Sanguinamide B analogs: Identification of active macrocyclic structures

Article abstract of DOI:10.1016/j.tetlet.2014.02.106

We report the synthesis of three new sanguinamide B (San B) analogs. We substituted in amino acids along the San B backbone with an N-Me, glycine, or an aromatic moiety (Phe or d-Phe) generating twelve derivatives in total. Testing in HCT-116 colon cancer

Full text of DOI:10.1016/j.tetlet.2014.02.106

Tetrahedron Letters 55 (2014) 2389–2393
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sanguinamide B analogs: identification of active macrocyclic
structures
⇑
Hendra Wahyudi, Worawan Tantisantisom, 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
a b s t r a c t
Article history:
Available online 5 March 2014
We report the synthesis of three new sanguinamide B (San B) analogs. We substituted in amino acids
along the San B backbone with an N-Me, glycine, or an aromatic moiety (Phe or
derivatives in total. Testing in HCT-116 colon cancer cell lines resulted in establishing a structure–activity
relationship. Our data show that the substitution of - or -Phe adjacent to the thiazole in the San B back-
bone locks the macrocycle into a single conformer, but only -Phe analogs are cytotoxic. We demonstrate
D-Phe) generating twelve
Keywords:
L
D
Sanguinamide B
Macrocycle
Heterocycle
Cytotoxicity
trans prolyl
cis prolyl
D
that the conformation of the macrocycle is extremely sensitive to stereochemistry and amino acid
placement.
Ó 2014 Elsevier Ltd. All rights reserved.
S
Natural products provide outstanding lead structures for phar-
maceutical drugs, and almost 50% of marketed drugs are derived
from natural product backbones.1–3 Macrocycles are a class of nat-
ural products that have been heavily utilized as starting points for
drug development.4–6 Indeed, developing and understanding the
trends within the macrocyclic space has increased dramatically,
and over half of the 12 biotech companies investigating this space
were established since 2008.4,7 These companies, have targeted
effectively cancer, hypertension, HIV infections, and osteoporosis.8
Successfully utilizing macrocycles as drugs relies on controlling
their rigid structure, which limits the molecules’ conformations,9
and produces a high binding affinity and selectivity to protein
targets.10
O
O
N
HN
O
NH
O
NH
N
O
2
N
1
N
N
S
O
trans, trans Sanguinamide B
(San B, 1)
Figure 1. trans,trans-Sanguinamide B (1), the natural product.
Sanguinamide B (San B) (Fig. 1, 1), isolated by Molinski and co-
workers from a nudibranch, Hexabranchus sanguineaus,11 is a mac-
rocyclic peptide containing a tandem oxazole–thiazole moiety and
a trans,trans di-prolyl configuration. The first total synthesis of San
B by McAlpine and co-workers12 identified three conformers of San
B, each of which had a unique prolyl configuration about prolines 1
and 2 (trans,trans, trans,cis,cis,cis). Biological assay data showed
that only trans,trans San B (1) disrupted the twitching activity of
Pseudomonas aeruginosa.12 We have discovered that three of these
analogs were ribosomal inhibitors.13
molecules. We also report new biological activity on all
twelve compounds (Fig. 2) in HCT-116 cell lines. We observed a
unique structure–activity relationship, where the
D-phenylalanine
(
D
-Phe) is crucial for the cytotoxicity of San B.
Heterocycles,14,15
prolines
(Pro),16–18
and N-methyl
(N-Me)9,19,20 moieties are key features known to dictate overall
macrocyclic conformation. A structure–activity relationship (SAR)
was established by making analogs using an N-Me scan, a glycine
scan, and both
L and D-Phe scans (Fig. 3). N-Me moieties are well
established at locking macrocycles into specific conforma-
tions,9,19,21–27 and they provide important properties to facilitate
entry into the cell.28,29 Thus, we substituted an N-Me moiety at
each of the three amino acid positions (Fig. 2: 2, 3, and 4). In pre-
vious work, we only reported the compounds 3 and 4,30 herein we
also report the synthesis of 2, a new molecule key to establishing
the importance of an N-Me moiety.
Herein we describe the synthesis of three new San B analogs
(Fig. 2, compounds 2, 8, and 11), which allowed us to complete
the structure–activity relationship analysis on this class of
⇑
Corresponding author. Tel.: +61 4 1672 8896; fax: +61 2 9385 6111.
E-mail address: s.mcalpine@unsw.edu.au (S.R. McAlpine).
http://dx.doi.org/10.1016/j.tetlet.2014.02.106
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2390
H. Wahyudi et al. / Tetrahedron Letters 55 (2014) 2389–2393
98%
100%
N-Methyl Series of San B analogs
87%
91%
(A)
100
92%
89%
S
S
S
90
80
70
60
50
40
30
20
10
0
O
O
O
78%
76%
O
O
O
N
N
N
N
HN
HN
NH
N
NH
68%
O
O
O
NH
N
NH
N
N
N
O
O
O
2
2
2
53%
N
N
N
1
1
1
N
N
N
N
N
N
50%
S
S
S
O
O
O
O
O
O
33%
4
2
3
Glycine Series of San B analogs
S
S
S
O
O
O
O
O
O
N
N
N
HN
HN
HN
NH
NH
NH
O
O
O
NH
NH
NH
N
N
N
O
O
O
2
2
2
Treatment Condition (50 uM)
N
N
N
1
1
N
1
N
N
N
N
N
S
S
S
(B)
O
100%
97% 99%
95%
O
O
O
O
O
100
90
80
70
60
50
40
30
20
10
0
84%
5
6
7
72%
L
-Phe Series of San B analogs
62%
57%
57%
S
S
S
O
O
O
50%
O
O
O
N
N
N
HN
HN
HN
NH
NH
NH
33%
O
O
O
NH
NH
NH
N
N
N
O
O
O
2
2
2
N
N
N
1
1
1
N
N
N
N
N
N
S
S
S
O
O
O
O
O
O
8
9
10
D
-Phe Series of San B analogs
Treatment Condition (50 uM)
S
S
S
O
O
O
100%
(C)
O
N
100
90
80
70
60
50
40
30
20
10
0
O
O
N
N
HN
NH
HN
HN
NH
NH
82%
82%
O
O
O
NH
79%
NH
NH
N
N
N
O
O
O
2
71%
2
2
N
N
N
1
N
1
1
N
64%
N
N
N
N
S
S
S
59%
O
O
O
O
O
O
13
11
12
50%
33%
30%
Figure 2. San B analogs based on single amino acid (N-Me, Gly, L-Phe or D-Phe)
24%
substitution on three different positions within the macrocycle.
In contrast, utilizing glycine (Gly) as an unconstrained amino
acid allows conformational changes to occur within the macrocycle
(Fig. 2: 5, 6, and 7). Comparison of the cytotoxicity of the N-Me
analogs to the activity of the glycine compounds permits evalua-
tion of how ring flexibility and the number of conformers impact
Treatment Condition (50 uM)
biological activity. Finally, we incorporated an L-Phe and a D-Phe
Compound 12
Compound 13
38.6 2.1 μΜ
(D)
(Fig. 2: 8–13), which was based on Kessler’s work on a preclinical
candidate, cilengitide.31 Two new compounds were synthesized
and reported here for the first time, compounds 8 and 11. Both
of these molecules allowed us to complete the structure–activity
IC50 Values 43.0 4.8 μΜ
(HCT-116)
Figure 3. (A) Cytotoxicity of San B Natural Product (1) and N-Me analogs (2–4); (B)
Cytotoxicity of Gly analogs (5–7); (C) Cytotoxicity of -Phe analogs (8–10) and -Phe
analogs (11–13) as evaluated by growth inhibition at 50 M on the colon cancer cell
L
D
relationship study on the L and D-Phe series.
l
The synthesis of compound 2 was accomplished using a strat-
egy that was unique from the previous synthetic route reported
for other San B analogs (Scheme 1).30 Our attempts to use our pre-
vious synthesis strategy were unsuccessful because the N-Me moi-
ety inhibited coupling to an extended peptide containing the Pro
residue. Our successful approach involved coupling the N-Me va-
line (Val) and Pro first (Fragment 2A, 18). The synthesis of 2 was
afforded by convergent peptide coupling of two fragments: Frag-
ment 1 (14) and Fragment 2 (17). Fragment 1 was synthesized
via a Hantzsch modified thiazole reaction between alanine (Ala)
thioamide 15 and ethyl bromo pyruvate 16. Fragment 2 was ob-
tained by a peptide coupling reaction between Fragment 2A (18)
and Fragment 2B (21). Fragment 2A was produced via peptide
line HCT-116 (⁄ = 100 nM of 17-AAG); (D) IC50 values of compounds 12 and 13.
Cytotoxicity assays (against HCT-116) were repeated in triplicate using nine
different concentrations, with each data point performed in quadruplicate. IC50
values were calculated from the average of three cytotoxicity assays with error
calculated as the Standard Error of Mean (SEM).
coupling between Pro 19 and N-Me Val 20. Fragment 2B was
formed via
a Hantzsch modified thiazole reaction between
oxazole bromoketone 24 and Pro thioamide 25, followed by subse-
quent peptide elongation with leucine (Leu) 22. Oxazole bromoke-
tone 24 was prepared via cyclization and oxidation of peptidyl
serine (Ser).

H. Wahyudi et al. / Tetrahedron Letters 55 (2014) 2389–2393
2391
PyBrop
TFA,
S
O
O
O
CH2Cl2,
Anisole
DIPEA,CH2Cl2
O
O
O
O
0ºC to rt
OMe 79% yield
Br
O
NH2
N
N
+
N
OH
Quant.
Yield
HN
OMe
OMe
NBoc
NH
Boc
NHBoc
15
OEt
20
18-1
19
16
Fragment 2A, 18
TBTU,
ring closing
O
HATU,
DIPEA,
CH2Cl2
OMe
NH
OMe
H2, Pd/C,
EtOH
MeO
O
O
O
S
MeO
Br
O
+
S
NH2
90% Yield
99% Yield
BnO
OH
Br
BnO
OMe
OMe
N
O
O
N
OEt
BocHN
HN
NH
30
28
29
Fragment 1, 14
O
N
N
O
O
OMe
NH
1. a) DAST,CH2Cl2, -78º
b) K2CO3, -78ºC to rt
C
Formic Acid,
OMe
O
Br
O
rt to 60º
C
N
Br
N
O
OMe
N
O
N
N
HO
S
2. DBU, BrCCl3,CH2Cl2,
-46ºC to rt
85% Yield over 2 steps
90% Yield
OMe
OMe
OMe
O
O
BocHN
OMe
O
N
O
N
32
31
N
O
N
2
O
BocN
S
H2N
Fragment 2, 17
S
25
OMe
OMe
BocN
S
Br
1.TFA,CH2Cl2,
Anisole
1. KHCO3, DME
N
O
N
O
O
O
N
O
2. Pyridine, TFAA,
DME, 0 ºC, 2hr,
then TEA, rt, 2hr
99% Yield over 2 steps
2. TBTU, HATU,
O
O
DIPEA, 22, CH2Cl2
OMe
N
Boc
O
OH
95% Yield over 2 steps
24
23
BocHN
O
O
N
N
19
N
N
OMe
NBoc
O
S
O
18
Fragment 2A,
O
O
N
TBTU, HATU, PyBrop
DIPEA, 18-1,CH2Cl2
Fragment 2B, 21
OMe
BocHN
OH
O
BocHN
LiOH, MeOH
O
O
HN
OMe
N
N
N
N
N
Quant. Yield
40% yield
20
O
S
S
OMe
BocN
Fragment 2B, 21
21-1
O
N
O
O
N
S
O
BocHN
OH
O
22
23
OMe
O
N
BocHN
N
N
OMe
N
N
Br
O
BocN
O
N
O
O
H2N
S
O
S
Fragment 2,17
Scheme 3. Synthesis of Fragment 2, 17.
24
25
Scheme 1. Retrosynthetic strategy for compound 2.
Synthesis of Fragment 2 (Scheme 3, and 17) was afforded by
coupling NHBoc-Pro-OH 19 and NHMe-Val-OMe 20 using bromo-
tris-pyrrolidino phosphonium hexafluorophosphate (PyBrop) to
generate Fragment 2A (Scheme 1, and 18). A coupling reaction
between bromo-ketal acid 28 and NH2-Ser(Bn)-OMe 29 yielded
Br-methoxyketal serine derivative 30, which was subjected to
hydrogenation to give compound 31. Cyclization of 31 using
dimethylaminosulfur trifluoride (DAST), followed by oxidation with
bromotrichloroform (BrCCl3) and 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) generated the oxazole 32. Ketone deprotection of 32
using formic acid formed 24, which was reacted with Pro thioamide
derivative 25 using modified Hantzsch thiazole conditions to give
the bisheterocycle 23. Amine deprotection of 23 with trifluoroacetic
acid (TFA) and elongation by peptide coupling with NHBoc-Leu-OH
22 gave 21. Coupling between 18–1 and 21–1 yielded 17.
Coupling between free amine 14 and free acid 17, after respec-
tive amine and acid deprotection reactions, yielded linear precur-
sor 33 (Scheme 4). Subsequent acid and amine deprotection of
33, followed by macrocyclization under dilute conditions gener-
ated compound 2.
1. TMSD, benzene/
MeOH (3:2)0.1 M
99%
Lawesson's
reagent (0.75 eq),
DME (0.7 M)
S
O
O
NH2
OH
NH2
NHBoc
NHBoc
NHBoc
60%
2. NH4OH/MeOH
(1:1)0.025 M
Quant.
27
26
15
O
O
16
OEt
Br
O
S
1. KHCO3 (8 eq), DME (0.05 M), rt,
16 h
N
NHBoc
OEt
2. TFAA (4 eq), Py (9 eq),
DME (0.05 M); then Et3N (2 eq)
0 oC to rt
Fragment 1, 14
51% over 2 steps
Scheme 2. Synthesis of Fragment 1, 14.
The synthesis of Fragment 1 (Scheme 2) began by protecting the
acid group of NHBoc-Ala-OH 26 using trimethylsilyl diazomethane
(TMSD). The resulting ester was converted into an amide 27 using
ammonium hydroxide, followed by subsequent conversion into
thioamide 15 using Lawesson’s reagent. Condensing 15 and 16 in
the presence of KHCO3 gave the thiazoline intermediate, which
was oxidized using trifluoroacetic anhydride (TFAA) in the pres-
ence of pyridine (Py) and triethylamine (Et3N) to yield 14.
The synthesis of compounds 8 and 11 was accomplished using
our published route that successfully generated compounds 9, 10,
12, and 13.30 This route (see Supporting information, Schemes
S1–S3) generated compound 8 in 53% overall yield and 11 in 19%
overall yield.
Purification of each analog by HPLC and LCMS showed that all
three new analogs had structural conformers. Based on our

2392
H. Wahyudi et al. / Tetrahedron Letters 55 (2014) 2389–2393
TFA,
CH2Cl2,
anisole
S
configuration of each prolyl amide bond present in the macrocycle.
O
Examination of the Pro Cb and C chemical shifts provides evidence
N
c
OEt
BocHN
Quant.
of the Pro being ‘cis’ or ‘trans’. A Pro amide bond that adopts cis ori-
Fragment 1, 14
TBTU, HATU,
DIPEA, CH2Cl2
entation has a larger
DdCb than a Pro with an amide bond in the
c
trans orientation.32 A table of the Pro Cb and C shifts for each con-
c
70%
O
former is shown in Table 1.
O
OMe
N
O
Compound 2 had three conformational isomers which were iso-
lated, whereas only two conformations were isolated with com-
pounds 3 and 4. Thus, placing the N-Me residue next to the
proline (i.e., 2) creates significant steric strain that induces an addi-
tional conformation (Table 1). We have verified that the two cis,cis
conformers (2A and 2B) identified in 2 are unique from each other,
with a difference of 1.5 ppm shifts based on 13C NMR of the N-Me
group. In addition, verification with NOESY showed that there was
a correlation between the H of the N-Me substituent and the H of
LiOH,
MeOH
BocHN
N
N
N
O
N
Quant.
O
S
17
Fragment 2,
O
OEt
S
S
O
O
N
N
O
HN
NH
1. LiOH, EtOH
2. TFA, CH2Cl2,
anisole
3. TBTU, HATU,
DMTMM,
BocHN
NH
O
N
O
N
N
O
CHa Pro 1 on compound 2B only (see Supporting information). We
N
O
show that these compounds are rotamers around the N-Me moiety,
whereby both Pro residues are cis, but compound 2A is cis and 2B is
trans around the N-Me. Interestingly, the methylated amide bond
forces Pro 1 to sit in a cis configuration, (Table 1, 2A–2C) while
Pro 2 has more freedom than Pro 1 and can adopt either a cis (2A
and 2B) or a trans (2C) configuration.
N
N
N
N
S
S
DIPEA, CH2Cl2
29% over 3 steps
N
N
O
O
O
O
2
San B-2,
33
Linear Precursor,
Scheme 4. Cyclization and synthesis of compound 2.
Both compounds
8 and 11 had two conformations each
previous experience, it was not surprising to see that compound 2
had three conformers (Table 1). Identification of each conformer
utilized 1H and 13C NMR and 2D NMR experiments (1H–1H COSY,
1H–13C HSQC, 1H–13C HMBC), as well as HPLC, LC/MS, and HRMS
(see Supporting information). Utilizing a gradation of temperatures
in 1H NMR analysis provided the optimal temperature in
which sharp peaks were observed in the NMR.30 Upon determining
the optimal temperature for evaluation, 2D NMR data were
collected at that temperature, which allowed identification of the
(Table 1), versus only one conformation seen with compounds 9,
10, 12, and 13. Both conformers of each compound, 8 and 11,
had different retention times on HPLC (see Supporting informa-
tion). These data indicate that placing either an L-Phe or D-Phe be-
tween Pro 1 and Ala (Fig. 2, 8 and 11) allowed more flexibility
around the prolyl 1 amide bond than positioning the aromatic res-
idue adjacent to the thiazole (Fig. 2, 9, 10, 12, and 13).
Having identified the specific Pro orientation of each conformer
from all analogs, these analogs were tested for their ability to
Table 1
Conformational assignment of San B (1) and its analogs 2–13
Compound
Conformer
A
D
dCb Pro 1
D
dCb Pro 2
Assignment
c
c
1
4.2
3.8
9.4
2.4
13.5
15.5
trans,trans = Natural products
trans,cis
cis,cis
B
NMe analogs
2
A
B
C
A
B
A
B
7.9
9.2
10.4
7.5
9.6
6.7
9.2
9.4
8.1
4.9
14.2
10.9
15.0
15.4
cis,cis
cis,cis
cis,trans
trans,cis
cis,cis
trans,cis
cis,cis
3
4
Gly analogs
5
A
B
C
A
B
C
A
B
4.0
9.6
4.1
14.7
7.7
5.2
5.4
5.7
9.4
15.3
9.6
6.8
14.3
7.1
trans,cis
cis,cis
trans,cis
cis,trans
trans,cis
trans,trans
trans,cis
trans,trans
6
7
13.0
7.6
L
8⁄
-Phe analogs
A
B
6.4
10.3
9.4
14.3
9.8
15.4
10.4
trans,cis
cis,cis
cis,cis
9
10
4.7
trans,cis
D
11⁄
-Phe analogs
A
B
13.5
9.6
9.4
6.4
cis,trans
cis,cis
cis,cis
15.5
15.4
8.0
12
13
2.4
trans,cis
32
The orientation of the prolyl amide bond is determined by
D
dCb
.
c
Data for 1 were referenced from the published result.12 Data for 3–7, 9, 10, 12, and 13 were referenced
from the published result.30 (⁄See Supporting information for details on structure conformation.)

H. Wahyudi et al. / Tetrahedron Letters 55 (2014) 2389–2393
2393
as IC50 curves of San B-12 and San B-13 are provided) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.02.106.
O
O
S
O
HN
O
N
HN
NH
O
NH
N
O
References and notes
2
N
1
N
N
S
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O
12-Lys(Cbz)-1
Figure 4. Compound 12-Lys(Cbz)-1 (IC50 = 15.9 1.3
l
M).
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L
-
D
D
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In conclusion, this Letter describes the synthesis of three new
San B analogs. We also define the structure activity relationship
of twelve San B analogs and their cytotoxicity against the HCT-
116 colon cancer cell line and evaluate how structural modifica-
tions impact their ability to induce cell death. Taken together,
our data show that the amino acid stereochemistry and its position
within the macrocycle dictate the overall conformation, which ulti-
mately determines its biological activity.
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Acknowledgement
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We thank the University of New South Wales for a scholarship
to H.W.
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Supplementary data
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Supplementary data (synthesis of San B-8 and San B-11, NMR
spectral, LCMS and HRMS for San B-2, San B-8, San B-11 as well