Solution structural features of N-acyl homoserine lactones

Article abstract of DOI:10.1016/j.tetlet.2015.08.078

Here we demonstrate that in interbacterial quorum signal moderators, N-acylhomoserine lactones (AHLs), the stabilization of bioactive pharmacophore lactone against lysis is through the e^- withdrawing N-acyl motif which reduces lactone carbonyl polarization. This lysis is assisted by weak (<0.05 kcal mol^-1) contacts between N-acyl O and lactone C′. The interactions that preclude this weak contact, in the free and receptor-bound AHLs, improve lactone halflife and hence are key to the design of the antibacterial AHL analogues.

Full text of DOI:10.1016/j.tetlet.2015.08.078

Tetrahedron Letters 56 (2015) 5771–5775
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solution structural features of N-acyl homoserine lactones
⇑
Shama Tumminakatti, Bhavesh Khatri, Vinayak Krishnamurti, Vishikh Athavale, Erode N. Prabhakaran
Department of Organic Chemistry, Indian Institute of Science, Bangalore, Karnataka 560012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Here we demonstrate that in interbacterial quorum signal moderators, N-acylhomoserine lactones
(AHLs), the stabilization of bioactive pharmacophore lactone against lysis is through the eꢀ withdrawing
N-acyl motif which reduces lactone carbonyl polarization. This lysis is assisted by weak
(<0.05 kcal molꢀ1) contacts between N-acyl O and lactone C0. The interactions that preclude this weak
contact, in the free and receptor-bound AHLs, improve lactone halflife and hence are key to the design
of the antibacterial AHL analogues.
Received 13 July 2015
Revised 25 August 2015
Accepted 26 August 2015
Available online 28 August 2015
Keywords:
AHL
Ó 2015 Elsevier Ltd. All rights reserved.
Bimodular
Lactone
n ? p⁄
Solvolysis
In a process known as quorum sensing, bacteria use chemicals
such as ComX pheromones,1,2 CAI-1,3,4 autoinducer-2,5,6 N-acyl
homoserine lactones (AHL),7,8 diffusible signal factors9,10 and qui-
nolone derivatives,11 as signals to induce intercellular information
about their cell density. Of recent interest are the AHL (Fig. 1a)
inducers which are used by Gram-negative bacteria. AHLs pro-
duced by different bacteria vary in the length of the R side chain
rendering AHLs with longer biological half-life.25 We reasoned that
this is contrary to physical organic understanding of nucleophilic
catalysis of addition to carbonyls, according to which any such
interaction involving a neutral nucleophile (Oacyl) and the lactone,
should rather increase its rate of solvolysis. Owing to its funda-
mental importance for understanding complex cell–cell signalling
pathways, we undertook the first analyses of key interactions
involving the adjacent carbonyls in model AHLs (Fig. 2) in solution,
and their influence on solvolysis. We demonstrate that the propen-
sity for lysis of lactones in AHLs is diminished by the eꢀ withdraw-
ing N-acyl group and augmented by the Oacylꢁ ꢁ ꢁC0lact contact.
To start with, two key intramolecular interactions are prevalent
between adjacent carbonyls in peptides, in solution—(a) the n ? p⁄
interactions (Fig. 1b) and (b) the C5 hydrogen bond (H-bond)
(Fig. 1c)—both of which we investigated in the model AHLs. First,
group and its substituent.8,12–15 The
c-lactone motif is crucial to
QS as its hydrolysis to homoserine (Hse) leads to loss of their bio-
logical activity.16,17 The signalling mechanism involves the binding
of AHLs to intracellular LuxR type receptors. In response, bacterial
colonies undergo remarkable AHL concentration-dependent phys-
iological transformations. Biofilm formation18,19 and virulence are
particularly influenced as responses, to AHL stimuli. There is signif-
icant recent interest in understanding the features of AHLs, for
biomedical20 and environmental applications21,22 and for broad
spectrum and species selective bacterial pathogenesis.23,24
the C5 H-bond is reminiscent of those in 2.05 helical turns at a,a-
dialkyl glycine (Dag) oligomers (Fig. 1d),26,27 whose solution FT-
IR in the low polar solvent chloroform (CHCl3) are characterized
by red shift (ꢂ10 to 15 cmꢀ1) in the stretching vibrational absorp-
tion bands of the acceptor carbonyl C@O, compared to a free amide
C@O.26,27 In 2, on the contrary, there is appreciable blue shift (by
10 cmꢀ1, 10 mM, CHCl3) of the lactone carbonyl band compared
Crystal structures of two sterically encumbered synthetic AHL
analogues (R = tBu– and (Br3)C–) have been analyzed.25 Due to
sub van der Waals proximity between the acyl carbonyl oxygen
(Oacyl) eꢀ donor and the lactone carbonyl eꢀ acceptor (C0lact) in
the crystal structures, the presence of an n ? p⁄ orbital overlap
type interaction between them (Oacyl ? C0lact) has been suggested
(Fig. 1b). Based primarily on this, the operation of similar
to the free c
-butyrolactone (1)28 (1772 cmꢀ1) (Fig. 3a), implying a
strengthening of the C@O bond. Although this clearly suggests
the lack of intramolecular H-bond at AHLs, a weak N–H stretch
band appears at 3335 cmꢀ1 which is characteristic of H-bonded
N–H. This band undergoes red shift with increase in concentration
(1–100 mM)29 implying its involvement in inter-rather than
intramolecular H-bonding. These data are consistent with the
absence of C5 H-bonds at AHL. This is expected in spite of the cyclic
O
acyl ? C0lact interaction has been proposed in all AHLs in their
solution conformations as well. More intriguingly, the interaction
is hypothesized to decrease the rates of lactone hydrolysis,
⇑
Corresponding author.
E-mail address: erodeprabhakaran@gmail.com (E.N. Prabhakaran).
http://dx.doi.org/10.1016/j.tetlet.2015.08.078
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

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S. Tumminakatti et al. / Tetrahedron Letters 56 (2015) 5771–5775
employing two strategies. We investigated 4, the thioamide ana-
HL
N
Dag
O
R
R
O
C'lact
O
H
H
logue of 2. This is because the S atom is much larger than O; the
C@S bond is longer than C@O and due to similar electronegativities
of S and C there is greater mesomeric electron delocalization from
N to S in thioamide, than from N to O in amide (Fig. 3b)37–39 and S
is less electronegative than O. Due to these reasons, the thioamide
S in 4 is better placed than the amide O in 2, to donate its electronic
charge to the lactone C0. There is still only a slight upfield shift in
O
N
R
N
H
N
C5
C5
O
O
R
R
Oacyl
H
O
n
<2.5 A
O
Oacyl
O
O
o
o
C'lact
>3.2 A
(a)
(b)
(c)
(d)
Figure 1. (a) General structure of N-acyl homoserine lactones (AHLs).
(b) Oacylꢁ ꢁ ꢁC0lact interaction in AHLs. (c) Possible C5 H-bond in AHLs. (d) C5 H-bond
in 2.05 helical turn in oligo Dag.
13
the C signal of C0lact in 4. The C@Olact stretch band also remains
unchanged, denoting that the negative inductive effect of the acyl
motif is similar in 4 and 2. Second the peptide analogue 5 was
investigated because Ala is known to form intramolecular C7
constraint in the lactone motif, because the HL motif lacks the
a
Thorpe–Ingold effect at C , a unique characteristic of the gem
(
c
-turn) H-bonds (Fig. 3c), that would polarize the acyl C@O, favoring
the imidate tautomer where the acyl O is negatively charged. Here,
-turn H-bond formation is confirmed by the downfield shift of
acyl NH in 5 in the 1H NMR (
d ppm = 0.75) and red shift of its
stretch band in FT-IR (
cmꢀ1 = 9), compared to that in 2
di-substituents in Dag residues.30,31
Natural bond order (NBO) analysis of structures optimized by
density functional theory (DFT) calculations in vacuo at the
B3LYP/6311+G(2d,p) level of theory,32 using second-order pertur-
bation theory as implemented by NBO 5.9,33 have been prevalently
used to determine the energies of intramolecular non-covalent
interactions in molecules.34,35 Our NBO analyses further substanti-
ated the absence of C5 H-bonds in the minimum energy extended
conformations of 2, since the donor-acceptor distances are P3.2 Å
(Fig. 1c).29
c
D
D
m
(Fig. 5). There is again a slight upfield shift of the 13C signal (Fig. 3a)
of C0lact, compared to 3. In 6, where both these effects are opera-
tive29 there is more pronounced 13C upfield shift, further substan-
tiating that the eꢀs of Oacyl are felt by C0lact, but there is no evidence
for n ? p⁄ orbital overlap.
This weak 5-membered Oacylꢁ ꢁ ꢁC0lact interaction occurs in the
forward direction, between an N-terminal carbonyl O charge donor
and a C-terminal carbonyl C0 acceptor. In order to determine the
energy of this interaction, we reasoned that if a 5-membered
C0 Oacyl interaction is simultaneously present in the competing
reverse direction (C-terminal O donor to N-terminal acceptor) in
model compounds, then the forward interaction will perturb it
(Fig. 6b) and the extent of perturbation will represent the
Oacylꢁ ꢁ ꢁC0lact interaction energy.
Second, n ? p⁄ interactions are characterized by the down field
shift in 13C NMR signal (by ꢂ4–5 ppm) of the acceptor carbonyl
due to mixing of its paramagnetic component with the donor
13
orbitals.34 In 2, on the contrary, the C signal of C0lact is upfield
shifted by 1.8 ppm compared to that in 1. This is in agreement with
the shortening of C@Olact, and indicates decreased polarization
along this bond. The increased eꢀ density at C0lact clearly undermi-
nes the presence of an n ? p⁄ orbital overlap type Oacylꢁ ꢁ ꢁC0lact
interaction in 2, unlike suggested earlier (Fig. 4). On the other hand
a van der Waal’s proximity between n eꢀs of Oacyl and C0lact, by
which the electronic shielding at C0lact increases, could explain
the upfield shift of 13C NMR signal.
Reverse C0 Nacyl interactions, where N of imidate is the elec-
tron donor are known to selectively stabilize the cis Boc-Pro con-
formers (Fig. 6a).34 Here the equilibrium constant (Kc/t) value for
the trans to cis conformational isomerism at the Xaa-Pro peptide
bond acts as a direct reporter for the interaction energy. However,
Nacyl cannot donate its lone pair electrons simultaneously along
both of forward and reverse directions. The carbonyl O and S,
can. Thus we first investigated the selective cis Boc-Pro stabiliza-
tion by the reverse interactions in 7, 8 (donor is Oacyl or Sacyl).
The Kc/t value for Boc-Pro in 8 is 1.29 compared to 0.82 in 7.
There is 15 cmꢀ1 red shift in stretching frequency of Boc C@O in
8, compared to 7.29 There is concomitant down field shift
In the absence of spectral evidence for either n ? p⁄ orbital
overlap or C5 H-bond, the shortening of the lactone C@O and the
decrease in polarization towards Olact in 2, could arise from the
negative induction of electrons from the lactone C@O, by the
N-acyl group. In order to investigate the effect of countering this
negative inductive effect, we synthesized 3 where the tBu provides
strong positive induction of eꢀs. There is little change in the 13C
signal of C0lact, but the C@O stretching band red shifts from that
of 2, implying its lengthening due to this eꢀ donation. This is
consistent with the N-acyl group attenuating the lactone C@O
polarization and bond order through inductive effects. Similar
electron withdrawing effects of the N-acyl group are known to
increase polarization of their ring C–H bonds at Pro residues.36
Next in order to understand the nature of the OacylꢁꢁꢁC0lact inter-
actions, we improved the electronic charge of the acyl carbonyl
13
(1 ppm) in the C NMR signals of respective Boc C0 atoms. These
indicate that the C0Boc Sacyl
(
p⁄ n) interaction in the cis
Boc-Pro conformer, involving the larger sulfur atom of thioamide
in 8, is stronger than the C0Boc Oacyl interaction in 7, by
(a)
AHL
No.
(b)
13
b
Lactonea
C=O ν cm
C
ppm
δ
3.44
2.55
2.58
2.55
O
S
-1
-
H
N
C'lact
H
N
H
N
N
H
N
H
1
2
1772
1782
1778
1782
1783
1785
1786
1785
177.6
175.8
175.8
175.3
175.2
174.1
174.9
174.0
HN
R
3.04
3.04
X
O
O
O
O
S
O
(C)
O
O
O
O
O
O
tBu
3
2
3
5
6
R = CH3
R = tBu
X = O
X = S
4
1
4
γ-turn
H-bond
5
O
O
X = O, S
O
O
6
H
N
δ+
H
N
H
H
N
N
C7
N
C7
H
N
H
H
10
11
N
N
N
O
N
X
X
O
X
X
O
O
O
tBu
O
O
O
O
δ-
O
O
O
a = 10 mM, CHCl3, b = 60 mM, CDCl3.
tBu
X = O
X = S
7
X = O 10
11
9
8
X = S
Figure 3. (a) FT-IR stretching frequency and 13C chemical shift for lactone carbonyl
Figure 2.
(7–9).
c
-Butyrolactone (1), AHL analogues (2–6, 10, 11) and model compounds
of AHL. (b) Electronegativity difference between the amide and thioamides. (c) C7
(c-turn) H-bonding in 5 and 6.

S. Tumminakatti et al. / Tetrahedron Letters 56 (2015) 5771–5775
5773
R
O
(a)
(b)
R
X
N
H
N
2
O
Kc/t
O
n
N
N
N
H
N
n
O
1
1
X
O
N
cis
O
cis
O
N
H
O
R
O
H
R
R
O
X = O, S
π
π
*
*
O
O
Boc-Pro(X)
-NH-Me
Boc-Pro(X)
-AHL
Kc/t
ΔΔGi
Kc/t
O
O
7
8
0.82
1.29
0.05
0.04
10
11
0.75
1.20
Oacyl
C'
Oacyl
C'
lact
lact
Figure 6. (a) The reverse p⁄ n (C0 Nacyl) interaction (1) selectively stabilizing
the cis Pro conformer and increasing the Kc/t values. (b) The Oacylꢁ ꢁ ꢁC0lact interaction
(2) in the forward direction, perturbing the reverse C0 Nacyl interaction (1) at cis
Pro. (i = kcal molꢀ1).
Figure 4. Chemdraw rendition of the Oacyl ? C0lact orbital overlap proposed earlier
and Oacylꢁ ꢁ ꢁC0lact contact interactions elucidated through current studies. The
puckered representation of lactone ring in 1 is based on similar puckering in its
powder XRD structure.
0.27 kcal molꢀ1. NBO analyses also show increase in the p⁄ n
orbital overlap at Boc-Pro in the minimum energy cis conformer
of 8 compared to that in 7 (Fig. 7). Additionally, the Kc/t of 9 which
has a weaker acetyl electrophile is only 0.14, compared to 0.82 of 7
which has a better, cross conjugated, carbamate electrophile—
corresponding to relative stabilization of cis Pro in
7 by
1.05 kcal molꢀ1. These results demonstrate that the reverse p⁄ n
orbital overlaps exist at cis Pro even with amide and thioamide
donors and improve with improved electrophilicity of the acceptor
carbonyls.
We synthesized 10 and 11 in order to ascertain the perturbation
in this p⁄ n energy resulting from the presence of weak
OacylꢁꢁꢁC0lact interaction at the AHL motif in the opposing direction
and involving the same electron donor. There is only a small
decrease in Kc/t values of 10 and 11, compared to those of 7 and
8 respectively (Fig. 6). The energies corresponding to this decrease
are 0.05 and 0.04 kcal molꢀ1 respectively (calculated using the
Gibbs free energy equation DDG = ꢀRT ln(K10/K7) (298 K). Remark-
ably, similar differences in energy (0.04 and 0.03 kcal molꢀ1) are
observed between the p⁄ n energies derived from NBO analyses
of the above pairs of model compounds (10 and 11, compared to 7
and 8 in Fig. 7). These small energies are consistent with the FT-IR
and 13C NMR spectral data which show very small shifts due to the
Oacylꢁ ꢁ ꢁC0lact interactions in AHLs. Our results clearly demonstrate
that the interaction energy associated with proximity between
Oacyl and C0lact of AHLs is significantly small.
Next we asked, how does the combined influence of the elec-
tron withdrawing N-acyl group and the weak Oacylꢁ ꢁ ꢁC0lact interac-
tion in AHLs, affect the rate of solvolysis of the biologically active
lactone to the inactive Hse. Lactone 1 does not undergo hydrolysis
Figure 7. NBO view images of p⁄ n interactions in 7, 8 and 10, 11.
even after 24 h of stirring in water and none of the model AHLs are
soluble in water. However in MeOH, a solvent which stabilizes
peptide helical conformations (where n ? p⁄ interactions are most
prevalent), all the compounds are soluble and undergo solvolysis.
The kinetics of methanolysis of the AHLs were followed by deter-
mining the ratio, (amount of Hse/amount of lactone) (Fig. 8) in 1
h (0.1 equiv triethylamine). 1 showed a ratio of 0.95, deviations
from which in the AHL models, report on the stereoelectronic
effects of their substituents.
Under this standard condition, when the eꢀ withdrawing acetyl
amide is present in 2, it halves (0.47) compared to 1. It increases to
0.65 for 4, consistent with the slightly increased nucleophilic con-
tact of S with C0lact. For 5 and 6, it is 1.61 and 7.59 respectively, in
agreement with the effect of improved negative charge on the acyl
O/S. These data demonstrate the operation of the known mecha-
nism of nucleophilic catalysis for solvolysis in AHLs. Herein a
Figure 5. Relevant spectral regions of 2 and 5: (a) NH d ppm (1H NMR, 10 mM,
CDCl3). (b) N–H asymmetric stretch (FT-IR, 10 mM, CHCl3).

5774
S. Tumminakatti et al. / Tetrahedron Letters 56 (2015) 5771–5775
0.065 mmol) under N2 atmosphere and stirred. After exactly 1 h,
OH
O
MeOH (0.06M)
R
R
2
R
O
O
dichloromethane (10 mL) was added to dilute the mixture. The
organic solvents were removed using rotary evaporator under vac-
uum without heating the mixture and 1H NMR spectrum of the
resulting mixture was recorded.
Et3N (0.1 eq)
1 hr
O
O
i
ii O
Lactone
Hse
ii / i
AHL
ii / i
AHL
ii / i
AHL
1
2
4
0.95
0.47
0.65
5
6
1.61
7.59
10
11
0.65
3.0
Acknowledgments
We thank Department of Science and Technology (DST-1382)
and Council of Scientific and Industrial Research (CSIR-0392), India,
for partial funding of this work. S.T. wishes to acknowledge finan-
cial support from University Grants Commission, India.
Figure 8. Kinetics of methanolysis of AHLs. Ratios obtained from integrations for
non-degenerate protons in 1H NMR (CDCl3) of the lactone/Hse mixtures.
strong polarizable nucleophile activates a weakly electrophilic car-
bonyl towards faster addition from a solvent or a weaker nucle-
ophile. This finding is opposite to that reported recently, where
the formation of a strong n ? p⁄ interaction was proposed between
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.08.
078.
O
acyl and C0lact, the improved strength of which was thought to dis-
courage solvolysis.25
As further evidence for the nucleophilic catalysis mechanism, in
10 the ratio is lower (0.65) than that for 5, which is consistent with
the electron density of Oacyl being pulled considerably away from
the forward direction in the cis Boc-Pro conformer. Similarly, the
ratio is only 3 for 11, lower than that for 6. Note that the improve-
ment in ratio for 11 than 10 is due to the larger size of S atom and
the longer length of C@S which allows greater proximity of the S
lone pair (than O lone pair) with p⁄ of lactone. The incipient sulfo-
nium ion is also an excellent leaving group (better than the oxo-
nium ion) that enables improved solvolysis of the lactone. These
data further demonstrate that the nature of the weak interaction
between n of Oacyl and p⁄ of C0lact in AHL is to improve the rate of
solvolysis of lactone. Additionally, these reveal that the sub-
stituents on acyl side chain are good handles for engaging the n
eꢀs of Oacyl so that their interaction with p⁄ of lactone, and hence
the rate of solvolysis of the lactone, are attenuated. Interestingly,
some natural AHLs contain 1,3-acyl motifs (3-oxo substituent on
acyl side chain),8,40 that will form stable 6-membered ring H-bonds
involving the n of Oacyl as the acceptor. Our results suggest the role
of the 3-oxo groups in attenuation of lactone hydrolysis in natural
AHLs, hence improving their biological half-lives.
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