1. Synthesis of macrocycles that inhibit protein synthesis:
stereochemistry and structural based studies on sanguinamide B
derivatives
Adrian L. Pietkiewicz, Hendra Wahyudi, Jeanette R. McConnell, Shelli R. McAlpine ⇑
School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia
a r t i c l e i n f o
Article history:
Received 25 August 2014
Revised 8 October 2014
Accepted 14 October 2014
Available online 25 October 2014
Keywords:
Sanguinamide B
Macrocycle
Heterocycle
Natural product
Conformation
Peptide
a b s t r a c t
We report the synthesis of seven new sanguinamide B (SanB) analogues. Substitution of amino acids
along the backbone of SanB and testing in HCT-116 colon cancer cell lines identified new biologically
active SanB derivatives. These compounds establish a structure–activity relationship and show that a
Cbz-lysine moiety is important for biological activity. We also identified the most effective stereochem-
istry at each position around the molecule. The biological activity of the macrocycle is extremely sensitive
to stereochemistry and amino acid placement.
Ó 2014 Elsevier Ltd. All rights reserved.
Currently, over 50% of pharmaceutical compounds are derived
from natural product backbones, and as such they are excellent
lead structures in the development of new therapeutic com-
pounds.1–3
Over the past two decades, peptidic macrocycles
derived from natural products have been extensively studied for
their biological activity against cancer, HIV, hypertension and oste-
oporosis.4,5
Cyclic structures are extremely promising drug candi-
dates as they have fewer potential conformations, which lead to
higher binding affinity, and they are less susceptible to protease
degradation compared with linear peptides.6,7
The macrocyclic peptide sanguinamide B (SanB) (1), was iso-
lated by Molinski et al. from the nudibranch mollusc, Hexabranchus
sanguineaus (Fig. 1).8
SanB contains a tandem 2,4-oxazole-thiazole moiety and a trans,
trans di-prolyl configuration. The first total synthesis of this com-
pound resulted in three conformers around the proline residues
(trans,trans; trans,cis; and cis,cis) in prolines A and B, respectively.9
Biological testing showed all three conformers disrupted the
twitching activity of Pseudomonas aeruginosa,9
although none was
biologically active in cancer cell growth inhibition assays.10–12
structure–activity relationship (SAR) was investigated by synthe-
sizing the analogues using N-Me, glycine, L- and D-phenylalanine
(Phe) variations and evaluating them in cytotoxicity assays.10–12
Compounds 2 and 3 had the lowest IC50 values of 43 lM and
38 lM, respectively, against HCT116 colon cancer cell lines
(Fig. 1), indicating that incorporation of D-Phe results in cancer cell
growth inhibition.12
En route to undertaking a pull-down assay on
both compounds in order to identify their biological target, com-
pound 4 was generated, which contained a carboxybenzyl-lysine
(N6-Cbz-Lys) residue at position I (Fig. 1). Biological testing
revealed that this compound had an IC50 value of 15.9 lM, by far
the most potent analogue.12
Compounds 2, 3 and 4 were tested
in protein translation assays, and all three demonstrated inhibition
of protein synthesis, which was consistent with the proteins iden-
tified in the pull-down assays.12
Herein we describe additional structure–activity relationship
studies starting with the lead structure 4. Seven new analogues
(5–11) were generated by altering the amino acids at positions I
and III, inverting the stereochemistry at position III and altering
the Cbz residue on the lysine (Fig. 2). Structures of these seven
compounds were confirmed, including the proline cis and trans
conformations. Each isolated conformation was then tested for
cytotoxicity against colon cancer cell lines and for their ability to
inhibit protein synthesis.
Compounds 5 and 6 (Fig. 2) had the Cbz removed, with com-
pound 6 incorporating an acetyl protecting group on the lysine. It
was anticipated that the acetyl group would be cleaved upon cell
entry, thus allowing us to evaluate the impact of the free amine
in the cell. Compound 7 was designed to mimic 4, but with the
http://dx.doi.org/10.1016/j.tetlet.2014.10.089
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
⇑ Corresponding author. Tel.: +61 4 1672 8896; fax: +61 2 9385 6111.
E-mail address: s.mcalpine@unsw.edu.au (S.R. McAlpine).
Tetrahedron Letters 55 (2014) 6979–6982
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

2. Cbz-Lys at position III instead of I, and as with SanB (1) maintained
the L-valine (Val) at position I. Compound 8 was based on the activ-
ity of 2 and 3, and had a D-Phe incorporated into positions II and III,
while maintaining the L-Val at I. Compound 9 maintained the
active moieties of 4, while including a D-Phe at position III. Com-
pounds 10 and 11 mimicked 4 but replaced the L-Leucine (Leu)
at III with an L-Phe or D-Leu, respectively.
The synthesis of each compound was achieved by convergent
peptide coupling of two fragments: Fragment A (12) and Fragment
B (13) (Scheme 1). Fragment A was synthesized via peptide
coupling of D-Phe thiazole 14 with the appropriate amino acid
15. Thiazole 14 was synthesized via a modified Hantzsch reaction
between D-Phe thioamide 16 and ethyl bromopyruvate (17). The
former was synthesized from Boc-D-phenylalanine. Fragment B
(13) was produced via peptide coupling between 18 and the
appropriate amino acid, and subsequent peptide coupling of this
intermediate with a proline ester. Intermediate 18 was formed
via a modified Hantzsch thiazole reaction between bromoketo-
oxazole 19 and Pro-thioamide 20. Bromoketo-oxazole 19 was
prepared via cyclization and oxidation of peptidyl serine (Ser)
21, which was synthesized via a coupling reaction between
methoxylated bromopyruvic acid 22 and benzyl-protected serine
ester-amine 23.
The synthesis of Fragment A used in the synthesis of analogues
5, 9, 10 and 11 (Scheme 2) began with the protection of the acid
NHBoc-D-Phe-OH using trimethylsilyl diazomethane (TMSD).
The resulting ester 24 was converted into the amide 25 using
ammonium hydroxide, followed by subsequent conversion into
the thioamide 16 using Lawesson’s reagent. Condensing 16 with
ethyl bromopyruvate in the presence of KHCO3 gave the thiazoline
intermediate, which was oxidized using trifluoroacetic anhydride
(TFAA) in the presence of pyridine and triethylamine yielding 14.
Deprotection utilizing trifluoroacetic acid (TFA) gave the free
amine 26 and subsequent coupling with N6-Cbz-L-Lys employing
O
N S
NO
N
O
HN
O
S
N
NH
O
NH
N
O
SanB-6
O
N S
NO
N
O
HN
O
S
N
NH
O
NH
N
O
H
N
O
O
SanB-9
O
N S
NO
N
O
HN
O
S
N
NH
O
NH
N
O
H
N
O
O
SanB-11
O
N S
NO
N
O
HN
O
S
N
NH
O
NH
N
O
SanB-5
O
N S
NO
N
O
HN
O
S
N
NH
O
NH
N
O
SanB-7
O
N S
NO
N
O
HN
O
S
N
NH
O
NH
N
O
O
N S
NO
N
O
HN
O
S
N
NH
O
NH
N
O
H
N
O
O
SanB-10
H
N
O
CH3
H2N
H
N
O
O
SanB-8
O
N S
NO
N
O
HN
O
S
N
NH
O
NH
N
OHN
4 A-trans B-cis
O
O
A
B
I
II
III
Figure 2. Synthesized SanB analogues, based on the lead structure 4. Residues that
are boxed were modified compared to 4.
O
N
S
N
O
N
O
HN
O
S
NN
H
O
NH
N
O
R2R1
O
S
N
N
H
EtO
O
NHBoc
S
N
N
N
O
O
N
OMe
O
OBocHN
R2
Fragment A
Fragment B
R1
SanB analogue
12
13
OS
N
NHBoc
OEt
BocHN OH
O
S
NH2
NHBoc
Br OEt
O
O
Modified
Hantzsch
R1
14
16
15
17
S
N
BocN
N
O
O
OMe
S
NH2
NBoc
N
O
O
OMe Br
O
Peptide
coupling
Modified
Hantzsch
18
2019
O
OMe
NH
HO
O OMe
OMe
Br
Br OH
O
MeO OMe
O
OMe
NH2
BnO
Peptide
coupling Cyclization
Oxidation
21
22
23
Hydrogenation
Peptide
coupling
Peptide
coupling
Scheme 1. Retrosynthetic strategy for SanB analogues.
O
OH
NHBoc
TMSD,
benzene:MeOH
(3:1)
(0.1 M)
NH4OH:MeOH (1:1)
(0.025 M)
Lawesson'sreagent(0.7 equiv.)
benzene(0.05 M), 50 o
C
quant.
62%
1. KHCO3 (9 equiv.)
BrCH2C(O)CO2Et (1.2 equiv.)
DME (0.05 M)
2. pyridine (8 equiv.),
TFAA (4 equiv.),
DME (0.05 M), 0 o
C, 2h,
3. Et3N (2 equiv.), rt, 2 h
71% over 2 steps
O
S
N
OEt
Boc-CbzLys-OH (1.2 equiv,)
TBTU (0.8 equiv.)
HATU (0.8 equiv.)
DIPEA (12 equiv.)
CH2Cl2 (0.1 M)
NHBoc
anisole(2 equiv.)
TFA:CH2Cl2 (1:3)
(0.1 M)
O
S
N
OEt
HN O
HN NHBoc
quant.
quant. 91%
O
OMe
NHBoc
O
NH2
NHBoc
S
NH2
NHBoc
O
S
N
OEt
NH2
O O
24 25
16 14
26
12
Fragment A used in the
synthesis of compounds
5, 9, 10 and 11
Scheme 2. Synthesis of Fragment A, 12.
2 A-cis, B-cis
IC50: 43.0 µM
O
N S
NO
N
O
HN
OS
N
NH
O
NH
N
O
sanguinamide B
1 A-trans, B-trans
IC50: inactive
I
II III
A
B
O
N S
N
O
N
O
HN
OS
N
NH
O
NH
N
O
A
B
O
N S
NO
N
O
NH
OS
N
NH
O
NH
N
O
3 A-trans, B-cis
IC50: 38.0 µM
4 A-trans, B-cis
IC50: 15.9 µM
O
N S
NO
N
O
HN
OS
N
NH
O
NH
N
O
A
B
A
B
HN
O
O
Figure 1. SanB (1) and first generation analogues (describing their proline
orientation) with IC50 values against the HCT-116 colon cancer cell line.
6980 A. L. Pietkiewicz et al. / Tetrahedron Letters 55 (2014) 6979–6982

3. TBTU and HATU as coupling agents, yielded Fragment A (12). Frag-
ment A required for synthesizing derivatives 7 and 8 had an L-Val
incorporated in place of Lys, and derivative 6 replaced the N6-Cbz-
L-Lys with an N6-Ac-L-Lys.
The synthesis of Fragment B (Scheme 3), 13, was achieved by
reacting Boc-Ser(Bn)-OH (27) with TMSD to generate the ester,
which was subsequently converted into the amine 23. A coupling
reaction between bromo-ketal acid 22 and NH2-Ser(Bn)-OMe (23)
yielded bromomethoxyketal serine derivative 28, which was sub-
jected to hydrogenation yielding compound 21. Cyclization of 21
using dimethylaminosulfur trifluoride (DAST), followed by oxida-
tion with bromotrichloromethane (BrCCl3) and 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) generated the oxazole 29. Ketone
deprotection of 29 using formic acid gave 19, which was reacted
with Pro-thioamide derivative 20 under modified Hantzsch thia-
zole conditions to give the bisheterocycle 18. Amine deprotection
of 18 with trifluoroacetic acid (TFA) and elongation by peptide cou-
pling with NHBoc-amino acid gave the ester 30, where coupling of
L-Leu, D-Leu, L-Phe, D-Phe or N6-Cbz-L-Lys generated the corre-
sponding Fragment B analogues for each derivative. Coupling
between 30 and NH-Pro-OMe yielded 13.
Coupling between the free amine and free acid, after respective
amine and acid deprotection reactions, yielded linear precursor 31
(Scheme 4). Subsequent acid and amine deprotection of 31, fol-
lowed by macrocyclization under dilute conditions generated all
the analogues, except 5. Compound 5 was generated by synthesiz-
ing compound 4 and removing the Cbz group from the lysine using
HBr and acetic acid (33% HBr in acetic acid) at 0.1 M.
Each analogue was purified by HPLC and LCMS, and the result-
ing NMR spectra showed that numerous analogues had more than
one conformation (Table 1). Identification of each conformer uti-
lized 1
H and 13
C NMR and 2D NMR experiments (1
H–1
H COSY,
1
H–13
C HSQC, 1
H–13
C HMBC), as well as HPLC, LC/MS, and HRMS
(see Supporting information).
Utilizing a gradation of temperatures in a 1
H NMR analysis pro-
vided the optimal temperature at which sharp peaks were
observed in the NMR.10
Upon determining the optimal tempera-
ture for evaluation, 2D NMR data were collected at that tempera-
ture, which allowed identification of the configuration of each
prolyl amide bond present in the macrocycle. Examination of the
Pro Cb and Cc chemical shifts provides evidence of the Pro being
‘cis’ or ‘trans’. A Pro amide bond that adopts cis orientation has a
larger DdCbc than a Pro with an amide bond in the trans orienta-
tion.13
The Pro Cb and Cc shifts for each conformer are shown in
Table 1.
From the data, it appeared that neither proline has a preferred
conformation. Although individual proline shifts were visible in
the 2D NMR data, which allowed us to assign the proline orienta-
tion, all but one compound (compound 11) were inseparable mix-
tures. As observed by isolating each peak of the inseparable
mixture on the LCMS and re-injecting into the LCMS, these mole-
cules were in fact oscillating between the two conformations. For
example, 6A and 6B were isolated as an interconverting mixture
of cis, cis and trans, cis, where prolyl A was rapidly oscillating
between cis and trans. Compound 8 was also isolated as two inter-
converting conformations with Pro A also oscillating between cis
and trans. Compounds 9 and 11 had Pro B oscillating between cis
and trans, where compound 11 interconverted slowly enough that
the two conformations could be isolated (Table 1).
The results of the biological testing show that the Cbz-Lys group
is essential for activity, since removal or modification of this resi-
DMTMM (1 equiv.),
HATU (1 equiv.),
DIPEA (12 equiv.)
CH2Cl2 (0.1 M)
O
N
S
N
O
N
O
R2
OEt
OS
N
NH
O
NH
N
O
BocHN
anisole (2 equiv.)
TFA:CH2Cl2 (1:3)
(0.1 M)
LiOH.H2O (8 equiv.)
H2O2 (3.4 equiv.)
MeOH (0.1 M)
quant.
quant.
R1
Fragment B
13
O
N
S
N
O
N
O
R2
OEt
OS
N
NH
O
NHBoc
N
O
BocHN
R1
OMe
O
N S
NO
N
O
HN
OS
N
NH
O
NH
R1
N
O
1. LiOH.H2O (8 equiv.)
EtOH (0.1 M)
2. anisole (2 equiv.)
TFA:CH2Cl2 (1:3)
(0.1 M)
3. HATU (1 equiv.)
DMTMM (1 equiv.)
T3P (1 equiv.)
DIPEA (12 equiv.)
CH2Cl2 (0.0005 M)
10-79% over 3 steps
* for compound 5 HBr/AcOH (33%) 0.1 M
was added to 4 which removed the Cbz group
SanB analogue
31
Fragment A
12
Yields ranged from
33-98% over 3 steps
R2
R1 =
NH2
H
N CH3
O
NHCbz
R2 =
NHCbz
A
B
Scheme 4. Cyclization and synthesis of SanB analogues.
22 (1.2 equiv.)
TBTU (1 equiv.)
HATU (1 equiv.)
DIPEA (12 equiv.)
CH2Cl2 (0.1 M)
OMe
O
BnO
NH
O
OMe
Br
OMe
formic acid (0.1 M)
rt to 60 o
C
O
N
O
O
OMe Br
S
N
BocN
N
O
O
OMe
H2, Pd/C (10% w/w)
EtOH (0.1 M)
OMe
O
HO
NH
O
OMe
Br
OMe
1. DAST (2 equiv.)
K2CO3 (2 equiv.)
-78 o
C to rt
CH2Cl2 (0.1 M)
2. DBU (2 equiv.),
BrCCl3 (2 equiv.)
-46 o
C to rt
CH2Cl2 (0.1 M)
OMe
N
O
OMe Br
OMe
93%
OH
O
BnO
NH
Boc
1. TMSD
MeOH:benzene
(1:3)
(0.1 M)
2. anisole (2 equiv.)
TFA:CH2Cl2 (1:3)
(0.1 M)
OMe
O
BnO
NH2
O
1. KHCO3 (8 equiv.)
20 (1.2 equiv.)
DME (0.05 M)
2. pyridine (9 equiv.),
TFAA (4 equiv.),
DME (0.05 M)
0 o
C, 2 h,
3. Et3N (2 equiv.),
0 oC to rt, 2 h,
72% over 3 steps
quant. for 2 steps
83% quant.
75% over 2 steps
1. anisole (2 equiv.)
TFA:CH2Cl2 (1:3)
(0.1 M)
quant.
2. NHBoc-Amino Acid-OH (1.2
equiv.)
TBTU (1 equiv.)
HATU (1 equiv.)
DIPEA (12 equiv.)
CH2Cl2 (0.1 M)
84% over 2 steps
OMe
S
N
N
N
O
O
O
R2
BocHN
1. LiOH (8 equiv.)
MeOH (0.1 M)
N
S
N
N
N
O
O
O
R2
BocHN
O
OMe
2. NH-Pro-OMe (1.2 equiv.)
TBTU (1 equiv,)
HATU (1 equiv.)
DIPEA (12 equiv.)
CH2Cl2 (0.1 M)
74% over 2 steps
Fragment B
2327 28
21 29 19
18
30
13
Scheme 3. Synthesis of Fragment B, 13.
Table 1
Conformational assignment of SanB-14 (4) and its analogues 6–11. Orientation of the
prolyl amide bond is determined by DdCbc.13
(Data for SanB-4 were referenced from
the published result.12
Compound Conformer DdCbc13
Pro A DdCbc Pro B Assignment
SanB-412
5.7 9.5 trans, cis-
SanB-6 A 9.5 15.0 cis, cis
B 4.4 10.9 trans, cis
SanB-7 7.5 14.2 trans, cis
SanB-8 A 7.0 7.7 trans, trans
B 9.6 2.5 cis, trans
SanB-9 A 4.3 8.6 trans, cis
B 6.6 5.0 trans, trans
SanB-10 9.3 14.7 cis, cis
SanB-11 A 9.9 14.0 cis, cis
B 9.7 7.8 cis, trans
(see Supporting information for details on structure conformation.)
A. L. Pietkiewicz et al. / Tetrahedron Letters 55 (2014) 6979–6982 6981

4. due obliterates biological activity in the cytotoxicity and protein
synthesis assay (e.g., compounds 5, 6 and 8 in Table 2). Further-
more, biological activity is retained when the residue is incorpo-
rated at position III (e.g., compound 7). This highlights the
importance of not only the presence of a lysine group containing
a long hydrocarbon chain in the macrocycle, but also a bulky
hydrophobic phenyl group at the terminus. Due to the large num-
ber of freely rotatable bonds in the residue, it can adopt the desired
3D conformation to interact with its target whether it is located at
position I or III. Modification at position III is also tolerated when
substituting the L-Leu for L-Phe (e.g., compounds 7 and 10). Inter-
estingly, substitution of a D-Leu is tolerated but a D-Phe is not
(11 versus 9). It appears that the stereochemical orientation of
L-Phe resembles that of L-Leu, while the orientation of D-Phe suffi-
ciently detracts from this favoured 3D conformation resulting in an
inactive compound. While this change from D to L stereochemistry
at position III is significant with a bulky Phe residue, the same
position can tolerate either a D- or L-Leu residue, probably due to
the smaller nature of the residue having little impact on the ana-
logue binding to its protein target. Overall, SAR seems to dictate
L, D, L stereochemical configuration for positions I–III in order for
the analogue to have biological activity, though this does not
always hold true when smaller residues are incorporated at posi-
tion III. The conformation of each compound resulting from the
proline residues appears unrelated to its biological activity, as
there is no correlation to active compounds and their trans or cis
conformation around the prolyl bonds. As is precedented,14–19
biological activity is primarily related to the positioning (i.e.,
stereochemistry of the amino acid) and the structure of the
moieties placed around the macrocyclic backbone.
In conclusion, the original natural product SanB (1) had no cyto-
toxicity or ability to inhibit protein synthesis. Through an SAR
study, we were able to show that biologically active derivatives
must contain a lysine residue with a Cbz protecting group. The
interaction with the protein translation machinery is structure
specific, whereby in addition to a Cbz-Lys in position I or III, only
a single D-Phe is tolerated. Position III can tolerate D-Leu, L-Leu,
L-Phe but not D-Phe. We have generated three new compounds that
have IC50 cytotoxicity values in HCT-116 colon cancer cell lines of
622 lM, where these three compounds have the ability to inhibit
protein synthesis. Although only low micromolar inhibitors, our
work highlights a successful approach useful for building biological
activity into a macrocycle using amino acid side chains, stereo-
chemistry and proline conformations.
Acknowledgements
We thank the University of New South Wales for the UIPA to
H.W. and the TFS for J.R.M. Thank you also to the Mark Wainwright
Analytical Centre staff, especially Dr. Donald Thomas, for their
assistance. Finally, we thank the Australian National Health and
Medical Research Council (NHMRC) grant APP1043561.
Supplementary data
Supplementary data (Synthetic details, NMR spectra, LCMS and
HRMS data on all SanB analogues and intermediates used to gener-
ate the products. Biological protocols including IC50 curves and
luciferase assays are provided.) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2014.10.089.
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Table 2
Summary table depicting the compound number, IC50 activity against HCT-116 colon
cancer cells, and % protein synthesis inhibition in a biochemical luciferase translation
assay
Luciferase Translation Assay
D
M
SO
SanB
4
SanB
7SanB
10SanB
11ASanB
11BG
418
5uM
0
10
20
30
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%LuciferaseInhibition
6982 A. L. Pietkiewicz et al. / Tetrahedron Letters 55 (2014) 6979–6982