Tetrahedron Letters
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.
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.