Lipase-catalyzed regioselective monoacetylation of unsymmetrical 1,5-primary diols

Article abstract of DOI:10.1021/jo902541c

"Chemical Equation Presented" Lipase B from Candida antarctica (CALB) has been selected as the most suitable enzyme to catalyze the regioselective monoacetylation of 1,5-diol isoprostane intermediate, using vinyl acetate as an acyl transfer reagent in TIIF. We next applied this reaction on linear 2-substituted, 2,2′-disubstituted-l,5pentanediols, and, cyclic 2,3-disubstituted-l,5-pentanediols. To rationalize the regioselectivity observed, molecular docking simulations were performed.

Full text of DOI:10.1021/jo902541c

pubs.acs.org/joc
Lipase-Catalyzed Regioselective Monoacetylation of Unsymmetrical
1,5-Primary Diols
†
Camille Oger, Zsuzsanna Marton, Yasmin Brinkmann, Valerie Bultel-Ponce,
‡
†
ꢀ
ꢀ †
Thierry Durand,† Marianne Graber,‡ and Jean-Marie Galano*,†
†
ꢀ
ꢀ
Institut des Biomolecules Max Mousseron (IBMM), UMR 5247 CNRS, Universite Montpellier I et II,
Faculteꢀ de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093 Montpellier, Cedex 05, France, and
‡
ꢀ
Universite de la Rochelle, Pole Sciences-Bat. Marie Curie, UMR 6250 LIENSs CNRS-ULR,
^
^
Avenue Michel Creꢀpeau, 17042 La Rochelle, Cedex 01, France
jgalano@univ-montp1.fr
Received November 30, 2009
Lipase B from Candida antarctica (CALB) has been selected as the most suitable enzyme to catalyze
the regioselective monoacetylation of 1,5-diol isoprostane intermediate, using vinyl acetate as an acyl
transfer reagent in THF. We next applied this reaction on linear 2-substituted, 2,20-disubstituted-1,5-
pentanediols, and cyclic 2,3-disubstituted-1,5-pentanediols. To rationalize the regioselectivity ob-
served, molecular docking simulations were performed.
SCHEME 1. Lipase-Catalyzed Monobenzoylation of 1,5-Diol
Introduction
Developed by Santaniello et al.a
The selective monoprotection of two chemically equivalent
primary hydroxyl groups constitutes a challenge in organic
chemistry.1 Protection of such compounds by chemical methods
usually generates a mixture of unreacted and mono- and dipro-
tected diols. Recently, Clarke described monoacylation of meso
1,3- and 1,4-diols, using cerium or ytterbium with modest regio-
selectivity.2 The development of enzymatic protecting group tech-
niques offers viable alternatives to classical chemical approaches.
However, enzymatic protection techniques of hydroxyl groups
was mainly developed on polyhydroxylated compounds such as
mono- and oligosaccharides3 and nucleosides4 and therefore
aReagents: (a) MML, VB, tert-butyl methyl ether.
rarely applied to primary alcohols differentiation.5 To the best
of our knowledge, there is only one example for the selective
monoprotection of primary non-meso 1,5-diols being furthermore
enzymatic. Indeed, in 2003 Santaniello et al. reported the mono-
benzoylation of the 2-methyl-1,5-pentanediol 1a (Scheme 1) using
the Mucor miehei lipase (MML) and vinyl benzoate (VB) as an
acyl transfer agent.6 The monobenzoylated compound 1b and its
regioisomer 1c were obtained in a 85:15 ratio.
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis;
Wiley: New York, 1991.
(2) Clarke, P. A. Tetrahedron Lett. 2002, 43, 4761.
(3) For seminal work see: (a) Riva, S.; Chopineau, J.; Kieboom, A. P. G.;
Klibanov, A. M. J. Am. Chem. Soc. 1988, 110, 584. (b) Therisod, M.;
Klibanov, A. M. J. Am. Chem. Soc. 1987, 109, 3977. (c) Hennen, W. J.;
Sweers, H. M.; Wang, Y. F.; Wong, C. H. J. Org. Chem. 1988, 53, 4939. For a
review on enzymatic protective group techniques, see: (d) Kadereit, D.;
Waldmann, H. Chem. Rev. 2001, 101, 3367.
(4) For seminal work see: (a) Wong, C. H.; Chen, S. T.; Hennen, W. J.;
Bibbs, J. A.; Wang, Y. F.; Liu, J. L. C.; Pantoliano, M. W.; Whitlow, M.;
Bryan, P. N. J. Am. Chem. Soc. 1990, 112, 945. (b) Moris, F.; Gotor, V. J.
Org. Chem. 1992, 57, 2490.
We recently developed a new strategy7 toward the synth-
esis of isoprostanes including a selective oxidation of 2a
using an iridium catalyst,8 which allowed the introduction
of the R chain (Scheme 2). A method that could differentiate
(6) Ciuffreda, P.; Casati, S.; Santaniello, E. Tetrahedron Lett. 2003, 44,
3663.
(5) For nonsymmetric primary 1,3-diols see: (a) Hisano, T.; Onodera, K.;
Toyabe, Y.; Mase, N.; Yoda, H.; Takabe, K. Tetrahedron Lett. 2005, 46,
6293. For primary 1,4-diols (acyclic R,ω-terpenediols) see: (b) Takabe, K.;
Mase, N.; Hisano, T.; Yoda, H. Tetrahedron Lett. 2003, 44, 3267.
(7) Oger, C.; Brinkmann, Y.; Bouazzaoui, S.; Durand, T.; Galano, J.-M.
Org. Lett. 2008, 10, 5087.
(8) Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. Org. Lett. 2002, 4,
2361.
1892 J. Org. Chem. 2010, 75, 1892–1897
Published on Web 02/26/2010
DOI: 10.1021/jo902541c
r
2010 American Chemical Society

Oger et al.
JOCArticle
SCHEME 2. Functionalization of 2a-1,5-Diola
aReagents and conditions: (a) Cp*Ir[OCH2C(C2H5)2NH] 0.8 mol %, butanone, reflux, 91%; (b) DIBAL-H, CH2Cl2, -78°C, 89%.
SCHEME 3a
TABLE 1. Lipase-Catalyzed Acetylation of 2a in Different Solvents
solvent (solvent, time
(h)
ratio
2b/2c/2d
yieldd
(%)
entry
enzymes
vinyl acetate)
1
2
3
4
5
6
7
8
9
MMLa
tBuOMe (220:1)
tBuOMe (220:1)
tBuOMe (220:1)
tBuOMe (220:1)
16
16
16
16
16
16
8
8
6
8
12
90/10/0
49e
Amano AKa
PCLa
PPLa
Candida rugosaa tBuOMe (220:1)
70/30/0
100/0/0
100/0/0
90/0/10
90/0/10
100/0/0c
100/0/0c
31e
96
98
90
82
97
97
CALBa
CALBb
CALBb
CALBb
THF (220:1)
THF (1:1)
vinyl acetate
tBuOMe (1:1)
CH2Cl2 (1:1)
Et2O (1:1)
aReagents: (a) lipase, vinyl acetate, solvent.
10 CALBb
11 CALBb
the two primary alcohol groups of the cyclic 2,3-disubstituted-
1,5-pentanediol key intermediate 2a would afford a complemen-
tary and more flexible strategy for the introduction of lateral
chains.
a50 mg of 2a, 10 mg of enzyme in 3 mL of solvent and 15 μL of vinyl
acetate. b100 mg of 2a, 30 mg of CALB in 10 mL of a mixture of solvent/
vinyl acetate (1:1). cDiacetylated compound 2d was not detected by 1H
NMR of the crude reaction, but traces were separated by column
chromatography; dYields refer to monoacetylated compounds isolated
after flash chromatography. eReaction was stopped after 16 h when
unsatisfactory ratio was observed by TLC.
Results and Discussion
We started our investigation by using a slight modification
of the Santaniello et al. reaction conditions for the regiose-
lective monoprotection of the diol 2a, employing vinyl
acetate instead of vinyl benzoate (Scheme 3). Unfortunately,
a mixture of monoacetylated compounds 2b/2c was obtained
(Table 1, entry 1).
dichloromethane did not improve the regiochemical out-
come of the reaction (entries 10 and 11). It is important to
note that similar results were obtained with the racemic
form of diol 2a and that no enantioselective discrimina-
tion was observed.
We then decided to screen various enzymes in order to
study the regioselective monoacetylation of the diol 2a.
The results obtained are summarized in Table 1. No
reaction occurs with the lipases from Pseudomonas
cepacia (PCL), Amano AK, porcine pancreas (PPL), and
Candida rugosa (entries 2-5). To our delight, full conver-
sion and highly regioselective monoprotection of 2a
(entry 6) were obtained when the lipase B from Candida
antarctica (CALB) was used. The desired monoacetylated
compound 2b was obtained as a sole product after 16 h in
THF. We then studied the effect of vinyl acetate concen-
tration with the aim to decrease the reaction time. Switch-
ing the ratio of solvent/vinyl acetate from 220:1 to 1:1
(v/v) still provided full conversion and a high regioselectivity
with significantly reduced reaction time (entry 7). Similar
result in terms of reaction rate was obtained when the
reaction was carried out in neat vinyl acetate or tBuOMe
albeit with a lower regioselectivity (90:10) (entries 8 and
9).9 Finally, other solvents such as diethyl ether or
With these results in hand, we sought to examine the scope
of the method. The above optimized conditions were then
applied to an array of cyclic 2,3-disubstituted-1,5-pentane-
diols (compounds 5a-13a, Figure 1).
The results are summarized in Table 2. In all cases full
conversion was obtained. For isoprostanes precursors
(5a-8a), complete regioselectivity in favor of monoacety-
lated compounds 5b-8b (entries 1-5) was obtained, whereas
3% of bis-acetylated compound 9d was observed with 9a-
diol (entry 6). Compound 10a, a prostaglandins precursor,
gave a similar result, providing exclusively the desired mono-
protected compound 10b (entry 7). Surprisingly, only the bis-
protected compound 11d was obtained when the reaction
was run with the hydroxylpentan-1,5-diol 11a (entry 8). Poor
results were obtained with the naked cyclohexane 12a (entry
9) with a ratio of bis-acetylated compound 12d/monoacety-
lated product 12b of 66:34. Finally, cyclopentane derivatives
13a (entry 10) gave only the bis-acetylated adduct 13d. It
should be noted that the reaction could be run on gram scale
on diols 2a and 5a-9a, with high yields (96-100%) and no
loss of regioselectivity.
(9) Solvent effects on enantioselectivities have been previously observed
which could account for the lowering in regioselectivy, see: (a) Carrea, G.;
D’Arrigo, P.; Piergianni, V.; Roncaglio, S.; Secundo, F.; Servi, S. Biochim.
Biophys. Acta 1995, 1255, 273. (b) Wescott, C. R.; Klibanov, A. M. Biochim.
Biophys. Acta 1994, 1206, 1.
Encouraged by the above results and to further extend the
scope of the reaction, we applied our optimized conditions to
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JOCArticle
FIGURE 1. Structure of 2,3-disubstituted 1,5-diols and their acetates (compounds 5a-d to 13a-d).
TABLE 2. CALB-Catalyzed Acetylation of Diols 5a-13a
TABLE 3. CALB-Catalyzed Acetylation of Diols 14a-18a
entry
diola
time (h)
products
ratiob b/c/d
yieldc (%)
entry
diola
time (h)
products
ratiob b/c/d
yieldc (%)
1
2
3
4
5
6
7
8
9
10
5a
2
2
2
2
2
23
24
2
3.5
24
5b
100/0/0
100/0/0
100/0/0
100/0/0
100/0/0
97/0/3
100/0/0
0/0/100
34/0/66
0/0/100
88
88
88
83
94
97
90
1
2
3
4
5
14a
15a
16a
17a
18a
1
42
0.5
3
14b/14d
15b/15d
16d
17b/17d
18b/18d
87/0/13
78/0/22
0/0/100
36/0/64
90/0/10
79
78
ent-5a
6a
7a
8a
9a
10a
11a
12a
13a
ent-5b
6b
7b
30
66
8b
3
a100 mg of diol, 30 mg of CALB in 10 mL of a mixture of THF/vinyl
9b/9d
10b
11d
12b/12d
13d
acetate (1:1). bDetermined by 1H NMR analysis of the crude reaction at
full conversion. Yields refer to monoacetylated product isolated after
flash chromatography.
c
25
a100 mg of diol, 30 mg of CALB in 10 mL of a mixture THF/ vinyl
acetate (1/1). bDetermined by 1H NMR analysis of the crude reaction at
full conversion. cYields refer to monoacetylated compound isolated
after flash chromatography.
FIGURE 3. Structure of the docked 1,5-diols and summary of the
regioselectivities observed.
Molecular Modeling Study
FIGURE 2. Structure of linear 2-substituted and 2,20-substituted
1,5-diols and their acetate analogues (compounds 14a-d to 18a-d).
Recently, computer-based modeling methodology has
been used to understand the regioselectivity in acylation of
complex substrate including several hydroxyl groups cata-
lyzed by enzymes.10 In order to explain the regioselectivity
obtained with the same enzyme during our study, docking
simulations were performed on five substrates with good
regioselectivities (5a, ent-5a and 6a; Figure 3), modest regio-
selectivity (15a; Figure 3), and without selectivity (11a;
Figure 3).
several linear 2-substituted diols (14a-18a, Figure 2). In all
cases, regioselectivities observed were lower than those
obtained for cyclic 2,3-disubstituted-1,5-pentane-diols com-
pounds. Good results were obtained for compounds 14a and
15a with 79% yields in favor of the monoprotected com-
pounds 14b and 15b (entries 1 and 2, Table 3). However, as
observed for cyclic diol 11a, the presence of a free hydroxyl
group seems to have a deleterious effect on the regioselec-
tivity.
Molecular docking experiments of compounds 5a, ent-5a,
6a, 11a, and 15a into the active site of the CALB were
performed using the CHARMm force field11 based docking
Indeed, acetylation of compound 16a bearing a free
tertiary hydroxyl group produced exclusively the bis-acety-
lated product 16d, whereas reaction of its silylated version
(compound 17a) gave a mixture of mono- and diacetate
adducts (entries 3 and 4). Finally, as observed with the 1,5-
diol 15a, good regioselectivity was obtained for the 1,4-diol-
18a, with 66% yield in favor of the monoacetylated com-
pound 18b. For all the substrates presented, monoprotected
compounds 2c-18c were never observed. The reaction was
completely regioselective toward the alcohol with the longer
chain.
(10) (a) De Oliveira, E. B.; Humeau, C.; Chebil, L.; Maia, E. R.; Dehez,
F.; Maigret, B.; Ghoul, M.; Engasser, J.-M. J. Mol. Catal. B: Enzym. 2009,
59, 96. (b) Pieraccini, S.; Sironi, M.; Colombo, G. Chem. Phys. Lett. 2006,
418, 373–376. (c) Colombo, G.; Riva, S.; Danieli, B. Tetrahedron 2004, 60,
741. (d) Fuentes, G.; Cruces, M. A.; Plou, F. J.; Ballesteros, A.; Verma, C. S.
ChemBioChem 2002, 3, 907. (e) Rich, J. O.; Bedell, B. A.; Dordick, J. S.
Biotechnol. Bioeng. 1995, 45, 426.
(11) MacKerell, A. D., Jr.; Bashford, D.; Bellott, M.; Dunbrack, R. L.,
Jr.; Evanseck, J.; Field, M. J.; Fischer, S.; Gao, J.; Guo, H.; Ha, S.; Joseph,
D.; Kuchnir, L.; Kuczera, K.; Lau, F. T. K.; Mattos, C.; Michnick, S.; Ngo,
T.; Nguyen, D. T.; Prodhom, B.; Reiher, I., W. E.; Roux, B.; Schlenkrich, M.;
Smith, J.; Stote, R.; Straub, J.; Watanabe, M.; Wiorkiewicz-Kuczera, J.; Yin,
D.; Karplus, M. J. Phys. Chem. B. 1998, 102, 3586.
1894 J. Org. Chem. Vol. 75, No. 6, 2010

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TABLE 4. Distances between the Hydroxyl Group, Acetate Carbonyl,
and His224-Nε Atom, after Optimization for Diols 5a, ent-5a, 6a, and 15a
distance from
˚
ACE (A)
distance from
˚
His224 (A)
entry
1
complex
buried OH
5a-I
OHa
OHb
OHa
OHb
OHa
OHb
OHa
OHb
OHa
OHb
OHa
OHb
OHa
OHb
OHa
OHb
3.3
6.5
3.5
7.9
3.7
6.6
3.8
4.6
3.3
4.4
3.4
6.5
3.4
5.8
3.9
5.8
3.7
6.0
3.3
7.0
3.0
8.1
3.1
5.8
3.8
5.8
3.8
7.6
4.1
7.6
4.4
7.6
2
3
4
5
6
7
8
5a-II
ent-5a-I
ent-5a-II
6a-I
6a-II
15a-I
15a-II
SCHEME 4. Structural Requirements the Substrate Must
Satisfy To Be Considered Reactive
tool CDOCKER12 of Discovery Studio 2.1 (Accelrys Inc.,
San Diego, CA). The study was composed of the following
steps: preparation of the starting enzyme structure and
modeling of the acetyl-enzyme; docking of the 1,5-primary
diol substrates; scoring; optimization and structural analysis
of the best poses; verification of the reliability of the final
models. After scoring, poses with a good consensus score and
with a good orientation of the hydroxyl groups toward the
active site were retained and were submitted to further
optimizations. Three criteria have to be combined for the
complex to be considered as a productive binding mode, in
order to conclude that the acetylation reaction is able to take
place. First, the root-mean-square deviation (rmsd) value
between the initial crystal structure and the final optimized
structure must be small. As found by Valliki et al. for
˚
prostaglandins acetylation, a rmsd value of <3 A was
chosen, as a limit.13 Then, the complex must form a mini-
mum of two of the three hydrogen bond interactions between
the acetate oxygen and the hydrogen of the Thr40 and
Gln106 residues. Finally, the hydroxyl group of the 1,5-diol
2
˚
must be placed simultaneously at <4 A from the sp carbon
of the acetyl and the Nε atom of His224 to be considered as a
productive complex (Scheme 4).
In Table 4 are summarized the transacetylation distances
for structures having the best potential energy after optimi-
zations, for the diols 5a and its enantiomer 6a and 15a.
FIGURE 4. Orientations and hydrogen bond interactions (dashed
lines) of the best structures obtained with diols: (a) 5a (pink), (b) ent-
5a (orange), (c) 6a (purple), and (d) 15a (green). For clarity, only the
residues useful for discussion are shown (gray).
(12) Wu, G.; Robertson, D. H.; Brooks, C. L. III; Veith, M. J. Comput.
Chem. 2003, 24, 1549.
€
(13) Valliki, I.; Fransson, L.; Hult, K.; Jarving, I.; Pehk, T.; Samel, N.;
Tougu, V.; Villo, O.; Parve, J. J. Mol. Catal. B: Enzym. 2005, 35, 62.
~
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TABLE 5. Distances between the Hydroxyl Group, Acetate Carbonyl,
and His224-Nε Atom, after Optimization for Diol 11a
distance from
˚
ACE (A)
distance from
˚
His224 (A)
entry
1
complex
buried OH
11a-I
OHa
OHb
OHa
OHb
OHa
OHb
OHa
OHb
5.7
3.2
7.6
3.2
4.1
7.1
3.9
9.2
4.8
3.9
7.0
3.8
4.3
8.7
4.1
9.2
2
3
4
11a-II
11a-III
11a-IV
TABLE 6. Distances between the Hydroxyl Group, Acetate Carbonyl,
and His224-Nε Atom, after Optimization for Compounds 11b and 11c
distance from
˚
ACE (A)
distance from
˚
His224 (A)
FIGURE 5. Orientations for diols 11a-I (cyan) and 11a-III (blue)
compared to the protected diol 5a (orange). For clarity, only the
residues useful for discussion are shown (gray). Connolly surface of
the enzyme is represented in white. OHb in pink and OHc in yellow.
entry
complex
buried OH
1
2
3
4
11b-I
11b-II
11c-I
OHb
OHb
OHa
OHa
3.3
3.2
4.0
3.6
4.5
4.4
4.8
4.4
11c-II
To complete this study, one more docking experience was
performed, replacing one hydroxyl with an acetate, to prove
that a second acetylation reaction could be done thereafter.
In Table 6 are summarized the results of the docking with
monoacetylated products 11b and 11c. For these molecules,
the free alcohols (OHb and OHa, respectively) were orien-
tated toward Ser105 and His224 residues. After optimiza-
tions, the distances between the non-acetylated hydroxyl
In all cases, the different complexes obtained with diols 5a,
ent-5a, and 6a (entries 1-6, Table 4) adopted the acetylation
distances criterion, with distances between the OHa hydroxyl,
˚
the acetate carbon, and the His224:Nε nitrogen <4 A. For the
diol 15a (entries 7 and 8), the distance between the hydroxyl
group OHa and the His224:Nε nitrogen is slightly larger than
the fixed criteria. However, the OHbhydroxyl is too far from the
˚
group (OHa or OHb) and the acetate were <4 A. The
distances between the Nε atom of His224 and the same free
˚
alcohol were ranged from 4.4 to 4.8 A. The two other criteria
˚
catalytic residues with distances from 4.4 to 7.9 A. The super-
imposition of the protein structure in the complex and the
crystal structure showed minor displacements (rmsd values
(rmsd value and at least two hydrogen bonds with the
oxyanion hole) were also respected. This suggests that after
a first acetylation reaction, the residual hydroxyl group
(OHa or OHb) could be acetylated.
It is important to note that after optimization, the second-
ary alcohol (OHc) of the diol 11a was placed into the cavity
of the enzyme. However, in the case of the diol 5a, where the
same secondary alcohol was protected, the protecting group
stands outside the cavity (Figure 5).
˚
about 0.7 A). Finally, two hydrogen bond interactions between
oxyanion hole residues and OHawere formed for each complex.
The docking experiments of diols 5a, ent-5a, 6a, and 15a
showed that the substrates are preferentially orientated to
form productive complexes with the OHa hydroxyl rather
than the OHb (Figure 4). Those results are in accordance
with the experimental acetylation of the OHa hydroxyl.
Encouraged by the above results, we applied this docking
procedure to the diol 11a. In this case, both hydroxyl OHa
and OHb were acetylated during the experimental proce-
dure, to form the bis-acetylated compound 11d. Our first
investigation led us to consider an effect of the free alcohol
OHc even though the mechanism of this contribution is
presently unclear. In 50% of the poses obtained after the
docking experiment, the OHahydroxyl was orientated in order
to form a productive binding mode with the catalytic site, and
the other 50% were orientated toward the OHb hydroxyl.
After optimization, four complexes were then retained: two in
favor of OHa and two in favor of OHb (Table 5).
Conclusion
In conclusion, we have developed for the first time a highly
regioselective monoacetylation of unsymmetrical 1,5-diols
substituted at the C2 or C2/C3 carbons. This reaction, useful
for the synthesis of isoprostanes derivatives, could also be
extended to other derivatives, as shown with linear struc-
tures.
Docking experiments were used to study CALB-catalyzed
acetylation of four 1,5-diols, and all substrates tested were
able to dock with the CALB active site, in order to produce
reactive complexes. The docking results corroborate with the
regioselectivities observed experimentally and lead consid-
eration of the use of docking experiments as a predictive tool.
The results summarized in Table 5 hold with those afore-
mentioned and tend to corroborate the experience. Indeed,
complexes 11a-I and 11a-II are able to form productive
binding modes with the OHb alcohol (entries 1 and 2).
Acetylating distances OHb-ACE and OHb-His224:Nε fit
the distance criterion. In the same way, productive binding
modes are formed with the OHa alcohol in complexes 11a-III
and 11a-IV (entries 3 and 4) with distances OHa-ACE and
Experimental Section
General Procedure for Regioselective Enzymatic Acetylation.
To a solution of the diol (1a-18a, 100 mg), in 10 mL of a mixture
THF/vinyl acetate (1:1, v/v) was added the Candida antarctica
lipase B (30 mg). The mixtures were stirred with a rotavapor and
followed by TLC for the appropriate time (see tables), then
filtered, and rinsed with diethyl ether, and the solvents were
˚
OHa-His224:Nε close to 4 A. In fact, diol 11a is able to form
two productive binding modes with the active site of the
CALB, in order to acetylate both hydroxyls.
1896 J. Org. Chem. Vol. 75, No. 6, 2010

Oger et al.
JOCArticle
ꢁ
evaporated under reduced pressure. The ratio of acetate pro-
ducts was checked by NMR of the crude before purification by
flash chromatography.
Acknowledgment. We thank the Ministere de l’Education
Nationale et de la Recherche for a PhD fellowship (C.O). We
are deeply grateful to Pr. Jean-Yves Lallemand and the
ICSN for their generous financial support. A part of this
work was also supported by a University Montpellier I grant
(BQR-2008).
Computational Methods. Molecular dynamics calculations
and docking simulations were performed with CHARMm force
field, using the 2.1 version of Discovery Studio (Accelrys Inc.).
˚
MD simulations were carried out by adopting a 12 A nonbound
spherical cutoff, using the isothermal-isochoric ensemble
(NVT)14 and with distance-dependent dielectric implicit solvent
model.
Supporting Information Available: Additional experimen-
tal details, NMR data of all compounds, and molecular
dynamics calculations and docking simulations details. This
material is available free of charge via the Internet at http://
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