, 10.08; N,
51 3 2
H N O ) = 509.77. Ele-
1, as presented in Fig. 3. Stacking interactions between thiophene
51 3 2
H N O
rings were not observed. An infinite tail-to-head chains were found
to be formed with O3–H3ꢂ ꢂ ꢂN26 hydrogen bonds. Some geometric
parameters are also collected in Table 3. The bile acid side chain
lies on anti (trans) conformation, which can be deduced from
C17–C20–C22–C23 dihedral angle value close to 180°. Overall side
chain conformation can be expressed as a combination of the first
four dihedral angles in Table 3, being ttgi, and the letters indicating
the trans (t), gauche (g) and intermediate (i) conformation related
angle values [23]. The angle between planes formed by thiophene
rings is 13.7°.
8
.24. Found C, 74.99; H, 10.02; N, 7.71.
3
. Results and discussion
3.1. NMR spectroscopy
Structures and numbering of compounds 1–4 are presented in
1
3
Fig. 1. C NMR chemical shifts are collected in Table 2. The chem-
1
3
ical shift assignments of the steroidal part of 1–4 are based on
C
Fig. 3. A view of molecular packing of 1.

J. Koivukorpi et al. / Journal of Molecular Structure 892 (2008) 53–57
57
Table 3
Some geometric parameters of 1
X–Y
d(X–Y) [Å]
W–X–Y–Z
(WXYZ) [°]
D–Hꢂ ꢂ ꢂA
d(Dꢂ ꢂ ꢂA) [Å]
(DHA) [°]
S(1)–C(28)
S(1)–C(31)
S(2)–C(32)
S(2)–C(35)
O(3)–C(3)
O(24)–C(24)
N(24)–C(24)
N(24)–C(25)
N(26)–C(26)
N(26)–C(27)
1.720(8)
1.725(7)
1.712(8)
1.714(12)
1.414(7)
1.245(6)
1.327(8)
1.452(8)
1.453(7)
1.467(7)
C13–C17–C20–C22
C17–C20–C22–C23
C20–C22–C23–C24
C22–C23–C24–N24
C23–C24–N24–C25
C24–N24–C25–C26
N24–C25–C26–N26
C25–C26–N26–C27
C26–N26–C27–C28
N26–C27–C28–S1
S1–C31–C32–S2
168.4(4)
ꢀ176.7(5)
54.0(7)
O3–H3ꢂ ꢂ ꢂN26
N24–H24ꢂ ꢂ ꢂO3
N26–H26ꢂ ꢂ ꢂO24
2.786(6)
2.849(6)
2.918(8)
174
175
132
ꢀ145.0(5)
175.3(5)
ꢀ85.8(7)
ꢀ179.8(5)
ꢀ78.6(6)
ꢀ66.6(8)
ꢀ83.3(7)
ꢀ170.8(4)
Table 4
hydes are useful starting compounds in preparation of bile acid–
heteroaromatic conjugates. Reduction of the formed Schiff bases
The glass transition temperatures, melting points, enthalpy and heat capacity changes
of 1-4
4
by NaBH produced methylene linked heteroaryl derivatives in
Compound
T
m
, T
g
p
(DH); [DC ]
moderate to good yields. These conjugates are forwarded further
for complex formation studies and for using as building blocks in
bile acid derived receptors. Especially interesting is also their use
in preparation of silver and other metal nanoparticles. These stud-
ies are in progress.
1
T
T
g
44.3
44.6
[0.57]
[0.59]
1st scan
2nd scan
g
2
3
4
T
T
g
g
61.6
80.6
[0.30]
[0.59]
1st scan
2nd scan
T
T
g
g
62.9
99.5
[0.32]
[0.49]
1st scan
2nd scan
Acknowledgements
T
T
m
160.8
45.3
[99.56]
[0.37]
1st scan
2nd scan
g
The authors acknowledge Spec. Lab. Tech. Mirja Lahtiperä for
running ESI-TOF mass spectra, Spec. Lab. Tech. Reijo Kauppinen
for his help in running the NMR spectra, and Lab. Tech. Elina Hau-
takangas for elemental analysis.
T
m
= melting temperature (°C),
D
H = enthalpy change (J gꢀ1), T
g
= glass transition
+
1
ꢀ1
temperature (°C), = heat capacity change (J g °C ).
DC
p
References
[
[
[
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[
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[
[
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3
.3. Differential scanning calorimetry
g
For the compounds 1–3 only glass transitions (T ) can be ob-
served on both consecutive heating scans, indicating that the mea-
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1
[
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161 °C. On cooling, the sample enters to a glassy state, therefore
g
[
[
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4
ꢁ
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4
. Conclusions
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We have shown that lithocholyl and cholyl N-(2-amino-
ethyl)amides when reacted with various heteroaromatic carbalde-