Design and Solution-Phase Synthesis of Membrane-Targeting Lipopeptides with Selective Antibacterial Activity

Article abstract of DOI:10.1002/chem.201702227

Designing selective antibacterial molecules remains an unmet goal in the field of membrane-targeting agents. Herein, we report the rational design and synthesis of a new class of lipopeptides, which possess highly selective bacterial killing over mammalian cells. The selective interaction with bacterial over mammalian membranes was established through various spectroscopic, as well as microscopic experiments, including biophysical studies with the model membranes. A detailed antibacterial structure–activity relationship was delineated after preparing a series of molecules consisting of the peptide moieties with varied sequence of amino acids, such as d-phenylalanine, d-leucine, and d-lysine. Antibacterial activity was found to vary with the nature and positioning of hydrophobicity in the molecules, as well as number of positive charges. Optimized lipopeptide 9 did not show any hemolytic activity even at 1000 μg mL^?1 and displayed >200-fold and >100-fold selectivity towards S. aureus and E. coli, respectively. More importantly, compound 9 was found to display good antibacterial activity (MIC 6.3–12.5 μg mL^?1) against the five top most critical bacteria according to World Health Organization (WHO) priority pathogens list. Therefore, the results suggested that this new class of lipopeptides bear real promises for the development as future antibacterial agents.

Full text of DOI:10.1002/chem.201702227

A Journal of
Accepted Article
Title: Design and Solution Phase Synthesis of Membrane Targeting
Lipopeptides with Selective Antibacterial Activity
Authors: Mohini Mohan Konai, Utsarga Adhikary, and Jayanta Haldar
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201702227
Link to VoR: http://dx.doi.org/10.1002/chem.201702227
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Chemistry - A European Journal
10.1002/chem.201702227
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Design and Solution Phase Synthesis of Membrane Targeting
Lipopeptides with Selective Antibacterial Activity
[
a]
Mohini M. Konai, Utsarga Adhikary, and Jayanta Haldar*
to tackle these drug-resistant bacteria, there is a critical need for
new classes of broad-spectrum antibacterial agents with novel
mechanism of action. To this end, the recent past has seen the
emergence of numerous classes of membrane active molecules
Abstract: Designing selective antibacterial molecules remains an
unmet goal in the field of membrane targeting agents. To this aim,
herein we report the rational design and synthesis of a new class of
lipopeptides which possess highly selective bacterial killing over
mammalian cells. The selective interaction with bacterial over
mammalian membranes was established through various
spectroscopic as well as microscopic experiments including
including even membrane active analogues of antibiotics,
[2-30]
offering some hope.
By targeting the bacterial membrane,
this class of compounds are typically advantageous over
conventional antibiotics, as bacterial resistance development is
much slower in the face of membrane disintegration. Living up to
the promise of this class of molecules; lipopeptide antibiotics,
such as daptomycin and colistin have already entered the clinic.
However, the potential of this class of molecules is largely
overshadowed by certain serious limitations. Firstly, lipopeptide
antibiotics possess narrow spectrum of antibacterial activity. For
example, daptomycin targets the membrane of Gram-positive
biophysical studies with the model membranes.
A detailed
antibacterial structure-activity relationship was delineated after
preparing a series of molecules consisting of the peptide moieties
with varied sequence of amino acids such as D-phenylalanine, D-
leucine and D-lysine. Antibacterial activity was found to vary with the
nature and positioning of hydrophobicity in the molecules as well as
number of positive charges. Optimized lipopeptide, 9 did not show
any hemolytic activity even at 1000 µg/mL and displayed >200-fold
and >100-fold selectivity towards S. aureus and E. coli respectively.
2+
bacteria in a calcium ion (Ca ) dependent manner and is active
[31]
only against these bacteria. The other class of FDA approved
More importantly, compound
9 was found to display good
lipopeptide antibiotics, polymyxins (polymyxin B and colistin)
antibacterial activity (MIC = 6.3-12.5 µg/mL) against the five top
most critical bacteria according to WHO (World Health Organization)
priority list. Therefore, altogether the results suggested that this new
class of lipopeptides bear real promises for the development as
future antibacterial agents.
specifically target the lipopolysaccharide (LPS) and are therefore
[32]
effective only against Gram-negative bacteria.
Furthermore,
issues such as toxicity and stability limit their broad-scale
usages in clinic. To address the above-mentioned limitations,
the scientific community responded with diverse classes of
[
22-30]
synthetic mimics of lipopeptides.
Even though many of
these synthetic lipopeptides were potent against bacteria, a big
caveat was their unimpressive selectivity towards bacteria over
mammalian cells. Quite notably, the preparation of most of the
existing lipopeptides require solid phase synthesis, which left
considerable space for the development of new class of
lipopeptides with simpler synthetic designs and more selective
antibacterial activity. Towards this goal, herein we report the
rational design and solution phase synthesis of a new class of
lipopeptides in order to achieve antibacterial activity with
superior selectivity towards bacterial killing. Other than above
mentioned motives, our additional interest for developing amino
acid based antibacterial agents was their high abundance due to
naturally occurring starting material and non-toxic nature. All of
these reasons make them attractive as starting materials in
chemical syntheses. Indeed, amino acids have attracted
enormous attention in diverse research areas in the field of
Introduction
The ever emerging phenomenon of bacterial resistance has
presented with an unprecedented challenge in global public
health. Recently, the World Health Organization (WHO) has
published for the first time a list of drug-resistant bacteria posing
the greatest threat and against which new antibiotics are
[
1]
urgently needed. In this catalogue, the Gram-negative bacteria
Acinetobacter baumannii, Pseudomonas aeruginosa and
Enterobacteriaceae (specifically Klebsiella pneumoniae and
Escherichia coli) were deemed to be the most critical ones.
Almost no treatment regimens exist to treat infections caused by
multi-drug resistant strains of these deadly pathogens. Gram-
positive bacteria, vancomycin•resistant Enterococcus faecium
[
33-35]
(
VRE) and Methicillin-resistant Staphylococcus aureus (MRSA)
medicinal chemistry owing to these several advantages.
are also a major cause of worry and were justifiably ranked next
in the priority list. Therefore, it goes without saying that in order
Importantly, research from various groups including ours have
already implicated the role of amino acids in dictating the
[36-38]
antibacterial activity.
Moreover, to the best of our knowledge,
solution phase synthesis of lipopeptide class of molecules that
display antibacterial activity has rarely been reported in literature.
Therefore, the highlight of this paper is the simple and flexible
synthetic strategy, allowing the generation of series of
lipopeptides via solution phase amide coupling reactions at
relative ease. To this end, we synthesized a series of molecules
consisting of nine compounds by varying all possible
combinations of the amino acids D-phenylalaine, D-leucine and D-
[
a] M. M. Konai, U. Adhikary, and Dr. J. Haldar
Antimicrobial Research Laboratory, New Chemistry Unit, Jawaharlal
Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru
560064, Karnataka, India.
Fax: (+91) 80-2208-2627
E-mail: jayanta@jncasr.ac.in
Homepage: http://www.jncasr.ac.in/jayanta/
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Chemistry - A European Journal
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Figure 1. Chemical structure of lipopeptides.
lysine in the peptide sequence. Following synthesis, all the
lipopeptides were then tested for antibacterial activity against
both Gram-positive (S. aureus) and Gram-negative (E. coli)
bacteria including the top most critical bacteria according to
WHO priority list. We next evaluated the selectivity of the
compounds by evaluating their toxicity against human red blood
cells (hRBCs), as a model for mammalian cells. The effect of
various structural parameters in the lipopeptides laid the
framework for a structure-activity analysis, based on the number
and position of positive charges, and the nature and positioning
of hydrophobicity in the design scaffold. Finally, we investigated
the mechanism of action of this series of lipopeptides by
employing various spectroscopic and microscopic techniques as
primarily acting through membrane disruption.
Results and Discussion
Rational Design and Synthesis: Our reported design
scaffold consisting of a norspermidine backbone to which amino
acids were symmetrically coupled on both ends, along with the
[
8]
presence of a central aliphatic long chain. As a next step
towards fine-tuning our design, the central goal in this research
undertaking was to increase the selectivity by rational chemical
modifications. Lessons learnt from our previous studies
Scheme 1. Synthesis of lipopeptides 1-6.
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Scheme 2. Synthesis of lipopeptides 7-9.
indicated that the hydrophobicity of the central aliphatic chain is
one of the main factors that dictate the antibacterial potency of a
candidate molecule. This increase in activity with increasing
hydrophobicity however comes at a price; indeed in many cases,
highly active molecules are also highly toxic towards mammalian
cells. To address this issue, we rationally incorporated aliphatic
chains of comparatively lower length (i.e. octanoyl moiety) in the
new design. This aliphatic moiety was flanked by two dipeptide
moieties on either end of the molecule to afford the final
lipopeptides (Figure 1). For interrogating the role of positive
charges, and the nature and spatial positioning of hydrophobic
moiety in the lipopeptides, amino acids with various structural
features were incorporated in the peptide sequence. These
included amino acids with hydrophobic side chains such as
phenylalanine (aromatic hydrophobicity) and leucine (aliphatic
hydrophobicity) and an amino acid with a positively charged side
chain, lysine, which we conjectured, would introduce distinct
properties in the molecular scaffold. We rationally incorporated
only D-amino acids in our lipopeptides; given the observation
made by others and us that D-amino acid containing small
molecules are stable in presence of proteases than their L
counterparts even while retaining their antibacterial activity. We
therefore synthesized a series of lipopeptides consisting of nine
compounds by varying all possible combination of the amino
acids D-phenylalanine, D-leucine and D-lysine in the peptide
sequence. Preparation of this class of lipopeptides (compounds
prepared through a sequence of reactions consisting of four
steps (Scheme1). In the first step, two amine groups of the
precursor amine (lipidated norspermidine derivative) were
coupled with the carboxylic acid group of either Boc-D-Phe-OH
or Boc-D-Leu-OH. After that, the Boc-groups of the resulting
compounds were removed by using excess of 50% of
trifluoroacetic acid (TFA) in DCM. In the third step, another
amide coupling reaction was performed to incorporate the
second amino acid. In the final step, all the Boc-groups were
deprotected by using excess of 1:1 (TFA:DCM) to achieve the
lipopeptides 1-6. The remaining lipopeptides 7-9 were prepared
by following a similar synthetic strategy, but involving orthogonal
protection and deprotection chemistry (Scheme 2). In the first
step of reactions, the carboxylic acid group of Fmoc-D-Lys
(Boc)-OH was coupled with two primary amine groups of the
precursor amine. In the next step, the Fmoc-groups were
selectively removed by using excess amount of 50% diethyl
amine (in DCM). The resulting compound was then subjected to
conjugation with a second amino acid by an amide coupling
reaction. After that, the Boc groups were removed (using 50%
TFA in DCM) to achieve the lipopeptides 7-9. The final
1
13
compounds were then characterized by H-NMR, C-NMR and
HR-MS (Supporting Information Figure S1-S28).
Selective Antibacterial Activity: We initially determined
the toxicity of this class of lipopeptides as a first approximation of
how selective these would be as antibacterial agents. Toxicity
1-9) was achieved by following a simple solution-based synthetic
strategy. Starting from a precursor amine, compounds 1-6 were
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Table 1 Hemolytic and antibacterial activity of the lipopeptides.
Table 2 Minimum inhibitory concentration (µg/mL) against
critical strains of bacteria.
owing to the presence of a lysine-lysine amino acid pair on either
side of the design, displayed the best efficacy with the MIC value of
5
µg/mL. More importantly, this compound also displayed potent
MICSA corresponds to antibacterial activity against S. aureus
activity against the Gram-negative bacteria, E. coli, with the MIC
value of 11.2 µg/mL (Table 1). Altogether, this analytical exercise
revealed a lead compound, 9, which displayed potent activity against
both S. aureus and E. coli. On computing the selectivity ratios
studies were performed against human erythrocytes (hRBCs) as
model mammalian cells. Briefly, we determined the HC50
(concentration corresponding to 50% lysis of the hRBCs) values for
(HC50/MIC) we observed that the two-charge bearing compounds
all the compounds (1-9) to quantify hemolytic activity. We observed
that all the compounds possess low toxicity as evidenced by high
HC50 values ranging from 320 µg/mL to >1000 µg/mL (Table 1). A
general observation from this dataset suggests that hemolytic
activity is strongly dependent on positive charges present in the
lipopeptides. Indeed, lipopeptides with only two charges (1, 2, 4 and
were less selective compared to four- and six-charge comprising
compounds (Figure 2a). This was in direct agreement with prior
experiments which showed that these compounds are not only more
active but also less toxic than compounds with lower number of
charges. Among four-charge containing compounds, compound 7
and 8 displayed a selectivity ratio of >150 and >100 respectively.
The best selectivity however, was observed for compound 9, bearing
six positive charges. It displayed >200 fold selectivity towards S.
aureus (Table 1).
5) showed higher toxicity, with HC50 ranging between 320 µg/mL to
640 µg/mL, whereas those bearing higher number of charges (3, 6,
7, 8 and 9) are evidently less toxic, as apparent from their high HC50
values of >1000 µg/mL. This was not surprising because a high
37
hemolysis is usually related with higher hydrophobicity. Here too,
the result suggested that molecules with higher density of positive
charges are better suited as selective antibacterial candidates. To
obtain definitive proof of functional relevance, we tested all the
lipopeptides (1-9) against various pathogenic bacteria including
clinically isolated strains. Encouragingly, general observations
suggested that the antibacterial efficacy of this class of lipopeptides
was also charge-dependent. Additionally, we found that spatial
positioning of the amino acid residues play an important role in
directing antibacterial activity. Two-charge bearing compounds 1 and
Activity against Critical Bacteria: In order to assess the
potential of this class of lipopeptides in the face of the most
threatening infections, we next tested the antibacterial activity of
compound 9 against five top most critical bacteria according to WHO
priority list. It can be seen from table 2 that lead compound 9 was
active against these deadly bacteria, including various clinical
4, where phenylalanine is present at the end of the design, showed
moderate antibacterial efficacy with MIC values of 15 µg/mL and 27
µg/mL against S. aureus, respectively (Table 1). Intriguingly, the
other two-charge comprising compounds, where the phenylalanine
moiety is either present at the middle of the molecule (compound 2)
or completely absent (compound 5), resulted in compromised activity
against this bacterial strain (MIC values of 2 and 5 were 32 and 50
µg/mL respectively). This could indicate that the presence of
phenylalanine as well as its spatial positioning in the lipopeptide is
important to achieve more potent antibacterial activity. We next
analysed the activity of the lipopeptides bearing four positive
charges. Overall, an improvement in antibacterial activity was
noticed compared to two-charge bearing compounds, although
compounds 3 and 6, where the lysine residue was present at the
end of the molecules, displayed lesser activity with the MIC values of
30 µg/mL and 95 µg/mL respectively. However, compounds 7 and 8,
with lysine moieties occupying an interior position showed drastic
improvement in antibacterial efficacy. Compounds 7 and 8 displayed
similar antibacterial activity with the MIC values of 7.3 µg/mL and
Figure 2. Fluorescence microscopy images of HEK cells; a) Untreated, b)
Treated with compound 9 (31.25 µg/mL) and c) Treated with Triton-X.
Scale bar: 50µm.
10.5 µg/mL. Finally, compound 9, which consisted of six charges
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isolates. The antibiotic meropenem remained inactive against all the
clinical isolates of Gram-negative bacteria even at 100 µg/mL and
methicillin did not display any activity at 50 µg/mL against the MRSA
strains, whereas the lipopeptide 9 displayed the activity against
these clinical isolates with the MIC values in the concentration
ranged 6.3-12.5 µg/mL depending on bacterial strain. Therefore,
nature of the lead candidate.
Membrane Targeting Mechanism of Action: We next
investigated a possible membrane targeting mechanism of
action of compound 9 by assessing its effect on bacterial
membrane permeability and membrane potential employing
complementary spectroscopic techniques. First, membrane
permeabilization was studied using the dye propidium iodide (PI),
collectively the results suggested that lipopeptide
9 not only
possessed broad spectrum of antibacterial activity but also retained
activity against clinically circulating bacterial strains that mounted
antibiotic-resistance.
a
robust fluorescent readout for compromised bacterial
membranes. We clearly demonstrated that compound 9 is
capable of causing membrane permeabilization of both S.
aureus and E. coli even at a low concentration of 5 µg/mL
(Figure 3a and 3b). From this study we could also account for
the observed lower activity against E. coli from the rather
modest increase in fluorescence intensity compared to S.
aureus. Next, other spectroscopic studies were performed to
observe the effect of compound 9 on membrane potential using
Toxicity against HEK Cells: To further validate the
selectivity of this class of lipopeptides, toxicity of optimized
lipopeptide 9 was investigated against HEK cells by performing live-
dead assay using dual staining with Calcein-AM and PI dyes. The
results suggested that even after 24 h exposure in presence of
compound 9 (31.25 µg/mL), all the cells were alive as in the
untreated case (Figure 2 ), which further showcased the non-toxic
3
the dye DiSC (5). Sensitive to membrane potential, this dye can
Figure 3. Membrane active mechanism of action; a) Membrane permeabilization of S. aureus, b) Membrane permeabilization of E. coli, Confocal laser-
scanning microscopy images of S. aureus; c) Untreated, d) Treated with compound 9 (31.25 µg/mL). Scale bar: 10µm.
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bacterial model membrane over the mammalian model
membrane. This is evident from the remarkable attenuation of
laurdan GP for bacterial model membrane with increasing
compound concentration, an effect much less pronounced for
the mammalian model membrane. Taken together, the above
results establish membrane disruption as the mechanism of
action of compound 9.
Conclusions
In summary, a new class of lipopeptides was rationally designed
and prepared by using simple solution phase amide coupling
reaction. Structure-activity relationship within this class of
compounds suggested that both nature and positioning of
hydrophobicity as well as positive charge density play an
important role in dictating antibacterial activity and toxicity. The
lead compound 9 displayed potent antibacterial activity with high
selectivity towards pathogenic bacteria including clinical isolates
of both Gram-negative and Gram-positive bacteria through
membrane targeted mechanism of action. Therefore, this class
of synthetic lipopeptides possess potential for further
development as broad-spectrum antibacterial agents.
Figure 4. Reduction in laurdan GP after treated with 9.
distribute itself inside the bacterial cells but can leak out into
external media upon disruption of normal membrane potential,
resulting in an increase in fluorescence intensity. We observed
that compound 9 could indeed disrupt the membrane potential of
both S. aureus and E. coli significantly even at concentrations as
low as 5 µg/mL (Supporting Information Figure S29). Finally, to
definitively confirm the membrane targeting mechanism of action,
we resorted to visualizing the effect of the compound on S.
aureus using confocal laser-scanning microscopy (CLSM). To
this end, we performed a live-dead assay by dual staining with
SYTO-9 and PI dyes in order to visualize live and dead cells
simultaneously. Our experiments confirmed that bacterial cell
membranes were indeed compromised due to compound
exposure. Under conditions of no treatment, we observed no
signal from the PI channel, which meant that all the S. aureus
cells were alive. This was cross validated by corresponding
SYTO-9 staining. In comparison, compound treated images
clearly suggested the presence of dead cells as observed from
the more abundant red fluorescence in PI channel, with only a
few SYTO-9 stained live cells (Figure 3d).
Experimental Section
Synthesis Protocols and Characterization
General protocol for synthesizing 10a and 10b: At first, 2.4
equivalents of Boc-D-Phe-OH or Boc-D-Leu-OH were
dissolved in dry DCM and anhydrous DMF in 4:1 ratio and the
solution containing RB was placed at 0-5 ºC ice bath. 4
equivalents of DIPEA were then added to the reaction mixture
followed by 2.4 equivalents of HBTU and allowed to stir for 10-
1
5 min. After that, 1 equivalent of precursor amine was added
drop wise by dissolving it in dry DCM in presence of additional
equivalents of DIPEA. The reaction mixture containing RB
2
Membrane Hydration Studies: Selective bacterial killing
was then brought to RT and allowed to stir for 48h. At the end
of the reaction, solvent was removed under reduce pressure by
using rotary evaporator and crude residue was diluted in ethyl
acetate. The reaction mixture was then washed by using 1N
of compound
biophysical
9
was further established by performing
studies. Laurdan (6-Dodecanoyl-2-
dimethylaminonaphthalene) dye encapsulated liposomes were
prepared by using the DPPG:DPPE (88:12) and DPPC lipids,
which mimic the membrane of the bacterial and mammalian
cells respectively. As the fluorescence of laurdan dye is
sensitive towards dipole moment of the lipid environment, an
HCl (3 times) and saturated Na CO3 solution (3 times)
2
respectively. Finally, the ethyl acetate layer was collected
increase in dipole moment due to hydration induces
a
2 4
through anhydrous Na SO and column chromatography was
perturbation in its fluorescence in the lipid bilayer. This change
in dipole moment is brought about by the exposure of membrane
interacting agents. This allows for the quantification of the extent
of interaction of the agent by calculating the general polarization
performed on silica gel (60-120 mesh) with various ratios of
MeOH and CHCl
3
as eluent to achieve pure 10a and 10b.
D
N,N-bis-[3-(N-Boc- Phe)amidopropyl]octanamide
(10a):
(
GP) at various concentrations. The difference in GP values of
1
untreated and compound treated samples is a direct measure of
the effect of a compound on the model membrane. Figure 4
clearly suggests a stronger interaction of compound 9 with the
Yield-65%; H-NMR (400 MHz, CDCl
3
) δ/ppm: 7.242-6.996 (m,
R-CO-N(-CH
2
-CH
2
-CH
2
-NH-CO-CH(NHBoc)-CH -PhH) , 12H),
2
2
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Chemistry - A European Journal
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FULL PAPER
5
.401-5.271 (m, R-CO-N(-CH
2
-CH
, 2H), 4.357-4.318 (t, J = 7.8 Hz, R-CO-N(-CH
-NH-CO-CH(NHBoc)-CH -Ph) , 2H), 3.382-2.869 (m, R-
-CH -CH -NH-CO-CH(NHBoc)-CH -Ph) 12H),
.215-2.184 (t, J = 6.2 Hz, CH -(CH -CH -CH - of R group,
H), 1.738-1.597 (m, CH -(CH -CH -CH -CO-N(-CH -CH
-Ph) , 6H), 1.349 (s, R-CO-NH(-
-NH-CO-CH(NH-COO-C(CH )-CH -Ph) 18H),
- of R group, 8H), 0.886-0.852
2
-CH
2
-NH-CO-CH(NHBoc)-
CH
2
-CH
2
- of R group , 8H), 0.864-0.830 (t, J = 6.8 Hz, CH
3
-
CH
2
2
-Ph)
2
2
-CH
2
-
(CH
2
)
4
2 2
-CH -CH - of R group, 3H); HRMS (m/z): 552.39456
+
+
CH
2
2
[(M+H) ] (Observed), 552.39137 [(M+H) ] (Calculated).
D
1
CO-N(-CH
2
2
2
2
2
,
N,N-bis-[3-( Leu)amidopropyl]octanamide (11b): H-NMR
2
2
3
2
)
4
2
2
(400 MHz, DMSO-d
6
2
); δ/ppm: 8.687-8.189 (m, R-CO-N(-CH -
+
3
2
)
4
2
2
2
2
-
CH -CH
2
2
-NH-CO-CH(NH
3
2 3 2 2
)-CH -CH(CH ) ) , 8H), 3.733-3.698
+
CH
2
2
-NH-CO-CH(NHBoc)-CH
2
2
(t, J = 7.0 Hz, R-CO-N(-CH
2
-CH
2
-CH -NH-CO-CH(NH
2
3
2
)-CH -
CH
-CH -CH
2
2
3
)
3
2
2
,
CH(CH
3
)
2
)
2
, 2H), 3.253-3.992 (m, R-CO-N(-CH
2
-CH
2
-CH -NH-
2
+
1.274 (bs, CH
3
-(CH
2
)
4
-CH
2
-CH
2
2
CO-CH(NH
3
)-CH
2
-CH(CH
3
)
2
)
2
, 8H), 2.262-2.223 (t, J = 7.8 Hz,
(
(
(
t, J = 6.8 Hz, CH
3
-(CH
2
)
4
-CH
-CH
2
- of R group, 3H); HRMS
CH
(CH
CH(CH
3
-(CH
2
)
4
2
2
-CH
2
2
-CH
2
3
- of R group, 2H), 1.685-1.464 (m, CH -
+
+
+
m/z): 752.49110 [(M+H) ] (Observed), 752.49662 [(M+H) ]
2
)
4
-CH
-CH
-CO-N(-CH
2
-CH
2
-CH
-(CH
-CH
2
-NH-CO-CH(NH
-CH -CH
-CH -CO-N(-CH
3
2
)-CH -
Calculated).
3
)
2
)
, 12H), 1.243 (bs, CH
3
2
)
4
2
2
- of R group,
D
N,N-bis-[3-(N-Boc- Leu)amidopropyl]octanamide
(10b):
8H), 0.906-0.834 (m, CH
3
-(CH
2
)
4
2
2
2
-CH -
2
1
+
Yield-62%; H-NMR (400 MHz, CDCl
3
); δ/ppm: 7.668-7.569 (d,
-NH-CO-CH(NHBoc)-CH CH(CH
(m, R-CO-N(-CH -CH -CH -NH-CO-
, 2H), 4.223-4.206 (d, J = 6.8 Hz,
-NH-CO-CH(NHBoc)-CH CH(CH
(m, R-CO-N(-CH -CH -CH -NH-CO-
, 8H), 2.326-2.207 (m, CH -(CH
- of R group, 2H), 1.864-1.478 (m, CH -(CH -CH
-CO-N(-CH -CH -CH -NH-CO-CH(NHBoc)-CH CH(CH
-CH -CH
, 18H), , 1.265 (bs, CH
- of R group, 8H), 0.907-0.839 (m, CH -(CH
CO-N(-CH -CH -CH -NH-CO-CH(NHBoc)-CH CH(CH
CH
2
-NH-CO-CH(NH
3
)-CH
2
-CH(CH
3
)
2
)
2, 15H); HRMS (m/z):
+
+
R-CO-N(-CH
H), 5.339-5.212
CH(NHBoc)-CH CH(CH
R-CO-N(-CH -CH -CH
H), 3.679-2.888
CH(NHBoc)-CH CH(CH
2
-CH
2
-CH
2
2
3
)
2
)
2
,
484.41843 [(M+H) ] (Observed), 484.42267 [(M+H) ]
(Calculated).
2
2
2
2
2
3
)
2
)
2
General protocol for synthesizing 12a-12f: Briefly, 2.4
equivalents Boc-protected amino acids such as; Boc-D-Phe-
OH, Boc-D-Leu-OH or Boc-D-Lys (Boc)-OH was dissolved in
dry DCM and anhydrous DMF (4:1) at 0-5 ºC ice bath. After
that, 4 equivalents of DIPEA were added followed by 2.4
equivalents of HBTU and allowed reaction mixture to stir for 10-
15 min. Now, 1 equivalent of 11a or 11b was added drop wise
to the reaction mixture after dissolving it in dry DCM in
presence of additional 2 equivalents of DIPEA. The RB
containing reaction mixture was then brought to RT and kept
for stirring. At the end of 48h, reaction solvent was removed by
using rotary evaporator. The crude reaction mixture was diluted
in ethyl acetate and then washed by using 1N HCl (3 times)
2
2
2
2
3 2 2
) ) ,
2
2
2
2
2
3
)
2
)
2
3
2 4
) -
CH
2
2
-CH
2
3
2
)
4
2
-
CH
2
2
2
2
3
)
2
)
2
,
1
2H), 1.404 (s, R-CO-N(-CH
C(CH )-CH CH(CH
CH
2
2
2
-NH-CO-CH(NH-COO-
3
)
3
2
3
)
2
)
2
3
-(CH
2
)
4
-CH
2
2
-
-
2
3
2
)
4
-CH
2
-CH
2
2
2
2
3 2 2,
) )
+
1
5H); HRMS (m/z): 684. 52044 [(M+H) ] (Observed), 684.
+
5
2752 [(M+H) ] (Calculated).
General protocol for synthesizing 11a and 11b: At first, 10a
or 10b was dissolved in excess of in 1:1 of DCM
followed by saturated Na
2
CO
3
solution (3 times). Finally, the
SO
4
(
dichloromethane) and TFA (trifluoroacetic acid). At the end of
h of stirring, the reaction solvent and unused TFA were
ethyl acetate layer was collected through anhydrous Na
2
2
and pure 12a-12f was achieved by performing column
removed by using rotary evaporator to afford pure 11a and 11b
chromatography on silica gel (60-120 mesh) with various ratios
with 100% yield.
of MeOH and CHCl
3
as eluent.
D
D
N,N-bis-[3-( Phe)amidopropyl]octanamide
N,N-bis-[3-(N-Boc- Phe-N-Boc-
1
D
1
bis(trifluoroacetate) (11a): H-NMR (400 MHz, DMSO-d
6
)
Phe)amidopropyl]octanamide (12a): Yield-66%; H-NMR
) δ/ppm: 7.335-6.354 (m, R-CO-N(-CH -CH
-NH-CO-CH-(CH -PhH)-NH-CO-CH(NHBoc)-CH -PhH)
24H), 5.011-4.854 (d, R-CO-N(-CH -CH -CH -NH-CO-CH-
(CH -Ph)-NH-CO-CH(NHBoc)-CH -Ph) , 2H), 4.667-4.614 (m,
R-CO-N(-CH -CH -CH -NH-CO-CH-(CH -Ph)-NH-CO-
CH(NHBoc)-CH -Ph) , 2H), 4.316-4.197 (m, R-CO-N(-CH
CH -CH -NH-CO-CH-(CH -Ph)-NH-CO-CH(NHBoc)-CH -Ph)
2H), 3.252-2.907 (m, R-CO-N(-CH -CH -CH -NH-CO-CH-(CH
δ/ppm: 8.473-8.231 (m, R-CO-N(-CH
2
-CH
2
2
-CH -NH-CO-
(400 MHz, CDCl
CH
3
2
2
-
+
CH(NH
3
)-CH
2
-Ph)
2
, 8H), 7.339-7.219 (m, R-CO-N(-CH
2
-CH
2
-
2
2
2
2
,
+
CH
2
2
-NH-CO-CH(NH
3
)-CH
2
-PhH)
+
3
2
, 10H), 3.938 (bs, R-CO-N(-
-Ph) 2H), 3.187-2.889
2
2
2
CH
-CH -CH
2
2
-NH-CO-CH(NH
-CH -CH
.200-2.165 (t, J = 7.0 Hz, CH
)-CH
2
2
,
2
2
2
+
(
m, R-CO-N(-CH
2
2
2
-NH-CO-CH(NH
-(CH -CH
-(CH -CH -CH
-Ph) , 6H), 1.221 (bs, CH
3
)-CH
-CH - of R group,
-CO-N(-CH
-(CH
2
-Ph)
2
, 12H),
2
2
2
2
2
2
3
2
)
4
2
2
2
2
2
-
H), 1.526-1.445 (m, CH
3
2
)
4
2
2
2
-CH
2
-
-
2
2
2
2
2
,
+
CH
2
-NH-CO-CH(NH
3
)-CH
2
2
3
2
)
4
2
2
2
2
-
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201702227
FULL PAPER
Ph)-NH-CO-CH(NHBoc)-CH
.6 Hz, CH -(CH -CH -CH
CH -(CH -CH -CH -CO-N(-CH
Ph)-NH-CO-CH(NHBoc)-CH -Ph)
CH -CH -CO-N(-CH -CH -CH
CH(NH-COO C(CH )-CH
2
-Ph)
2
, 16H), 2.242-2.204 (t, J =
NH-CO-CH(NHBoc)-CH
3.079 (m, R-CO-N(-CH
CO-CH(NHBoc)-CH -CH -CH
2.219 (t, CH -(CH -CH -CH
-(CH -CH -CH -CO-N(-CH
-Ph)-NH-CO-CH(NHBoc)-CH -CH -CH
-(CH -CH -CH
-Ph)-NH-CO-CH(NH-COO-C(CH
-NH-COO-C(CH , 48H), 0.890-0.856 (t, J =
2
-CH
-CH
-CH
- of R group, 2H), 1.720-1.579
-CH -CH -NH-CO-CH-
-CH -NHBoc)
-CO-N(-CH
)-CH
2
-CH
-CH
-NHBoc)
2
-CH
-NH-CO-CH(CH
16H), 2.256-
2
-NHBoc)
2
, 2H), 3.323-
7
3
2
)
4
2
2
- of R group, 2H), 1.650-1.577 (m,
2
2
2
2
-Ph)-NH-
3
2
)
4
2
2
2
-CH
2
-CH
2
-NH-CO-CH-(CH
2
-
2
2
2
2
2
,
2
2
, 6H), 1.342 (s, CH
3
-(CH
2
)
4
-
-
3
2
)
4
2
2
2
2
2
2
2
-NH-CO-CH-(CH
2
-Ph)-NH-CO-
(m,
CH
3
2
)
4
2
2
2
2
2
3
)
3
2
-Ph)
2
, 18H), 1.281-1.251 (m, CH
3
(CH
2
2
2
2
2
2
,
(
CH
2
)
4
-CH
2
-CH
2
2
- of R group , 8H), 0.884-0.850 (t, J = 6.8 Hz,
14H), 1.468-1.206 (m, CH
3
2
)
4
2
2
2 2
-CH -
CH
3
-(CH
2
)
4
-CH
2
-CH -
of
R
group, 3H). HRMS (m/z):
CH
2
-NH-CO-CH(CH
-CH -CH
-(CH
2
3
)
3
2
-
+
+
1
046.62798 [(M+H) ] (Observed), 1046.63305 [(M+H) ]
CH
2
2
2
3 3 2
) )
(
Calculated).
6.8 Hz, CH
3
2
)
4
-CH
2
-CH
2
- of R group, 3H). HRMS (m/z):
D
+
+
N,N-bis-[3-(N-Boc- Phe-N-Boc-
1208.79098 [(M+H) ] (Observed), 1208.79101 [(M+H) ]
D
1
Leu)amidopropyl]octanamide (12b): Yield-68%; H-NMR
) δ/ppm: 7.296-6510 (m, R-CO-N(-CH -CH
-NH-CO-CH-(CH -PhH)-NH-CO-CH(NHBoc)-CH -CH-
, 14H), 4.909-4.797 (d, R-CO-N(-CH -CH -CH
CO-CH-(CH -Ph)-NH-CO-CH(NHBoc)-CH -CH-(CH
.689-4.659 (m, R-CO-N(-CH -CH -CH -NH-CO-CH(CH
NH-CO-CH(NHBoc)-CH -CH-(CH , 2H), 4.061-3.925 (m, R-
CO-N(-CH -CH -CH -NH-CO-CH-(CH -Ph)-NH-CO-
CH(NHBoc)-CH -CH-(CH , 2H), 3.242-3.033 (m, R-CO-N(-
CH -CH -CH -NH-CO-CH-(CH -Ph)-NH-CO-CH(NHBoc)-CH
CH-(CH , 12H), 2.247-2.209 (t, J = 7.6 Hz, CH
CH - of R group, 2H), 1.667-1.494 (m, CH -(CH
CO-N(-CH -CH -CH -NH-CO-CH-(CH -Ph)-NH-CO-
CH(NHBoc)-CH -CH-(CH , 12H), 1.412 (s, R-CO-N(-CH
-NH-CO-CH-(CH -Ph)-NH-CO-CH(NH-COO-C(CH
-CH-(CH , 18H), 1.282 (bs, CH -(CH -CH -CH - of R
-(CH -CH -CH -CO-N(-CH
(Calculated).
D
(
400 MHz, CDCl
CH
CH
3
2
2
-
N,N-bis-[3-(N-Boc- Leu-N-Boc-
D
1
2
2
2
Phe)amidopropyl]octanamide (12d): Yield-68%;
(400 MHz, CDCl ) δ/ppm: 7.326-7.183 and 6.630-6.390 (m, R-
CO-N(-CH -CH -CH -NH-CO-CH(CH -CH-(CH )-NH-CO-
CH(NHBoc)-CH -PhH) , 14H), 5.011-4.931 (m, R-CO-N(-CH
-NH-CO-CH(CH -CH-(CH )-NH-CO-CH(NHBoc)-
, 2H), 4.491-4.306 (m, R-CO-N(-CH
-CH-(CH )-NH-CO-CH(NHBoc)-CH
3.411-2.988 (m, R-CO-N(-CH -CH -CH -NH-CO-CH(CH
(CH )-NH-CO-CH(NHBoc)-CH -Ph)
= 7.6 Hz, CH -(CH -CH -CH - of R group, 2H), 1.667-1.443
CH -(CH -CH -CH
-CH-(CH -NH-CO-CH(NHBoc)-CH
-(CH -CH -CH -CO-N(-CH -CH
-CH-(CH )-NH-CO-CH(NHCOO-C(CH
18H), 1.274 (bs, CH -(CH -CH -CH - of R group , 8H), 0.910-
0.856 (m, CH -(CH -CH -CH -CO-N(-CH
CH(CH -CH-(CH
H-NMR
(
3
)
2
)
2
2
2
2
-NH-
2H),
-Ph)-
3
2
2
3
)
2
)
2
,
2
2
2
2
3 2
)
4
2
2
2
2
2
2
2
-
2
3
)
2
)
2
CH
2
2
-CH
2
2
3 2
)
2
2
2
2
CH
-Ph)
2
2
-CH
2
-CH
2
-NH-
4H),
-CH-
2
3
)
2
)
2
CO-CH(CH
2
3
)
2
2
-Ph)
2
,
2
2
2
2
2
-
2
2
2
2
3
)
2
)
2
3
-(CH
2
)
4
-CH
2
2
-
-
3
)
2
2
2
, 12H), 2.288-2.250 (t, J
2
3
2
)
4
-CH
2
-CH
3
2
)
4
2
2
2
2
2
2
(m,
3
2
)
4
2
2
-CO-N(-CH
2
-CH
-Ph)
-CH
2
-CH
2
-NH-CO-
12H),
2
3
)
2
)
2
2
-
CH(CH
2
3
)
2
)
2
2
2
,
CH
2
2
-CH
2
2
3
)
3
)-
1.402 (s, CH
3
2
)
4
2
2
2
2
2
-NH-CO-
CH
3
)
2
)
2
3
2
)
4
2
2
CH(CH
2
3
)
2
3 3 2 2
) )-CH -Ph) ,
group , 8H), 0.923-0.855 (m, CH
3
2
)
4
2
2
2
-
3
2
)
4
2
2
CH
2
-CH
2
-NH-CO-CH-(CH
2
-Ph)-NH-CO-CH(NHBoc)-CH
2
-CH-
3
2
)
4
2
2
2
-CH
2
-CH
2
-NH-CO-
+
(
CH
3
)
2
)
2
, 15H). HRMS (m/z): 978.66302 [(M+H) ] (Observed),
2
3
)
2
)-NH-CO-CH(NHBoc)-CH
2
-Ph)
2
,
15H).
+
+
9
78.66435 [(M+H) ] (Calculated).
HRMS (m/z): 978.66022 [(M+H) ] (Observed), 978.66435
D
+
N,N-bis-[3-(N-Boc- Phe-N,N´-Di-Boc-
[(M+H) ] (Calculated).
D
1
D
Lys)amidopropyl]octanamide (12c): Yield-65%;
H-NMR
N,N-bis-[3-(N-Boc- Leu-N-Boc-
D
1
(
400 MHz, CDCl
3
) δ/ppm: 7.310-7.085 (m, R-CO-N(-CH
-NH-CO-CH-(CH -PhH)-NH-CO-CH(NHBoc)-CH -CH
-CH -NHBoc) , 12H), 6.677-6.487 (d, R-CO-N(-CH
-NH-CO-CH-(CH -Ph)-NH-CO-CH(NHBoc)-CH -CH
NHBoc) , 2H), 5.619-5.328 (d, R-CO-N(-CH -CH
-Ph)-NH-CO-CH(NHBoc)-CH -CH -CH
, 2H), 4.770 (bs, R-CO-N(-CH -CH -CH -NH-CO-CH-
-Ph)-NH-CO-CH(NHBoc)-CH -CH -CH -CH -NHBoc)
H), 4.700-4.654 (m, R-CO-N(-CH -CH -CH -NH-CO-CH(CH
Ph)-NH-CO-CH(NHBoc)-CH -CH -CH -CH -NHBoc)
.983-3.884 (m, R-CO-N(-CH -CH -CH -NH-CO-CH(CH
2
-CH
2
-
-
-
Leu)amidopropyl]octanamide (12e): Yield-70%; H-NMR
(400 MHz, CDCl ) δ/ppm: 7.571-7.462 (d, R-CO-N(-CH -CH
CH -NH-CO-CH(CH -CH-(CH )-NH-CO-CH(NHBoc)-CH -CH-
(CH , 2H), 6.739-6.537 (m, R-CO-N(-CH -CH -CH -NH-CO-
CH(CH -CH-(CH )-NH-CO-CH(NHBoc)-CH -CH-(CH
2H), 4.929-4.881 (m, R-CO-N(-CH -CH -CH -NH-CO-CH(CH
CH-(CH )-NH-CO-CH(NHBoc)-CH -CH-(CH , 2H), 4.557-
4.490 (m, R-CO-N(-CH -NH-CO-CH(CH
NH-CO-CH(NHBoc)-CH
CH
CH
CH
CH
2
2
2
2
2
2
2
-
3
2
2
-
2
2
2
-CH
2
2
2
3
)
2
2
2
2
2
2
-CH -
3
)
2
)
2
2
2
2
2
2
2
-CH
2
2
3
)
2
2
3 2 2
) ) ,
NH-CO-CH-(CH
NHBoc)
CH
2
2
2
2
-CH
2
-
2
2
2
2
-
2
2
2
2
3
)
2
2
3 2 2
) )
(
2
2
2
2
2
2
,
2
-CH
2
-CH
2
2
-CH-(CH
3
)
)
2
)-
)-
2
2
2
2
2
-
2
-CH-(CH
3
)
2
)
2
, 2H), 4.082-4.050 (t, J =
2
2
2
2
2
,
2H),
6.4 Hz, R-CO-N(-CH
2
-CH
2
-CH
2
-NH-CO-CH(CH
2
-CH-(CH
3
2
3
2
2
2
2
-Ph)-
NH-CO-CH(NHBoc)-CH
2
-CH-(CH
3
)
2
)
2
, 2H), 3.650-2.986 (m, R-
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201702227
FULL PAPER
CO-N(-CH
2
-CH
2
-CH
-CH-(CH
-CH - of R group, 2H), 1.745-1.435 (m, CH
-CO-N(-CH -CH -CH -NH-CO-CH(CH -CH-
-CH-(CH , 18H), 1.429 (s,
-NH-CO-CH(CH -CH-(CH )-NH-CO-
)-CH -CH-(CH , 18H), 1.282 (bs, CH
- of R group , 8H), 0.954-0.853 (m, CH -(CH
-CO-N(-CH -CH -CH -NH-CO-CH-(CH -CH-(CH )-
-CH-(CH
2
-NH-CO-CH(CH
2
-CH-(CH
3
)
2
)-NH-CO-
2 2 2
δ/ppm: 8.850-8.800 (m, R-CO-N(-CH -CH -CH -NH-CO-CH-
+
CH(NHBoc)-CH
2
3
)
2
)
2
, 8H), 2.265-2.234 (t, J = 6.2 Hz,
(CH
CO-N(-CH
CH -Ph)
2
-Ph)-NH-CO-CH(NH
3
)-CH
2
-Ph)
2
, 2H), 8.175-8.004 (m, R-
+
CH
3
2
-(CH )
4
-CH
2
2
2
3
-
2
-CH -CH
2
2
-NH-CO-CH-(CH
2
-Ph)-NH-CO-CH(NH
3
)-
(
(
CH
2
)
4
2
-CH
2
-CH
2
2
2
2
2
2
, 8H), 7.293-7.199 (m, R-CO-N(-CH
2
-CH
, 20H), 4.548-
-NH-CO-CH-(CH -Ph)-NH-
2 2
-CH -NH-
+
CH
3
)
)-NH-CO-CH(NHBoc)-CH
-CH -CH
CH(NH-COO-C(CH
CH -CH -CH
CH -CH
2
3
)
2
)
2
CO-CH-(CH
2
-PhH)-NH-CO-CH(NH
3
)-CH
2
-PhH)
2
R-CO-N(-CH
2
2
2
2
3
)
2
4.467 (m, R-CO-N(-CH
2
-CH
2
-CH
2
2
+
3
)
3
2
3
)
2
)
2
3
4
-
-
CO-CH(NH
CO-N(-CH
CH -Ph)
3
)-CH
2
-Ph)
2
, 2H), 4.050-4.019 (t, J = 6.2 Hz, R-
+
(
2
)
4
2
2
3
2
)
2
-CH
2
-CH
2
-NH-CO-CH-(CH
2
-Ph)-NH-CO-CH(NH
3
)-
2
2
2
2
2
2
3
)
2
2
2
, 2H), 3.139-2.831 (m, R-CO-N(-CH
2
-CH
16H), 2.209-
- of R group, 2H),
-CO-N(-CH -CH -CH
-Ph) , 6H), 1.234-
2 2
-CH -NH-
+
NH-CO-CH(NHBoc)-CH
2
3
)
2
)
2
,
27H). HRMS (m/z):
CO-CH-(CH
2.177 (t, J = 6.4 Hz, CH
1.563-1.454 (m, CH -(CH
NH-CO-CH-(CH
1.203 (m, CH -(CH
(t, J = 6.8 Hz, CH -(CH
(100 MHz, DMSO-d ) δ/ppm: 171.80, 167.79, 167.58, 135.01,
2
-Ph)-NH-CO-CH(NH
-(CH
-CH
3
)-CH
2 2
-Ph) ,
+
+
910.68365 [(M+H) ] (Observed), 910.69565 [(M+H) ]
3
2
)
4
-CH
2
-CH
2
(
Calculated).
3
2
)
4
2
-CH
2
2
2
2
-
D
+
N,N-bis-[3-(N-Boc- Leu-N,N´-Di-Boc-
2
-Ph)-NH-CO-CH(NH
-CH -CH
-CH
3
)-CH
2
2
D
1
Lys)amidopropyl]octanamide (12f): Yield-66%; H-NMR
3
2
)
4
2
2
- of R group , 8H), 0.839-0.805
1
3
(
400 MHz, CDCl
3
) δ/ppm: 7.544-7.449 (d, R-CO-N(-CH
-NH-CO-CH(CH -CH-(CH )-NH-CO-CH(NHBoc)-CH
-NHBoc) , 2H), 6.636-6.488 (d, R-CO-N(-CH
-NH-CO-CH(CH -CH-(CH )-NH-CO-CH(NHBoc)-
-NHBoc) , 2H), 5.503-5.268 (d, R-CO-N(-
-NH-CO-CH(CH -CH-(CH )-NH-CO-
-CH -CH -CH -NHBoc) , 2H), 4.860 (s, R-CO-
-NH-CO-CH(CH -CH-(CH )-NH-CO-
-CH -CH -CH -NHBoc) , 2H), 4.514-4.483 (m,
-CH -CH -NH-CO-CH(CH
CH(NHBoc)-CH -CH -CH -CH -NHBoc)
R-CO-N(-CH -CH -CH -NH-CO-CH(CH
CH(NHBoc)-CH -CH -CH -CH -NHBoc)
R-CO-N(-CH -CH -CH -NH-CO-CH(CH
CH(NHBoc)-CH -CH
2
-CH
2
-
3
2
)
4
2
-CH
2
- of R group, 3H). C-NMR
CH
CH
CH
CH
CH
2
2
2
2
2
2
3
)
2
2
-
6
-CH
-CH
-CH
-CH
2
2
2
2
-CH
2
2
2
-
129.42, 128.47, 127.09, 53.62, 44.97, 42.76, 37.14, 36.28,
32.06, 31.29, 29.03, 28.70, 28.35, 27.27, 25.08, 22.09, 13.94.
2
3 2
)
+
-CH
2
-CH
2
2
HRMS (m/z): 846.50588 [(M+H) ] (Observed), 846.52819
+
2+
-CH
2
2
3
)
2
[(M+H) ] (Calculated). 423.75794 [(M+2H) ]/2 (Observed),
2
+
CH(NHBoc)-CH
N(-CH -CH -CH
CH(NHBoc)-CH
R-CO-N(-CH
2
2
2
2
2
423.76746 [(M+2H) ]/2 (Calculated).
D
D
2
2
2
2
3
)
2
N,N-bis-[3-( Phe- Leu)amidopropyl]octanamide
1
2
2
2
2
2
bis(trifluoroacetate) (2): H-NMR (400 MHz, DMSO-d
6
)
2
2
2
2
-CH-(CH
3
)
2
)-NH-CO-
)-NH-CO-
δ/ppm: 8.805-8.769 (t, J = 7.2 Hz, R-CO-N(-CH
2
-CH
2
-CH
2
-NH-
2H),
+
2
2
2
2
2
, 2H), 4.053-3.982 (m,
CO-CH-(CH
2
-Ph)-NH-CO-CH(NH
3
)-CH
-CH
, 8H), 7.290-7.178 (m, R-
-NH-CO-CH-(CH -PhH)-NH-CO-
2
-CH-(CH
3 2 2
) ) ,
2
2
2
2
-CH-(CH
3
)
2
8.175-7.981 (m, R-CO-N(-CH
2
-CH
2
2
-NH-CO-CH-(CH
2
-Ph)-
+
2
2
2
2
2
, 2H), 3.400-3.091 (m,
-CH-(CH )-NH-CO-
, 12H), 2.283-2.245 (t,
- of R group, 2H), 1.778-1.488
-CO-N(-CH -CH -CH -NH-CO-
-CH -CH -CH
-CH -CH -NH-CO-
)-NH-CO-CH(NH-COO-C(CH )-CH -CH
-NH-COO-C(CH , 36H), 1.292 (bs, CH -(CH
-of R group, 8H), 0.890-0.856 (t, J = 6.8 Hz, CH
NH-CO-CH(NH
3
)-CH
2
-CH-(CH
3
)
2
)
2
2
2
2
2
3
)
2
CO-N(-CH
2
-CH
2
-CH
2
2
+
2
2
2
2
-CH
2
-CH
2
-NHBoc)
2
CH(NH
3
)-CH
2
-CH-(CH
3
)
2
)
2
, 10H), 4.536-4.454 (m, R-CO-N(-
+
J = 7.6 Hz, CH
m, CH
CH(CH
NHBoc)
CH(CH
3
-(CH
-(CH
)
4
-CH
2
-CH
2
CH -CH
2
2
-CH
2
-NH-CO-CH-(CH
2
-Ph)-NH-CO-CH(NH
3
)-CH
-NH-CO-
, 2H), 3.091-
-NH-CO-CH-(CH -Ph)-NH-
, 12H), 2.200-2.164 (t, J = 7.2
- of R group, 2H), 1.623-1.449 (m,
-CO-N(-CH -CH -CH -NH-CO-CH-(CH
-CH-(CH , 12H), 1.232 (bs, CH
- of R group , 8H), 0.878-0.820 (m, CH -(CH
-Ph)-NH-CO-
2
-
(
3
)
4
-CH
2
-CH
2
2
2
2
CH-(CH
3
2
)
2
)
2
2 2 2
, 2H), 3.771 (bs, R-CO-N(-CH -CH -CH
+
2
-CH-(CH
24H), 1.436 (s, R-CO-N(-CH
-CH-(CH
3
)
2
)-NH-CO-CH(NHBoc)-CH
2
2
2
2
-
CH-(CH
-Ph)-NH-CO-CH(NH
3
2 3 2 2
)-CH -CH-(CH ) )
2
,
2
2
2
2.838 (m, R-CO-N(-CH
2
-CH
2
-CH
2
2
+
2
3
)
2
3
)
3
2
2
-
CO-CH(NH
Hz, CH
CH -(CH
Ph)-NH-CO-CH(NH
(CH -CH -CH
CH -CO-N(-CH
CH(NH )-CH -CH-(CH
3
)-CH
-CH
-CH
2
-CH-(CH
3 2 2
) )
CH
2
2
-CH
2
2
3
)
3
)
2
3
2
)
4
-
-
3
-(CH
2
)
4
2
-CH
2
CH
-CH
3
3
2
)
4
-CH
2
2
2
2
2
2
-
+
(
CH
2
)
4
-CH
2
-CH
2
- of R group, 3H). HRMS (m/z): 1140.80527
3
)-CH
2
3
)
2
)
2
3
4
-
-
+
+
[
(M+H) ] (Observed), 1140.82231 [(M+H) ] (Calculated).
2
)
4
2
2
3
2
)
General protocol for synthesizing 1-6: At first, 12a-12f were
dissolved in excess amount of 1:1 (DCM:TFA) and kept for
stirring at RT. At the end 2h, the reaction solvent and unused
TFA were removed to afford pure 1-6 with 100% yield.
2
-CH
2
2
-CH
2
-CH -NH-CO-CH-(CH
2 2
+
13
3
2
3 2 2
) ) , 15H). C-NMR (100 MHz, DMSO-
6
d ) δ/ppm: 171.93, 170.04, 168.88, 137.47, 129.16, 128.23,
126.49, 54.64, 50.82, 45.08, 42.76, 37.93, 36.19, 32.12, 31.24,
28.77, 28.68, 27.46, 25.14, 23.46, 22.78, 22.07, 21.76, 13.96.
D
D
N,N-bis-[3-( Phe- Phe)amidopropyl]octanamide
1
+
bis(trifluoroacetate) (1): H-NMR (400 MHz, DMSO-d
6
)
HRMS (m/z): 778.53923 [(M+H) ] (Observed), 778.55949
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201702227
FULL PAPER
+
2+
+
13
[
(M+H) ] (Calculated). 389.77317 [(M+2H) ]/2 (Observed),
3 2 2 6
CH(NH )-CH -Ph) , 15H). C-NMR (100 MHz, DMSO-d )
2
+
3
89.78311 [(M+2H) ]/2 (Calculated).
δ/ppm: 171.94, 171.02, 167.67, 134.81, 129.55, 128.50,
127.14, 53.21, 51.38, 45.12, 41.50, 36.96, 36.37, 32.09, 31.22,
28.78, 28.66, 27.55, 25.10, 24.15, 22.87, 22.06, 21.88, 13.94.
D
D
N,N-bis-[3-( Phe- Lys)amidopropyl]octanamide
1
tetrakis(trifluoroacetate) (3): H-NMR (400 MHz, DMSO-d
6
)
+
δ/ppm: 8.731-8.680 (m, R-CO-N(-CH
2
-CH
2
2
-CH -NH-CO-CH-
HRMS (m/z): 778.53750 [(M+H) ] (Observed), 778.55949
+
+
+
2+
(
CH
2
-Ph)-NH-CO-CH(NH
3
)-CH
-CH
-CH
-CH
2
-CH
2
-CH
2
-CH
2
-NH
3
)
2
,
2H),
[(M+H) ] (Calculated). 389.77402 [(M+2H) ]/2 (Observed),
2
+
8
.253-7.859 (m, R-CO-N(-CH
2
2
-CH
2
-NH-CO-CH-(CH
2
-Ph)-
389.78311 [(M+2H) ]/2 (Calculated).
+
+
NH-CO-CH(NH
3
)-CH
2
-CH
2
2
-CH
2
-NH
3
)
2
,
14H), 7.293-
-PhH)-NH-
, 10H), 4.528-4.447 (m, R-CO-
D
D
7
.190 (m, R-CO-N(-CH
2
-CH
2
2
-NH-CO-CH-(CH
2
N,N-bis-[3-( Leu- Leu)amidopropyl]octanamide
+
1
CO- CH
N(-CH -CH
CH -CH
2
-CH
2
-CH
2
-CH
2
-NH
3
)
2
bis(trifluoroacetate) (5): H-NMR (400 MHz, DMSO-d
6
)
+
2
2
-CH
2
-NH-CO-CH-(CH
2
-Ph)-NH-CO-CH(NH
-CH
-CH -CH
-CH
-CH
3
)-CH
2
-
δ/ppm: 8.646-8.595 (m, R-CO-N(-CH
2
-CH
-CH-(CH
-CH -NH-CO-CH-(CH
-CH-(CH
-NH-CO-CH-(CH
2 2
-CH -NH-CO-CH-
+
+
2
2
-CH
2
-NH
3
)
2
, 2H), 3.755 (bs, R-CO-N(-CH
2
2
-CH
2
-
(CH
2
-CH-(CH
3
)
2
)-NH-CO-CH(NH
3
)-CH
2
3
)
2
)
2
,
2H),
+
NH-CO-CH-(CH
2
-Ph)-NH-CO-CH(NH
3
)-CH
2
-CH
2
2
2
-
8.195-8.005 (m, R-CO-N(-CH
2
-CH
2
2
2
-CH-
+
+
NH
3
)
2
, 2H), 3.120-2.740 (m, R-CO-N(-CH
2
-CH
2
2
-NH-CO-
(CH
3
)
2
)-NH-CO-CH(NH
3
)-CH
2
3 2 2
) ) , 8H), 4.346-4.258
+
+
CH-(CH
2
-Ph)-NH-CO-CH(NH
6H), 2.221-2.183 (m, CH
.706-1.317 (m, CH -(CH
3
)-CH
2
-CH
2
-CH
2
2
-NH
3
)
2
,
(m, R-CO-N(-CH
2
-CH
-CH-(CH
-CH-(CH
2
-CH
2
2
-CH-(CH
3
)
2
)-NH-
+
1
1
3
-(CH
2
)
4
-CH
2
-CH
2
- of R group, 2H),
-CO-N(-CH -CH -CH
-CH -CH
- of R group, 8H),
-CH - of R group,
) δ/ppm: 171.99, 170.60,
CO-CH(NH
CH -CH
CH-(CH
CO-CH-(CH
8H), 2.234-2.200 (t, J = 6.8 Hz, CH
group, 2H), 1.667-1.416 (m, CH -(CH
CH -CH -NH-CO-CH-(CH -CH-(CH
CH-(CH , 18H), 1.240 (bs, CH -(CH
8H), 0.901-0.832 (m, CH -(CH -CH
-CH-(CH
3
)-CH
2
3 2 2 2
) ) , 2H), 3.796 (bs, R-CO-N(-CH -
+
3
2
)
4
-CH
2
-CH
2
2
2
2
-
2
2
-NH-CO-CH-(CH
2
3
)
2
)-NH-CO-CH(NH
3
)-CH
2
-
+
NH-CO-CH-(CH
2
-Ph)-NH-CO-CH(NH
-(CH
-(CH
H). C-NMR (100 MHz, DMSO-d
3
)-CH
2
-CH
2
2
2
-
3
)
2
)
2
, 2H), 3.515-2.927 (m, R-CO-N(-CH
2
-CH
-CH-(CH
-CH -CH - of R
2
-CH -CO-N(-CH -
-CH -NH-
2 2
+
+
NH
3
)
2
, 18H), 1.223 (bs, CH
3
2
)
4
-CH
2
-CH
2
2
-CH-(CH
3
)
2
)-NH-CO-CH(NH
-(CH
-CH
3
)-CH
2
3 2 2
) ) ,
0
3
1
3
2
.849-0.815 (t, J = 6.8 Hz, CH
3
2
)
4
-CH
2
2
3
2
)
4
2
2
1
3
6
3
2
)
4
2
2
+
3
68.49, 137.38, 129.17, 128.22, 126.52, 54.68, 51.90, 38.55,
6.49, 36.21, 32.14, 31.23, 30.54, 28.78, 28.67, 28.52, 26.44,
2
2
2
3
)
2
)-NH-CO-CH(NH
-CH -CH
-CH
)-CH
2
-
3
)
2
)
2
3
2
)
4
2
2
- of R group ,
+
5.14, 22.06, 21.03, 13.96. HRMS (m/z): 808.58202 [(M+H) ]
3
2
)
4
2
2
-CO-N(-CH
2
2
-CH -
+
+
(
Observed), 808.58129 [(M+H) ] (Calculated). 404.79507
CH
2
-NH-CO-CH-(CH
2
3
)
2
)-NH-CO-CH(NH
3
2
)-CH -CH-
2
+
2+
13
[
(M+2H) ]/2 (Observed), 404.79401 [(M+2H) ]/2 (Calculated).
(CH
3 2 2 6
) ) , 27H). C-NMR (100 MHz, DMSO-d ) δ/ppm: 173.60,
D
D
N,N-bis-[3-( Leu- Phe)amidopropyl]octanamide
172.43, 169.58, 52.48, 51.66, 45.89, 41.30, 40.75, 36.96,
32.77, 31.79, 29.19, 25.79, 24.79, 24.17, 23.40, 23.18, 22.66,
22.44, 22.34, 22.30, 22.24, 14.55. HRMS (m/z): 710.57239
1
bis(trifluoroacetate) (4): H-NMR (400 MHz, DMSO-d
6
)
δ/ppm: 8.675-8.635 (t, J = 8.0 Hz, R-CO-N(-CH
2
-CH
2
-CH
2
-NH-
2H),
-CH-
+
+
+
CO-CH-(CH
2
-CH-(CH
3
)
2
)-NH-CO-CH(NH
-CH -CH
-Ph)
-NH-CO-CH-(CH
3
)-CH
2
-Ph)
2
,
[(M+H) ] (Observed), 710.59079 [(M+H) ] (Calculated).
2
+
2+
8
.137-7.977 (m, R-CO-N(-CH
2
2
2
-NH-CO-CH-(CH
2
355.79120 [(M+2H) ]/2 (Observed), 355.79876 [(M+2H) ]/2
+
(
CH
3
)
2
)-NH-CO-CH(NH
3
)-CH
2
2
, 8H), 7.293-7.227 (m, R-
-CH-(CH )-NH-CO-
(Calculated).
D
D
CO-N(-CH
2
-CH
2
-CH
2
2
3
)
2
N,N-bis-[3-( Leu- Lys)amidopropyl]octanamide
+
1
CH(NH
CH -CH
Ph)
3
)-CH
2
-PhH)
2
, 10H), 4.324-4.277 (m, R-CO-N(-CH
2
-
tetrakis(trifluoroacetate) (6): H-NMR (400 MHz, DMSO-d
6
)
+
2
2
-NH-CO-CH-(CH
2
-CH-(CH
3
)
2
)-NH-CO-CH(NH
-CH -CH
-Ph)
3
)-CH
2
-
δ/ppm: 8.588-8.537 (m, R-CO-N(-CH
2
-CH
2
2
-CH -NH-CO-CH-
+
+
2
, 2H), 4.006 (bs, R-CO-N(-CH
2
2
2
-NH-CO-CH-(CH
2
-
(CH
2
-CH-(CH
3
)
2
)-NH-CO-CH(NH
3
)-CH
-CH
-CH
-CH -CH
-CH -CH
-CH -CH
-CH -CH
-CH -CH
-CH -CH
2
-CH
2
2
-CH
2
2 3 2
-CH -NH ) ,
+
CH-(CH
3
)
2
)-NH-CO-CH(NH
3
)-CH
2
2
, 2H), 3.234-2.899 (m,
-CH-(CH )-NH-CO-
, 12H), 2.251-2.214 (t, J = 7.2 Hz, CH
- of R group, 2H), 1.636-1.443 (m, CH -(CH
-CH-(CH )-
2H), 8.241-7.903 (m, R-CO-N(-CH
2
2
-CH
2
-NH-CO-CH-(CH -
+
+
R-CO-N(-CH
2
-CH
-Ph)
-CH
2
-CH
2
-NH-CO-CH-(CH
2
3
)
2
CH-(CH
3
)
2
)-NH-CO-CH(NH
3
)-CH
2
2
-CH
2
-CH
2
-NH
3
)
2
, 14H),
+
CH(NH
CH
CH
3
)-CH
2
2
3
4
-
-
4.323-4.236 (m, R-CO-N(-CH
2
2
2
-NH-CO-CH-(CH
2
-CH-
2H),
2
-CH-
2H),
2
-CH-
+
+
(
2
)
4
-CH
2
2
3
2
)
(CH
3.799
(CH
3
)
2
)-NH-CO-CH(NH
3
)-CH
2
2
2
-CH
2
-NH
3
)
2
,
2
-CH
2
-CO-N(-CH
2
-CH
2
-CH
, 12H), 1.216 (bs, CH
-(CH
-CH-(CH
2
-NH-CO-CH-(CH
2
3
)
2
(bs,
R-CO-N(-CH
2
2
2
-NH-CO-CH-(CH
+
+
+
NH-CO-CH(NH
CH
CO-N(-CH
3
)-CH
2
-Ph)
2
3
-(CH
2
)
4
-CH
2
-
-
3
)
2
)-NH-CO-CH(NH
3
)-CH
2
2
2 2 3 2
-CH -NH ) ,
2
- of R group , 8H), 0.906-0.815 (m, CH
3
2
)
4
-CH
2
-CH
2
3.217-2.749 (m, R-CO-N(-CH
2
2
2
-NH-CO-CH-(CH
+
+
2
-CH -CH -NH-CO-CH-(CH
2
2
2
3
)
2
)-NH-CO-
(CH
3
)
2
)-NH-CO-CH(NH
3
)-CH
2
2
2
-CH
2
-NH
3
)
2
,
12H),
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201702227
FULL PAPER
2
.246-2.200 (m, CH
.348 (m, CH -(CH
-CH-(CH
3
-(CH
2
)
4
-CH
2
-CH
2
- of R group, 2H), 1.698-
CH
3
-(CH
2
)
4
-CH
2
-CH
2
-
+
of
R
group, 3H); HRMS (m/z):
+
1
3
2
)
4
-CH
2
-CH
2
-CO-N(-CH
2
-CH
-CH -CH
- of R group, 8H),
2
-CH
2
-NH-CO-
1158.67996 [(M+H) ] (Observed), 1158.68548 [(M+H) ]
(Calculated).
+
CH-(CH
2
3
)
2
)-NH-CO-CH(NH
-(CH
-CH -CH
)-NH-CO-CH(NH
3
)-CH
2
2
2
2
-CH -
+
NH
3
)
2
, 24H), 1.242 (bs, CH
-(CH
-CH-(CH
3
2
)
4
-CH
2
-CH
2
Protocol for synthesizing 14: Fmoc group of compound 13
was selectively deprotected to achieve compound 14. Briefly,
compund 13 was dissolved in excess amount of 1:1 of
Diethylamine and DCM and allowed to stir at RT. At the end of
3h, the reaction mixture was evaporated to dryness and the
0.899-0.832 (t, CH
3
2
)
4
2
2
-CO-N(-CH
2
-CH
2
2
-CH -NH-
+
CO-CH-(CH
2
3
)
2
3
)-CH
2
-CH -CH
2
2
-
+
13
CH
2
-NH
3
)
2
, 15H). C-NMR (100 MHz, DMSO-d
6
) δ/ppm:
171.80, 171.49, 168.34, 51.89, 51.59, 45.12, 42.81, 41.05,
38.57, 36.50, 32.10, 31.26, 30.48, 28.70, 26.41, 25.13, 24.19,
22.92, 22.09, 21.69, 21.06, 13.98. HRMS (m/z): 740.59400
3
crude product was dissolved in minimum volume of CHCl and
MeOH mixture. After that, pure compound 14 was isolated
+
+
[
(M+H) ] (Observed), 740.61259 [(M+H) ] (Calculated).
through precipitation by adding diethyl ether to the crude
2
+
2+
1
3
70.80232 [(M+2H) ]/2 (Observed), 370.80966 [(M+2H) ]/2
reaction mixture. Yield: 90%; H-NMR (400 MHz, CDCl
3
)
(
Calculated).
δ/ppm: 7.675-7.235 (m, R-CO-N(-CH
CH(NH )-CH -CH -CH -CH -NHBoc) , 6H), 4.569 (bs, R-CO-
N(-CH -CH -CH -NH-CO-CH(NH )-CH
2H), 4.186-4.151 (t, J = 7.0 Hz, R-CO-N(-CH
CO-CH(NH )-CH -CH -CH -CH -NHBoc)
R-CO-N(-CH -CH -CH -NH-CO-CH(NH
-NHBoc) , 12H), 2.258-2.222 (t, J = 7.2 Hz, CH
-CH - of R group, 2H), 1.801-1.542 (m, CH -(CH
-CO-N(-CH -CH -CH -NH-CO-CH(NH )-CH -CH
-NHBoc) , 18H), 1.241 (bs, CH -(CH -CH
-(CH
2 2 2
-CH -CH -NH-CO-
Protocol for synthesizing 13: At first, 2.4 equivalents of
Fmoc-D-Lys (Boc)-OH was dissolved in dry DCM and
anhydrous DMF (4:1) at 0-5 ºC ice bath. 4 equivalents of
DIPEA were then added to the solution followed by 2.4
equivalents of HBTU. After that, the reaction mixture allowed
2
2
2
2
2
2
2
2
2
2
2
-CH
2
-CH
2
-NHBoc)
2
,
2
-CH -CH -NH-
2
2
2
2
2
2
2
2
,
2H), 3.410-3.061
(m,
CH
CH
CH
CH
2
2
2
2
)-CH
2
-CH
-(CH
-CH
2
-CH
2
-
4
-
2
-
stirring for 10-15 min. To the reaction mixture then,
1
2
2
2
2
2
3
2
)
equivalent of precursor amine was added drop wise after
dissolving it in dry DCM in presence of additional 2 equivalents
of DIPEA. The reaction mixture was then brought to RT and
allowed to stir for 48h. At the end of the reaction, solvent was
removed by using rotary evaporator. The crude reaction
mixture was diluted in ethyl acetate and then washed by using
2
3
2
)
4
2
2
2
2
2
2 2
-CH -
2
3
2
)
4
2
-CH
2
- of R
group, 8H), 0.886-0.853 (t, J = 6.6 Hz, CH
3
2
)
4
-CH
2
-CH - of
2
+
R group, 3H); HRMS (m/z): 714.54903 [(M+H) ] (Observed),
+
714.54932 [(M+H) ] (Calculated).
1
N HCl (3 times). At the end, the ethyl acetate layer was
General protocol for synthesizing 15a-15c: Briefly, 2.4
equivalents of Boc-D-Phe-OH, Boc-D-Leu-OH or Boc-D-Lys
(Boc)-OH was dissolved in dry DCM and anhydrous DMF (4:1)
at 0-5 ºC ice bath. To this solution, 4 equivalents of DIPEA
were then added followed by 2.4 equivalents of HBTU and kept
for stirring. At the end of 10-15 min, 1 equivalent of 14 was
added drop wise to the reaction mixture after dissolving it in dry
DCM in presence of additional 2 equivalents of DIPEA. The RB
containing reaction mixture was then brought to RT and
allowed to stir for 48h. At the end, the reaction solvent was
removed by using rotary evaporator and the crude reaction
mixture was diluted in ethyl acetate and then washed by using
1N HCl (3 times). Finally, the ethyl acetate layer was collected
collected by passing through anhydrous Na SO and the
2
4
compound was purified by performing column chromatography
on silica gel (60-120 mesh) with various ratios of MeOH and
1
CHCl
3
as eluent. Yield-60%; H-NMR (400 MHz, CDCl
3
) δ/ppm:
-NH-CO-CH(NH-COO-
, 18H), 5.923-5.877 (d,
-NH-CO-CH(NHFmoc)-CH -CH -CH
, 2H), 4.855 (bs, R-CO-N(-CH -CH -CH -NH-CO-
2H), 4.368-4.169
-NH-CO-CH(NH-COO-CH -Fl-H )-
7
.747-7.088 (m, R-CO-N(-CH
CH -FlArH)-CH -CH -CH -CH
R-CO-N(-CH -CH -CH
CH -NHBoc)
CH(NHFmoc)-CH
m, R-CO-N(-CH
2
2 2
-CH -CH
2
2
2
2
2
-NHBoc)
2
2
2
2
2
2
2
-
2
2
2
2
2
2
-CH
-CH
-NHBoc)
-NH-CO-CH(NHFmoc)-CH
2
-CH
2
-CH
2
-NHBoc)
2
,
(
2
2
-CH
2
2
9
CH
2
2
-CH
2
-CH
2
2
, 8H), 3.426-3.068 (m, R-CO-N(-CH
-CH -CH -CH -NHBoc)
-(CH -CH -CH - of R
-CH -CH -CO-N(-CH
-CH -NHBoc)
-NH-CO-CH(NHFmoc)-
18H), 1.238 (bs, CH
- of R group, 8H), 0.891-0.856 (t, J = 7.0 Hz,
2
-
CH
-CH
2
2
2
2
2
2
,
1
2H), 2.259-2.221 (t, J = 7.6 Hz, CH
group, 2H), 2.046-1.544 (m, CH -(CH
CH -CH -NH-CO-CH(NHFmoc)-CH -CH
8H), 1.424 (s, R-CO-N(-CH -CH -CH
3
2
)
4
2
2
through anhydrous Na
2 4
SO and pure 15a-12c was achieved by
3
2
)
4
2
2
2
-
performing column chromatography on silica gel (60-120 mesh)
2
2
2
2
-CH
2
2
2
,
3
with various ratios of MeOH and CHCl as eluent.
D
1
2
2
2
N,N-bis-[3-(Nε-Boc- Lys-N-Boc-
D
1
CH
2
-CH
2
-CH
2
-NH-COO-C(CH
3
)
3
)
2
,
3
-
Phe)amidopropyl]octanamide (15a): Yield-62%; H-NMR
) δ/ppm: 7.289-7.086 (m, R-CO-N(-CH -CH
(
CH
2
)
4
-CH
2
-CH
2
(400 MHz, CDCl
3
2
2
-
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201702227
FULL PAPER
CH
CH(NHBoc)-CH
CH -CH -NH-CO-CH-(CH
CH(NHBoc)-CH
CH -NH-CO-CH-(CH
CH(NHBoc)-CH -Ph)
NH-CO-CH-(CH -CH
2
-NH-CO-CH-(CH
2
-CH
, 12H), 6.677-6.487 (d, R-CO-N(-CH
-CH -CH -CH -NHBoc)-NH-CO-
, 2H), 5.620-5.329 (d, R-CO-N(-CH
-CH -CH -CH -NHBoc)-NH-CO-
2H), 4.767 (bs, R-CO-N(-CH -CH
-CH -CH
2
-CH
2
-CH
2
-NHBoc)-NH-CO-
CH
CH-(CH
8H), 0.937-0.872 (m, CH
CH -NH-CO-CH(CH -CH -CH
-CH-(CH
2
-NH-COO-C(CH
, 36H), 1.283 (bs, CH
-(CH
-CH
2
3
)
3
)-NH-CO-CH(NH-COO-C(CH
-(CH -CH -CH -of R group,
-CH -CH -CO-N(-CH -CH
-NHBoc)-NH-CO-
3 3 2
) )-CH -
2
-PhH)
2
2
2
2
2
2
2
-
-
-
-
-
-
3
)
2
)
2
3
2
)
4
2
2
2
2
2
2
2
2
3
2
)
4
2
2
2
2
-
2
-Ph)
2
2
2
2
2
2
-CH
-CH
2
2
2
2
2
2
2
2
CH(NHBoc)-CH
2
3
)
2
)
2
, 15H). HRMS (m/z): 1140.80527
+
+
2
2
[(M+H) ] (Observed), 1140.82231 [(M+H) ] (Calculated).
D
2
2
2
-NHBoc)-NH-CO-CH(NHBoc)-
N,N-bis-[3-(Nε-Boc- Lys-N,N´-Di-Boc-
D
1
CH
2
-Ph)
-NH-CO-CH-(CH
-Ph)
-NH-CO-CH-(CH
CH(NHBoc)-CH -Ph)
CH -CH
CH(NHBoc)-CH
CH -CH -CH
-CH -CO-N(-CH
-NHBoc)-NH-CO-CH(NHBoc)-CH
CH -(CH -CH -CH -CO-N(-CH
-CH -CH -CH -NH-COO-C(CH )-NH-CO-CH(NH-
COO-C(CH )-CH -Ph) , 44H), 0.890-0.856 (t, J = 6.8 Hz,
CH -(CH -CH -CH
2
, 2H), 4.685-4.654 (t, J = 6.2 Hz, R-CO-N(-CH
2
-CH
Lys)amidopropyl]octanamide (15c): Yield-63%; H-NMR
(400 MHz, CDCl ) δ/ppm: 7.545-7.449 (d, R-CO-N(-CH -CH
CH -NH-CO-CH(CH -CH -CH -CH -NHBoc)-NH-CO-
CH(NHBoc)-CH -CH -CH -CH -NHBoc) , 2H), 6.636-6.488 (d,
R-CO-N(-CH -CH -CH -NH-CO-CH(CH -CH -CH -CH
NHBoc)-NH-CO-CH(NHBoc)-CH -CH -CH -CH -NHBoc)
5.503-5.268 (d, R-CO-N(-CH -CH -CH -NH-CO-CH(CH
CH -CH -NHBoc)-NH-CO-CH(NHBoc)-CH
NHBoc) 2H), 4.861 (bs, R-CO-N(-CH
CH(CH -CH -CH -CH
-CH -NHBoc) , 4H), 4.514-4.483 (m, R-CO-N(-CH
-NH-CO-CH(CH -CH -CH -CH -NHBoc)-NH-CO-
-CH -CH -CH -NHBoc) , 2H), 4.40-3.983 (m,
-CH -CH -NH-CO-CH(CH -CH -CH -CH
NHBoc)-NH-CO-CH(NHBoc)-CH -CH -CH -CH -NHBoc)
3.457-3.092 (m, R-CO-N(-CH -CH -CH -NH-CO-CH(CH
CH -CH -NHBoc)-NH-CO-CH(NHBoc)-CH
NHBoc) , 16H), 2.283-2.245 (t, CH -(CH
group, 2H), 1.778-1.488 (m, CH -(CH -CH
CH -CH -NH-CO-CH(CH -CH -CH -CH -NHBoc)-NH-CO-
CH(NHBoc)-CH -CH -CH -CH -NHBoc) , 30H), 1.436 (s, R-
CO-N(-CH -CH -CH -NH-CO-CH(CH -CH -CH -CH -NH-COO-
C(CH )-NH-CO-CH(NH-COO-C(CH )-CH -CH -CH -CH
NH-COO-C(CH , 54H), 1.283 (bs, CH -(CH -CH -CH -of R
group, 8H), 0.882-0.852 (t, J = 6.0 Hz, CH -(CH -CH -CH - of
CH
2
2
2
2
2
-CH
2H), 3.983-3.884 (m, R-CO-N(-CH
-CH -CH -CH -NHBoc)-NH-CO-
, 2H), 3.323-3.079 (m, R-CO-N(-CH
-CH -CH -CH -NHBoc)-NH-CO-
, 16H), 2.257-2.219 (t, J = 7.6 Hz, CH
- of R group, 2H), 1.720-1.580 (m, CH -(CH
-CH -CH -NH-CO-CH-(CH -CH -CH
-Ph) , 18H), 1.479-1.276
-CH -CH -NH-CO-
2
-CH
2
-CH
2
-NHBoc)-NH-CO-
3
2
2
-
CH(NHBoc)-CH
2
2
-CH
2
2
2
2
2
CH
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
-
2
2
-NH-CO-CH(CH
2
2
2
2
2
2
2
2
2
, 2H),
-CH
2
-Ph)
2
3
-
-
2
2
2
2
2
-
(
2
)
4
2
2
3
2
)
4
2
2
2
-CH
2
-CH
2
-CH
2
-
CH
2
2
2
2
2
2
2
2
-
2
,
2
-CH
2
-CH
2
-NH-CO-
-CH
-CH
CH
2
2
2
2
2
2
2
-NHBoc)-NH-CO-CH(NHBoc)-CH
2
2
-
(
m,
3
2
)
4
2
2
2
2
2
CH
2
2
2
2
2
2
-
CH(CH
2
2
2
2
3
)
3
CH
2
2
2
2
3
)
3
2
2
CH(NHBoc)-CH
2
2
2
2
2
3
2
)
4
2
2
-
of
R
group, 3H). HRMS (m/z):
R-CO-N(-CH
2
2
2
2
2
2
2
-
+
+
1
208.79084 [(M+H) ] (Observed), 1208.79101 [(M+H) ]
2
2
2
2
2
, 2H),
-CH
(
Calculated).
2
2
2
2
2
-
D
N,N-bis-[3-(Nε-Boc- Lys-N-Boc-
2
2
2
-CH
-CH
-CH
2
-CH
2
-CH
2
-
D
1
Leu)amidopropyl]octanamide (15b): Yield-64%; H-NMR
) δ/ppm: 7.545-7.449 (d, R-CO-N(-CH -CH
-NH-CO-CH(CH -CH -CH -CH -NHBoc)-NH-CO-
CH(NHBoc)-CH -CH-(CH , 2H), 6.636-6.488 (d, R-CO-N(-
CH -CH -CH -NH-CO-CH(CH -CH -CH -CH -NHBoc)-NH-CO-
CH(NHBoc)-CH -CH-(CH , 2H), 5.503-5.268 (d, R-CO-N(-
CH -CH -CH -NH-CO-CH(CH -CH -CH -CH -NHBoc)-NH-CO-
CH(NHBoc)-CH -CH-(CH , 2H), 4.861 (bs, R-CO-N(-CH
CH -CH -NH-CO-CH(CH -CH -CH -CH -NHBoc)-NH-CO-
CH(NHBoc)-CH -CH-(CH , 2H), 4.514-4.483 (m, R-CO-N(-
CH -CH -CH -NH-CO-CH(CH -CH -CH -CH -NHBoc)-NH-CO-
CH(NHBoc)-CH -CH-(CH , 2H), 4.400-3.983 (m, R-CO-N(-
CH -CH -CH -NH-CO-CH(CH -CH -CH -CH -NHBoc)-NH-CO-
CH(NHBoc)-CH -CH-(CH , 2H), 3.457-3.092 (m, R-CO-N(-
CH -CH -CH -NH-CO-CH(CH -CH -CH -CH -NHBoc)-NH-CO-
CH(NHBoc)-CH -CH-(CH , 12H), 2.283-2.245 (t, J = 7.6 Hz,
-CH - of R group, 2H), 1.778-1.488 (m, CH
-CO-N(-CH -CH -CH -NH-CO-CH(CH -CH
-CH-(CH , 24H),
-NH-CO-CH(CH -CH -CH
2
3
2
)
4
2
2
-CH - of R
(
400 MHz, CDCl
3
2
2
-
3
2
)
4
2
2 2
-CO-N(-CH -
CH
2
2
2
2
2
2
2
2
2
2
2
2
3
)
2
)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
)
2
)
2
3
)
3
3
)
3
2
2
2
2
-
2
2
2
2
2
2
2
3
)
3
)
2
3
2
)
4
2
2
2
3
)
2
)
2
2
-
3
2
)
4
2
2
+
2
2
2
2
2
2
R group, 3H). HRMS (m/z): 1370.94867 [(M+H) ] (Observed),
+
2
3
)
2
)
2
1370.94897 [(M+H) ] (Calculated).
D
D
2
2
2
2
2
2
2
N,N-bis-[3-( Lys- Phe)amidopropyl]octanamide
1
2
3
)
2
)
2
tetrakis(trifluoroacetate) (7): H-NMR (400 MHz, DMSO-d
6
)
2
2
2
2
2
2
2
δ/ppm: 8.731-8.679 (m, R-CO-N(-CH
2
-CH
2
-CH
2
-NH-CO-CH-
2H),
-CH
, 14H), 7.273-7.184
2
-CH -CH -CH -
+
+
2
3
)
2
)
2
(CH
2
-CH
2
-CH
2
-CH
2
-NH
3
)-NH-CO-CH(NH
3
)-CH
2
-Ph) ,
2
2
2
2
2
2
2
2
8.253-7.859 (m, R-CO-N(-CH
2
-CH
2
-CH
2
-NH-CO-CH-(CH
2
2
-
+
+
3
2
3
)
2
)
2
CH
(m,
NH
CH
2
-CH
2
-NH
3
)-NH-CO-CH(NH
-CH -CH
-PhH)
)-CH
2
-Ph)
2
CH
3
-(CH
-CH
-CH
2
)
4
-CH
2
2
2
3
-
R-CO-N(-CH
2
2
2
-NH-CO-CH-(CH
2
2
2
+
(
CH
2
)
4
2
-CH
2
2
2
2
2
-
3
2
)-NH-CO-CH
2
2
, 10H), 4.527-4.447 (m, R-CO-N(-
+
CH
2
2
-NHBoc)-NH-CO-CH(NHBoc)-CH
2
3
)
2
)
2
-CH
2
-CH
2
-NH-CO-CH-(CH
2
-CH
2
-CH
2
-CH
2
-NH
3
)-NH-CO-
2
-CH -CH -
+
1
.436 (s, R-CO-N(-CH
2
-CH -CH
2
2
2
2
2
-
CH(NH
3
)-CH
2
-Ph)
2
, 2H), 3.755 (bs, R-CO-N(-CH
2
2
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201702227
FULL PAPER
+
+
+
NH-CO-CH-(CH
2
-CH
2
-CH
2
-CH
2
-NH
3
)-NH-CO-CH(NH
3
)-CH
-NH-CO-CH-
-Ph) 16H),
- of R group,
2
-
CH
2
-CH
2
-NH
3
)
2
, 2H), 3.213-2.757 (m, R-CO-N(-CH
2
-CH
2
-CH
-CH
-(CH
-CH
2
-
+
+
Ph)
2
, 2H), 3.120-2.669 (m, R-CO-N(-CH
2
-CH
2
-CH
2
NH-CO-CH-(CH
2
-CH
, 16H), 2.233-2.217 (t, J = 6.4 Hz, CH
-(CH
-CH -CH
38H), 0.857-
2
-CH
2
-CH
2
-NH
3
)-NH-CH(NH
3
)-CH
2
2
-
+
+
+
3
(
CH
2
-CH
2
-CH
2
-CH
2
-NH
3
)-NH-CO-CH(NH
-(CH
-(CH -CH
-CH -CH
, 18H), 1.227 (bs, CH -(CH
3
)-CH
-CH
-CH -CO-N(-CH
2
2
,
CH
CH
CH
NH
2
2
2
3
-CH
-CH
2
-NH
)
2
3
2
)
4
-
-
2
.221-2.183 (t, J = 7.6 Hz, CH
H), 1.706-1.317 (m, CH
3
2
)
4
-CH
2
2
2
- of R group, 2H), 1.711-1242 (m, CH
3
2
)
4
2
2
3
2
)
4
2
2
2
-CH
2
-
-CO-N(-CH
2
-CH
2
-CH
2
-NH-CO-CH-(CH
2
-CH
2
2
2
-
+
+
+
+
+
CH
2
-NH-CO-CH-(CH
2
-CH
2
2
2
-NH
-CH
-(CH
group, 3H). C-NMR (100 MHz, DMSO-d
3
)-NH-CO-CH(NH
-CH
-CH
) δ/ppm: 170.33,
68.51, 137.38, 129.28, 128.23, 126.54, 54.69, 51.92, 38.57,
3
)-
)-NH-CH(NH
-(CH
MHz, DMSO-d ) δ/ppm: 172.63, 168.90, 168.53, 52.11, 46.23,
3
)-CH
2
-CH
2
-CH
2
-CH
2
-NH
3
)
2
,
1
3
CH
2
-Ph)
2
3
2
)
4
2
2
- of R group,
-CH - of R
0.841 (t, CH
3
2
)
4
-CH
2
-CH
2
- of R group, 3H). C-NMR (100
8
H), 0.849-0.815 (t, J = 6.8 Hz, CH
3
2
)
4
2
2
6
1
3
6
44.24, 38.46, 37.37, 32.21, 31.29, 30.34, 29.06, 29.01, 28.88,
28.69, 26.52, 24.93, 22.08, 21.20, 13.94. HRMS (m/z):
1
3
+
+
1.24, 30.57, 28.79, 28.69, 26.45, 25.15, 22.07, 21.04, 13.97.
770.63381 [(M+H) ] (Observed), 770.63439 [(M+H) ]
+
2+
HRMS (m/z): 808.58203 [(M+H) ] (Observed), 808.58129
(Calculated). 385.82142 [(M+2H) ]/2 (Observed), 385.82056
+
2+
2+
[
(M+H) ] (Calculated). 404.79551 [(M+2H) ]/2 (Observed),
[(M+2H) ]/2 (Calculated).
2
+
4
04.79401 [(M+2H) ]/2 (Calculated).
D
D
N,N-bis-[3-( Lys- Leu)amidopropyl]octanamide
1
Acknowledgements
tetrakis(trifluoroacetate) (8): H-NMR (400 MHz, DMSO-d
6
)
δ/ppm: 8.588-8.536 (m, R-CO-N(-CH
2
-CH
2
-CH
-CH-(CH
-NH-CO-CH-(CH
-CH-(CH
-NH-CO-CH-(CH
-CH-(CH , 2H), 3.798
-CH -CH -CH
2H), 3.217-2.749
-NH-CO-CH-(CH -CH -CH -CH
-CH-(CH , 12H), 2.245-2.199 (m,
- of R group, 2H), 1.698-1242 (m, CH
2
-NH-CO-CH-
We thank Prof. C.N.R. Rao (JNCASR) for his constant support. We
thank Dr. Sandip Samaddar for helping with cytotoxicity experiment.
We acknowledge JNCASR and SERB-DST (EMR/2016/001219),
Govt. of India for financial support. M.M.K thanks CSIR for research
fellowship.
+
+
(
CH
2
-CH
2
-CH
2
-CH
2
-NH
3
)-NH-CO-CH(NH
3
)-CH
2
3 2 2
) ) ,
2
H), 8.240-7.903 (m, R-CO-N(-CH
2
-CH
2
-CH
2
2
-
+
+
CH
2
-CH
2
-CH
2
-NH
3
)-NH-CO-CH(NH
3
)-CH
2
3
)
2
)
2
, 14H),
2
-CH -
4
.323-4.236 (m, R-CO-N(-CH
2
-CH
2
-CH
2
2
+
3
+
3
CH
2
-CH
2
-NH
)-NH-CO-CH(NH
)-CH
2
3 2 2
) )
Keywords: antibiotic resistance • synthetic lipopeptides• rational
design • solution phase synthesis • selective antibacterial
(
bs,
R-CO-N(-CH
2
-CH
2
-CH
-CH-(CH
-CH
2
-NH-CO-CH-(CH
2
2
2
2
-
+
+
NH
3
)-NH-CO-CH(NH
3
)-CH
2
3 2 2
) ) ,
[
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(
m,
R-CO-N(-CH
2
-CH
2
2
2
2
2
2
-
+
+
NH
3
3
)-NH-CH(NH
3
)-CH
2
3 2 2
) )
2
CH
-(CH
-CH
-CH
2
)
4
-CH
2
-CH
2
3
-
[
(
CH
2
)
4
2
-CH
2
-CO-N(-CH
2
-CH
2
-CH
-CH-(CH
-CO-N(-CH
2
-NH-CO-CH-(CH
2
-CH
32H), 0.899-
-CH -NH-CO-
-CH-
2
-
2
+
3
+
CH
2
2
-NH
)-NH-CH(NH
-(CH -CH
-CH -CH
3
)-CH
2
3
)
2
)
2
,
5
0
.850 (m, CH
CH-(CH -CH
CH
3
2
)
4
2
-CH
2
2
-CH
2
2
[
+
+
2
2
2
2
-NH
3
)-NH-CO-CH(NH
3
)-CH
2
13
(
3
)
2
)
2
, 15H). C-NMR (100 MHz, DMSO-d
6
) δ/ppm: 171.98,
[
1
3
2
71.50, 168.35, 51.89, 51.50, 45.12, 42.82, 41.19, 38.58,
[
6.16. 32.10, 31.26, 30.51, 28.80, 26.41, 25.13, 24.19, 22.98,
+
2.09, 21.70, 21.05, 13.98. HRMS (m/z): 740.61199 [(M+H) ]
[
+
(
Observed), 740.61259 [(M+H) ] (Calculated).
D
D
N,N-bis-[3-( Lys- Lys)amidopropyl]octanamide
[
1
tetrakis(trifluoroacetate) (9): H-NMR (400 MHz, DMSO-d
6
)
[
δ/ppm: 8.787-7.887 (m, R-CO-N(-CH
2
-CH
2
-CH
2
-NH-CO-CH-
-CH
-CH
-CH
-CH -NH-
-CH
+
+
X. Dai, C. Tang, F. H. Lim, L. Zhou, A. L. Tan, C. Verma, D. T. H. Tan, H. S.
(
CH
CH
CO-CH-(CH
2
-CH
2
-CH
2
-CH
2
-NH
3
)-NH-CO-CH(NH
3
)-CH
2
-CH
2
2
-
O. Chan, P. Saraswathi, D. Cao, S. Liu, R. W. Beuerman, J. Med. Chem.
+
2
-NH
3
)
2
, 22H), 4.211-4.197 (m, R-CO-N(-CH
2
-CH
2
2
-NH-
2013, 56, 2359−2373.
+
3
+
2
-CH
2
-CH
2
-CH
2
-NH
)-NH-CO-CH(NH
3
)-CH
2
2
-
[11] G. J. Gabriel, J. A. Maegerlein, C. F. Nelson, J. M. Dabkowski, T. Eren, K.
+
3
CH
2
-CH
2
-NH
)
2
, 2H), 3.839 (bs, R-CO-N(-CH
2
-CH
2
2
Nüsslein, G. N. Tew, Chem. Eur. J. 2009, 15, 433-439.
+
3
+
[12] J. Hoque, M. M. Konai, S. Samaddar, S. Gonuguntla, G. B. Manjunath, C.
Ghosh, J. Haldar, Chem. Commun. 2015, 51, 13670−13673.
CO-CH-(CH
2
-CH
2
-CH
2
-CH
2
-NH
)-NH-CO-CH(NH
3
)-CH
2
2
-
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Chemistry - A European Journal
10.1002/chem.201702227
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This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201702227
FULL PAPER
FULL PAPER
Mohini M. Konai, Utsarga Adhikary and,
Jayanta Haldar*
Page No. – Page No.
Design and Solution Phase
Synthesis of Membrane
Targeting Lipopeptides with
Selective Antibacterial
Activity
Text for Table of Contents
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